WO2011123668A2 - Stereoselective synthesis of phosphorus containing actives - Google Patents

Stereoselective synthesis of phosphorus containing actives Download PDF

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Publication number
WO2011123668A2
WO2011123668A2 PCT/US2011/030762 US2011030762W WO2011123668A2 WO 2011123668 A2 WO2011123668 A2 WO 2011123668A2 US 2011030762 W US2011030762 W US 2011030762W WO 2011123668 A2 WO2011123668 A2 WO 2011123668A2
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Prior art keywords
compound
group
salt
reacting
nucleoside
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PCT/US2011/030762
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French (fr)
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WO2011123668A3 (en
Inventor
Bruce S. Ross
Michael Joseph Sofia
Ganapati Reddy Pamulapati
Suguna Rachakonda
Hai-Ren Zhang
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Gilead Pharmasset LLC
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Pharmasset Inc
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Priority to KR1020127028582A priority Critical patent/KR101759369B1/en
Priority to BR112012024884A priority patent/BR112012024884A2/en
Priority to AP2012006535A priority patent/AP2012006535A0/en
Priority to HK13109048.8A priority patent/HK1181775B/en
Priority to SG2012072054A priority patent/SG184323A1/en
Priority to MX2012011324A priority patent/MX2012011324A/en
Priority to ES11714466.7T priority patent/ES2516466T3/en
Priority to AU2011235044A priority patent/AU2011235044A1/en
Application filed by Pharmasset Inc filed Critical Pharmasset Inc
Priority to CA2794671A priority patent/CA2794671C/en
Priority to EP11714466.7A priority patent/EP2552931B1/en
Priority to CN2011800230667A priority patent/CN102906102A/en
Priority to EA201290988A priority patent/EA201290988A1/en
Priority to JP2013502855A priority patent/JP2013527145A/en
Publication of WO2011123668A2 publication Critical patent/WO2011123668A2/en
Publication of WO2011123668A3 publication Critical patent/WO2011123668A3/en
Priority to IL222174A priority patent/IL222174A/en
Anticipated expiration legal-status Critical
Priority to ZA2012/07800A priority patent/ZA201207800B/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom

Definitions

  • phosphorus-containing actives their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same.
  • the liver is a vital organ whose functions include, among other things, detoxification, protein synthesis, maintaining an adequate supply of glucose and lipids to the surrounding tissues.
  • Chronic liver diseases such as hepatitis B virus and hepatitis C virus, liver cancer and certain metabolic diseases can seriously injure the liver.
  • Serious liver injury can give rise to a loss of any one of certain liver functions, which in turn can lead to liver failure and death of the organism.
  • Certain drugs that may be effective for treating identified liver diseases may cause unwanted and even serious side-effects that limit the drug's usefulness. Therefore, specific liver-targeting is an important consideration in developing a particular drug substance designed to combat certain liver diseases.
  • nucleoside kinase Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of an active to the triphosphate analog, the preparation of stable phosphate prodrugs has been reported.
  • phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C, et al, J Med. Chem., 1996, 39, 1748-1753; Valette, G., et al, J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al, Proc.
  • Erion further proposes strategies for circumventing the kinase-associated problems. For instance, Erion identifies a prodrug variant of adefovir, which is designated chemically as (2R,4S)- 2-(2-(6-amino-9H-purin-9-yl)ethoxy)-4-(3-chlorophenyl)-l,3,2-dioxaphosphinane 2- oxide, was designed to deliver an adefovir containing a phosphorus moiety to the liver. Erion discloses other strategies for delivering nucleosides and nucleoside- analogs to the liver, but does not disclose or suggest the phosphorus-containing actives.
  • nucleoside phosphoramidates improves the systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of these "pronucleotides" is masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the nucleoside monophosphate analog relative to administering the parent nucleoside alone.
  • liver-directed phosphoramidate approach can be applied to actives other than the above-mentioned 2'-deoxy-2'-a-F-2'-P-C-methyluridine phosphoramidates.
  • Such an approach would leverage the ability of the liver to metabolize the phosphoramidate moiety to the monophosphate and in the case of a non-nucleoside to lose the phosphate group ultimately releasing the active agent.
  • asymmetrically-substituted phosphoramidates can exist as either enantiomeric or diastereomeric mixtures.
  • mixtures may be purified to afford enantiomerically- or diastereomerically- enriched compositions, but the additional purification can increase overall costs for production of the phosphoramidate-derivatized active.
  • a methology has been developed to prepare enantiomerically- or diastereomerically-enriched phosphoramidate reagents, which may then be used as useful starting materials for the preparation of enantiomerically- or diastereomerically-enriched phosphoramidate-containing actives.
  • composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • Active comprises a functional group capable of forming a bond to P;
  • Group, W, and LG are as defined herein.
  • composition comprising an enantiomerically- or diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • Active comprises a functional group capable of forming a bond to P;
  • Group and W are as defined herein.
  • Active comprises at least two functional groups capable of forming a bond to P; Group is as defined herein; and each of LG and LG', independent of one another, is a leaving group.
  • Active comprises at least two functional groups capable of forming a bond to P; and Group is as defined herein.
  • composition comprising an enantiomerically- or a diasteromerically-enriched compound, hydrate, solvate, salt, or combinations thereof, represented by the formula II:
  • a or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • P* means that the phosphorus atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R” or "S” which have their accepted plain meanings.
  • enantiomerically-enriched and “diastereomerically-enriched,” as used herein refer to an instance where, due to the chirality at phosphorus, the mole amount of one enantiomer or diastereomer (Rp or Sp) exceeds the mole amount of the other enantiomer or disasteremoer (_3 ⁇ 4> or R P ). Recognizing that the phosphorus atom in a compound of formula I, a compound of formula II, a compound of formula III is chiral, one of ordinary skill will understand that a composition, comprised of a compound of formula I, a compound of formula II or a compound of formula III, comprises a mixture of enantiomers (when the substituents
  • Active/Group, ArO, and LG lack chirality) or a mixture of diastereomers (when at least one substituent Active/Group, ArO, and LG possesses chirality).
  • enantiomerically-enriched or “diastereomerically-enriched” as used herein, embraces a composition having at least about 51 mol% of one enantiomer or one diastereomer (Rp or S?) and at most about 49 mol% of the other enantiomer or the other diastereomer ( ⁇ 3 ⁇ 4 or R P ).
  • enantiomerically-enriched or “diastereomerically-enriched” includes a composition comprised of about 51 mol% to about 100 mol%, and all integers inbetween, of one enantiomer or one diastereomer (Rp or S P ) and about 49 mol% to about 0 mol%, and all integers inbetween, of the other enantiomer or the other diastereomer (Sp or R P ).
  • enantiomerically-enriched or “diastereomerically-enriched” includes a composition comprised of about at least about 60 mol% of one enantiomer or one diastereomer to about 40 mol% of the other enantiomer or the other diastereomer, about 70 mol% of one enantiomer or one diastereomer to about 30 mol% of the other enantiomer or the other diastereomer, about 80 mol% of one enantiomer or one diastereomer to about 20 mol% of the other enantiomer or the other diastereomer, about 90 mol% of one enantiomer or one diastereomer to about 10 mol% of the other enantiomer or the other diastereomer, about 95 mol% of one enantiomer or one diastereomer to about 5 mol% of the other enantiomer or the other diastereomer, about 96 mol% of one enantiomer or
  • purified refers to the purity of a given compound.
  • a compound is “purified” when the given compound is a major component of the composition, i.e., at least 50% w/w pure.
  • purified embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at least 80%) purity, at least 85%> purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96%) purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein "substantially pure” embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity.
  • substantially anhydrous means that a substance contains at most 10%) by weight of water, at most 1% by weight of water, at most 0.5% by weight of water, or at most 0.1% by weight of water.
  • halo or halogen as used herein, includes chloro, bromo, iodo and fluoro.
  • blocking group or "protecting group" which is derived from a “protecting compound” refers to a chemical protecting group which has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH 2 , etc.) that allows chemical modification of an unprotected part of a compound.
  • the group must react selectively in good yield to give a protected substrate that is stable to the projected reactions (see Protective Groups in Organic Synthesis, 3 nd ed. T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, N.Y., 1999).
  • groups include, but are not limited to: benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl (9- phenylxanthen-9-yl) group, thiopixyl (9-phenylthioxanthen-9-yl) or 9-(p- methoxyphenyl)xanthine-9-yl (MOX), etc.; C(0)-alkyl, C(0)Ph, C(0)aryl,
  • C(0)0(C 1-6 alkyl), C(0)0(Ci -6 alkylene)aryl e.g.,
  • C(0)Oaryl CH 2 0-alkyl, C3 ⁇ 40-aryl, S0 2 -alkyl, S0 2 -aryl, a protecting group comprising at least one silicon atom, such as, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, Si(Ci -6 alkyl) 2 0Si(Ci -6 alkyl) 2 0H (such as, -Si('Pr) 2 0Si Pr) 2 0H).
  • Acetals, such as MOM or THP and the like are considered possible groups.
  • Fluorinated compounds are also contemplated insofar that they can be attached to the compound and can be selectively removed by passing through a fluorous solid phase extraction media (e.g., FluoroFlash ® ).
  • a fluorous solid phase extraction media e.g., FluoroFlash ®
  • a specific example includes a fluorinated trityl analog, trityl analog l-[4- (lH,lH,2H,2H-perfluorodecyl)phenyl)-l ,l-diphenylmethanol.
  • fluorinated analogs of trityl, BOC, FMOC, CBz, etc. are also contemplated.
  • Sulfonyl chlorides like p-toluenesulfonyl chloride can react selectively on the 5' position.
  • Esters could be formed selectively such as acetates and benzoates.
  • Dicarboxylic anhydrides such as succinic anhydride and its derivatives can be used to generate an ester linkage with a free carboxylic acid, such examples include, but are not limited to oxalyl, malonyl, succinyl, glutaryl, adipyl, pimelyl, superyl, azelayl, sebacyl, phthalyl, isophthalyl, terephthalyl, etc.
  • the free carboxylic acid increases the polarity dramatically and can also be used as a handle to extract the reaction product into mildly basic aqueous phases such as sodium bicarbonate solutions.
  • phosphoramidate group is relatively stable in acidic media, so groups requiring acidic reaction conditions, such as, tetrahydropyranyl, could also be used.
  • protecting compound refers to a compound that contains a “protecting group” and that is capable of reacting with a compound that contains functional groups that are capable of being protected.
  • leaving group has the same meaning to the skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure- Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351-357) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (with for example a nucleophile), the leaving group is then displaced.
  • leaving groups include, but are not limited to: halogen (F, CI, Br, and I), CI, Br, or I; tosylate, mesylate, triflate, acetate, trifluoromethylacetate, camphorsulfonate, 2- thioxobenzo[d]thiazol-3(2H)-yl, aryloxide, and aryloxide substituted with at least one electron withdrawing group.
  • halogen F, CI, Br, and I
  • tosylate mesylate, triflate, acetate, trifluoromethylacetate, camphorsulfonate, 2- thioxobenzo[d]thiazol-3(2H)-yl, aryloxide, and aryloxide substituted with at least one electron withdrawing group.
  • electron withdrawing group is accorded its plain meaning.
  • Examples of an aryloxide substituted with at least one electron withdrawing group include, but are not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide, etc.
  • Examples of electron withdrawing groups include, but are not limited to, a halogen (F, CI, Br, or I), -N0 2 , -CN, -C(0)(C 1-6 alkyl), -C(0)(aryl), -C(0)0(Ci -6 alkyl), - C(0)0(aryl), etc.
  • base embraces the term “basic reagent” and is meant to be a compound that is capable of deprotonating a proton-containing compound, e.g., a Bransted base.
  • a base include, but are not limited to pyridine, collidine, 2,6-(Ci -6 alkyl)-pyridine, dimethyl- aniline, imidazole, N-methyl-imidazole, pyrazole, N-methyl-pyrazole, triethylamine, di-isopropylethylamine, etc.
  • basic reagent means a compound that is capable of deprotonating a hydroxyl group or an amino group.
  • Examples of basic reagents include, but are not limited to, a (Ci_ 6 alkyl)oxide ((Ci -6 alkyl)OM) in combination with an alcoholic solvent, where (Ci -6 alkyl)oxides include, but are not limited to, MeO " , EtO “ , “PrO “ , 'PrO “ , 3 ⁇ 4uO " , 'AmO- (iso-amyloxide), etc., and where M is an alkali metal cation, such as Li + , Na + , + , etc.
  • Alcoholic solvents include (Ci.
  • Non-alkoxy bases can also be used such as sodium hydride, sodium
  • non-nucleophilic base means a compound that is capable of acting as a Bransted base, but has low nucleophilicity.
  • non- nucleophilic bases include, but are not limited to, potassium carbonate, cesium carbonate, di-isopropylamine, di-isopropylethylamine, triethylamine, quinuclidine, naphthalene-1 ,8-diamine, 2,2,6,6-tetramethylpiperidine, 1 ,8-diazabicycloundec-7- ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-Cl-6-alkyl -pyridine, a 2,4,6-tri- Cl-6-alkyl-pyridine, l,5-diazabicyclo[4.3.0]non-5-ene, and 1,4- diazabicyclo[2.2.2]octane.
  • alkyl refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms.
  • C ⁇ . alkyl refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
  • C 1-20 alkyl refers to an alkyl comprising 1 to 20 carbon atoms.
  • Cj-ioalkyl refers to an alkyl comprising 1 to 10 carbons.
  • C] -6 alkyl denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms.
  • Examples of Ci -6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, z- propyl, n-butyl, z ' -butyl, /-butyl or pentyl, isopentyl, neopentyl, and hexyl.
  • C] -4 alkyl refers to an alkyl containing 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, z ' -propyl, n-butyl, z ' - butyl, /-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • the term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a heteroaryl group respectively.
  • alkaryl or “alkylaryl” refer to an alkyl group with an aryl substituent, such as benzyl.
  • Ci -6 alkaryl or “Ci- 6 alkylaryl” refer to a C]. 6 alkyl group with an aryl substituent, such as benzyl.
  • aralkyl or “arylalkyl” refer to an aryl group with an alkyl substituent, such as tolyl, xylyl, mesityl, etc.
  • cycloalkyl refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; 3 to 8 carbon atoms
  • cycloalkyl groups include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or cyclooctyl.
  • Examples of a C 3-7 cycloalkyl and a C 3-6 cycloalkyl include, but are not limited to, cyclopropyl ( c Pr), 2-methyl-cyclopropyl, etc., cyclobutyl ( c Bu), 2-methyl- cyclobutyl, 3-methyl-cyclobutyl, etc., cyclopentyl ( c Pn), 2-methyl-cyclopentyl, 3- methyl-cyclopentyl, 4-methyl-cyclopentyl, etc., cyclohexyl ( c Hx), cycloheptyl ( c Hp)etc.
  • alkenyl refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefmic double bond.
  • C 2- N alkenyl refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10.
  • C 2- ioalkenyl refers to an alkenyl comprising 2 to 10 carbon atoms.
  • C2 -4 alkenyl refers to an alkenyl comprising 2 to 4 carbon atoms.
  • aryl refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl.
  • the aryl group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, amino, alkyl, cycloalkyl, alkylamino, arylamino, alkoxy, alkenyl, aryl, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.
  • aryloxide refers to substituted or unsubstituted phenoxide (PhO-), p-phenyl- phenoxide
  • aryloxide refers to substituted or unsubstituted phenoxide.
  • the aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, -C(0)(Ci -6 alkyl),
  • Active refers to a compound capable of eliciting a biological response, which comprises at least one functional group capable of forming a bond to P.
  • Actives include, but are not limited to, nucleosides, nucleoside-analogs, and non-nucleoside compounds.
  • nucleoside and nucleoside-analog actives include, but are not limited to:
  • protected active refers to an active that comprises a blocking (or protecting) group.
  • a “protected active” is useful for preparing compound I or compound II, it is contemplated that said protected active is an embodiment of the disclosed invention and that said embodiment covers at least the following compounds.
  • Group as defined herein is hydrolyzable group meaning that when compound I or compound II is ingested the group is hydrolyzed, either enzymatically or non-enzymatically.
  • group precursor as used herein is a parent compound, existing as its salt, hydrate, or salt/hydrate thereof, of the Group. Examples of a Group include, but are not limited to, a radical comprising an amine (e.g., benzylamine) or an amine further comprising a chiral center, which includes, but is not limited to an amino acid or an R- or S-a-methylbenzylamine.
  • amino acid includes naturally occurring and synthetic ⁇ , ⁇ , ⁇ , or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.
  • the amino acid is in the L-configuration.
  • the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleucinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl, ⁇ -serinyl, ⁇ - threoninyl, ⁇ -cysteiny
  • amino acid when used, it is considered to be a specific and independent disclosure of each of the alkyl, cycloalkyl, or alkaryl esters of ⁇ , ⁇ , ⁇ , or ⁇ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-configurations, as well as acid-addition salts.
  • L-alanine is a specific and independent disclosure not only of the free acid, but of alkyl, cycloalkyl, or alkaryl esters of L-alanine or its acid-addition salts, as well as C] -6 alkyl, C 3-7 cycloalkyl, and Cj -6 alkaryl esters of L-alanine or its acid addition salts.
  • a solvent or anti-solvent (as used in reactions, crystallization, etc. or lattice and/or adsorbed solvents) includes at least one of a Ci to C 8 alcohol, a C 2 to C 8 ether, a C 3 to C 7 ketone, a C 3 to C 7 ester, a Cj to C 2 chlorocarbon, a C 2 to C 7 nitrile, a miscellaneous solvent, a C 5 to C J2 saturated hydrocarbon, and a C 6 to Cj 2 aromatic hydrocarbon.
  • the Ci to C 8 alcohol refers to a straight/branched and/or cyclic/acyclic alcohol having such number of carbons.
  • the C ⁇ to C 8 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, isobutanol, hexanol, and cyclohexanol.
  • the C 2 to C 8 ether refers to a straight/branched and/or cyclic/acyclic ether having such number of carbons.
  • the C 2 to C 8 ether includes, but is not limited to, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, methyl-t-butyl ether (MTBE), tetrahydrofuran, and dioxane
  • the C 3 to C 7 ketone refers to a straight/branched and/or cyclic/acyclic ketone having such number of carbons.
  • the C 3 to C 7 ketone includes, but is not limited to, acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl butyl ketone, and cyclohexanone.
  • the C 3 to C 7 ester refers to a straight/branched and/or cyclic/acyclic ester having such number of carbons.
  • the C 3 to C 7 ester includes, but is not limited to, ethyl acetate, propyl acetate, n-butyl acetate, etc.
  • the C 1 to C 2 chlorocarbon refers to a chlorocarbon having such number of carbons.
  • the Ci to C 2 chlorocarbon includes, but is not limited to, chloroform, methylene chloride (DCM), carbon tetrachloride, 1 ,2-dichloroethane, and
  • a C 2 to C 7 nitrile refers to a nitrile have such number of carbons.
  • the C 2 to C 7 nitrile includes, but is not limited to, acetonitrile, propionitrile, etc.
  • a miscellaneous solvent refers to a solvent commonly employed in organic chemistry, which includes, but is not limited to, diethylene glycol, diglyme
  • C 5 to Q 2 saturated hydrocarbon refers to a straight/branched and/or cyclic/acyclic hydrocarbon.
  • the C 5 to C 12 saturated hydrocarbon includes, but is not limited to, n-pentane, petroleum ether (ligroine), n-hexane, n-heptane, cyclohexane, and cycloheptane.
  • C 6 to Cj 2 aromatic refers to substituted and unsubstituted hydrocarbons having a phenyl group as their backbone.
  • C 6 to C 12 aromatic includes, but is not limited to, benzene, xylene, toluene, chlorobenzene, o-xylene, m- xylene, p-xylene, xylenes, mesitylene, etc.
  • salts refers to a compound comprising a cation and an anion, which can produced by the protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a physiological anion, whereas deprotonation of the proton-donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a physiological cation.
  • HX refers a Bronsted acid in the form of an acid addition salt to a synthetic reagent.
  • HX include, but are not limited to, HC1, HBr, p-toluenesulfonic acid, methanesulfonic acid, triflic acid, trifluoroacetic acid, etc.
  • pharmaceutically acceptable salt means a salt that is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • a first aspect of the first embodiment is directed to a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • Active comprises a nucleoside, nucleoside-analog, or non- nucleoside compound;
  • Group is as defined herein; and W is an aryl or
  • a second aspect of the first embodiment is directed to a composition
  • a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • Active comprises a nucleoside, nucleoside-analog, or non- nucleoside and Group is an N-amino-acyl having the following structure
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3.
  • a third aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l:
  • Rp-I-1 Sp-I-l wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3; R is a substituent for an amino acid as defined herein; and R' is an alkyl or a cycloalkyl.
  • Active comprises a nucleoside, nucleoside-analog, or non-nucleoside
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3
  • R is a substituent for an amino acid as defined herein; and R' is an alkyl or a cycloalkyl.
  • ArO > P 0 > NHCH(
  • a fourth aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i? P -I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; R is an alkyl; and R' is an alkyl or a cycloalkyl.
  • a fifth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH 2 )nSC(0)C(CH 3 ) m (CH 2 OH) 3 - m , where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Ci- 6 alkyl; and R' is a Ci -6 alkyl or a C 3-7 cycloalkyl.
  • a sixth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Ci_ 6 alkyl; and R' is a Cj -6 alkyl or a C 3-7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • a seventh aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • An eighth aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-1, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is a phenyl naphthalen-1 -yl, or -(CH 2 ) 2 SC(0)C(CH 3 ) 2 (CH 2 OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • a ninth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprised of a nucleoside selected from among compounds 1-8, 10- 13, 15-20, 22, 24-26, 28-32, 39, and 41-43, a nucleoside-analog selected from among compounds 33-38 and 40, or non-nucleoside compound selected from among compounds 44-90; W is a phenyl naphthalen-l-yl, or - (CH 2 ) 2 SC(0)C(CH3) 2 (CH 2 OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a Ci ⁇ alkyl or a C 3- 7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • Active comprised of a nucleoside selected from among compounds 1-8, 10- 13, 15-20, 22, 24-26,
  • Np represents naphthalen-l-yl.
  • Np represents naphthalen-l-yl.
  • R is a Ci -6 alkyl or a C 3-7 cycloalkyl.
  • R is a Ci -6 alkyl or a C3 -7 cycloalkyl.
  • a second embodiment is directed to a process for preparing a composition
  • a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I: O
  • step b) optionally deprotecting the compound obtained in step a) and
  • step c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound.
  • a first aspect of the second embodiment is directed to a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • OW II wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside; Group is as defined herein; W is an aryl or
  • step b) optionally deprotecting the compound obtained in step a) and
  • step c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound.
  • a second aspect of the second embodiment is directed to a process for preparing a composition
  • a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
  • Active is a nucleoside, a nucleoside-analog, or a non-nucleoside;
  • Group is as defined herein;
  • W is an aryl or
  • step b) optionally deprotecting the compound obtained in step a) and
  • step c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound;
  • LGP(0)(OW)(Group) which is represented by the following structures, comprises a mixture of enantiomers (when the substituents Group, WO, and LG lack chirality) or a mixture of diastereomers (when at least one substituent Group, WO, and LG possesses chirality).
  • CIP Cahn-Ingold-Prelog
  • a third aspect of the second embodiment is a process for preparing a composition
  • a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-l:
  • the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside compound
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH)3 -m , where n is 2 or 3 and m is 0, 1 , 2, or 3
  • LG is a leaving group
  • R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy-proline where the fragment N-C-R forms a ring-system, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstitute
  • step b) optionally deprotecting the compound obtained in step a) and
  • step c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain compound II- 1.
  • a fourth aspect of the second embodiment is a process for preparing a composition
  • a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-l:
  • W is an aryl or -(CH 2 ) n SC(0)C(CH3) m (CH 2 0H)3 -m , where n is 2 or 3 and m is 0, 1 , 2, or 3;
  • LG is a leaving group
  • R is a radical observed in any one of the naturally occurring amino acids, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl;
  • step b) optionally deprotecting the compound obtained in step a) and
  • step c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound said aspect further comprising
  • the leaving groups are as defined above.
  • LG is an aryloxide substituted with at least one electron withdrawing group.
  • LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide,
  • W is an aryl or - (CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; R is a Ci- 6 alkyl; and R' is a Ci -6 alkyl or a C 3 .. 7 cycloalkyl.
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; R is a C 1-6 alkyl; and R is a Ci -6 alkyl or a C 3-7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • W is a phenyl naphthalen-l-yl, or
  • R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • R'0 2 CCHRNH 2 'HX is substantially anhydrous.
  • R is methyl and R' is isopropyl.
  • R is methyl, R' is isopropyl, HX is HC1.
  • LG is a leaving group
  • Z is hydrogen or a protecting group
  • Bn is -CH 2 Ph
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the mixture comprising (LG)P(0)(OW)(NHCHRC0 2 R') which is represented by the following structures, comprises a mixture of enantiomers (when the substituents NHCHRC0 2 R', WO, and LG lack asymmetry thus imparting chirality to said substituent) or a mixture of diastereomers (when at least one substituent NHCHRC0 2 R, WO, and LG possesses asymmetry thus imparting chirality to said substituent).
  • LG is a leaving group
  • Z is hydrogen or a protecting group
  • Bn is -CH 2 Ph
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • LG is a leaving group and Np is naphthalen-l-yl
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • Z' is hydrogen or a protecting group
  • LG is a leaving group and Np is naphthalen-l-yl; and c) optionally deprotecting.
  • Z' is hydrogen.
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1 , about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • LG is a leaving group and R is a Ci -6 alkyl or a C 3-7 cycloalkyl.
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1 , about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • LG is a leaving group and R is a Ci -6 alkyl or a C 3-7 cycloalkyl.
  • LG is an aryloxide having at least one electron withdrawing group.
  • LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide.
  • the basic reagent is a Grignard reagent.
  • the basic reagent is a t-butylmagnesium halide.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound.
  • the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
  • a third embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III:
  • Active comprises at least two functional groups capable of forming a bond to P; and Group is as defined herein.
  • a first aspect of the third embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active comprises at least two functional groups capable of forming a bond to P and Group is an amino acid.
  • a second aspect of the third embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active is a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P and Group is an amino acid.
  • nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P include, but are not limited to compounds 2, 3, 4, 5, 7, 8, 9a, 9b, 9c, 13, 14, 15-23, 26, 28-32, 34a, 34b, 34c, 34d, 35, 37-39, 41-43, 49-51, 56-57, 59-62, and 79.
  • a fourth embodiment is directed to a process for preparing a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III:
  • Active comprises at least two functional groups capable of forming a bond to
  • each of LG and LG', independent of one another, is a leaving group.
  • a first aspect of the fourth embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active comprises at least two functional groups capable of forming a bond to P and Group is an amino acid.
  • a second aspect of the fourth embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active is a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P and Group is an amino acid.
  • nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P include, but are not limited to compounds 2, 3, 4, 5, 7, 8, 9a, 9b, 9c, 13, 14, 15-23, 26, 28-32, 34a, 34b, 34c, 34d, 35, 37-39, 41-43, 49-51, 56-57, 59-62, and 79.
  • LG is a leaving group, group is as defined herein, and -W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH)3- m , where n is 2 or 3 and m is 0, 1 , 2, or 3.
  • a first aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combinations thereof, represented by the formula i?p-II or Sp-II.
  • a utility of the a compound represented by formula Rp-II or Sp-II is that it is sufficiently stable, yet adequately reactive, so as to allow one to obtain the enantiomeric or diastereomeric I or III in substantially pure form by reaction of i?p-II or Sp-H with a protected or unprotected active, as disclosed herein.
  • a second aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 0H) 3-m , where n is 2 or 3 and m is 0, 1 , 2, or 3; LG is a leaving group;
  • R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy-proline where the fragment N-C-R forms a ring-systemor R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substitute
  • a third aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • a third aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • a fourth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is an alkyl; and R' is an alkyl or a cycloalkyl.
  • a fifth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Ci -6 alkyl; and R' is a Ci-i 0 alkyl or a C3 -8 cycloalkyl.
  • LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxid
  • a sixth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a C 1-6 alkyl; and R' is a Q. 6 alkyl or a C 3- cycloalkyl.
  • LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4
  • a seventh aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or £p-II-l wherein LG is an aryloxide or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a C ⁇ . 6 alkyl; and R' is a
  • An eighth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or Sp-II-l wherein LG is an aryloxide substituted with at least one electron
  • withdrawing group which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide;
  • R is selected from among methyl, ethyl, and isopropyl; and
  • R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • a ninth embodiment is directed to a a compound, hydrate, solvate, salt, or combinations thereof, represented by the formula II:
  • a tenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combinations thereof, represented by the formula i? P -II or Sp-II.
  • a utility of the a compound represented by formula Rp-II or Sp-II is that it is sufficiently stable, yet adequately reactive, so as to allow one to obtain the enantiomeric or diastereomeric I or III in substantially pure form by reaction of Rp-II or Sp-II with a protected or unprotected active, as disclosed herein.
  • An eleventh aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1
  • Rp-ll-l Sp-II-l wherein Ar is an aryl; LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy- proline where the fragment N-C-R forms a ring-system, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl.
  • a twelfth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
  • withdrawing group which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • a thirteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i? P -II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
  • withdrawing group which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • a fourteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
  • withdrawing group which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide;
  • R is an alkyl; and
  • R' is an alkyl or a cycloalkyl.
  • a fifteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or ⁇ Sp-II-1 wherein LG is an aryloxide or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Cj. 6 alkyl; and R' is a
  • a sixteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
  • withdrawing group which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide;
  • R is a Cj. 6 alkyl; and
  • R' is a
  • Ci -6 alkyl or a C 3-7 cycloalkyl Ci -6 alkyl or a C 3-7 cycloalkyl.
  • a seventeenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-1 wherein LG is aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Ci -6 alkyl; and R' is a C ⁇ . 6 alkyl or a C 3-7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • LG is aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide,
  • An eighth aspect of the sixth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • LG is an aryloxide substituted
  • LG' is chloride or bromide.
  • LG is chloride
  • LG is an aryloxide substituted with at least one electron withdrawing group.
  • LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • LG' is chloride or bromide.
  • LG' is chloride.
  • LG is an aryloxide substituted with at least one electron
  • LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
  • W is aryl or
  • a seventh embodiment is directed to a process for preparing compound of formula II-l
  • the leaving groups are as defined above.
  • LG is an aryloxide substituted with at least one electron withdrawing group.
  • LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide,
  • W is an aryl or -
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3; R is a C 1-6 alkyl; and R' is a Ci -6 alkyl or a C3 -7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • W is an aryl or -(CH 2 ) n SC(0)C(CH 3 ) m (CH 2 OH) 3-m , where n is 2 or 3 and m is 0, 1, 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • W is a phenyl naphthalen-l-yl, or
  • R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
  • R'0 2 CCHRNH 2 HX is substantially anhydrous.
  • R is methyl and R' is isopropyl.
  • R is methyl, R' is isopropyl, HX is HC1.
  • chromatographic techniques include, but are not limited to, chromatography on silica gel (using, e.g., 3-5% methanol in DCM or 4-6% isopropanol in DCM) to produce enhanced levels of one isomer (50-100%) and then crystallize it, if possible.
  • silica gel using, e.g., 3-5% methanol in DCM or 4-6% isopropanol in DCM
  • reversed phase chromatography using, e.g., 1-30% acetonitrile-aqueous mobile phase.
  • the compounds can be isolated by supercritical fluid chromatography SFC with carbon dioxide as the main solvent and alcohols such as methanol as a modifier, preferably using the appropriate chiral media, such as, Daicel Chiralpack IA.
  • SMB chromatography may be employed using the appropriate chiral media, such as, Daicel ChiralPack IA, using a mixture of solvents such as hexanes/isopropanol or single solvents such as ethyl acetate.
  • the compound represented by formula II may be purified by crystallization induced dynamic resolution, which is contemplated by the following embodiment.
  • An eighth embodiment is directed to a process for preparing a compound of formul -II-1 or 5p-II-l represented by the structures
  • composition comprising
  • the first composition comprises both i?p-II-l or Sp-II-1; and wherein LG is a leaving group, W is an aryl or
  • the mole amount of i?p-II-l and the mole amount of Sp-II-1 are the same or different.
  • the mole amount of i?p-II-l is greater than the mole amount of 5p-II-l or vice versa.
  • the leaving group precursor is 2,4-dinitrophenol, 4-nitrophenol, 2-nitrophenol, 2-chloro-4-nitrophenol, 2,4- dichlorophenol, or pentafluorophenol.
  • LG is 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, or 2,4,6-trichlorophenoxide.
  • LG is pentafluorophenoxide.
  • the second leaving group precursor is pentafluorophenol.
  • the amount of pentafluorophenol ranges from about 0.01 mole equivalents to about 10 mole equivalents relative to the mole amount of i?p-II-l and Sp-II-1 and all mole equivalents in between.
  • the amount of pentafluorophenol ranges from about 0.1 mole equivalents to about 1 mole equivalents relative to the mole amount of Rp-II-1 and Sp-II-l and all mole equivalents in between.
  • the crystallizing occurs at a temperature that ranges from about -10°C to about +40°C and all temperature values in between. In a first sub-aspect, the crystallizing occurs at about room temperature.
  • the non-nucleophilic base is selected from among potassium carbonate, cesium carbonate, di-isopropylamine, di- isopropylethylamine, triethylamine, quinuclidine, naphthalene- 1 ,8-diamine, 2,2,6,6- tetramethylpiperidine, l ,8-diazabicycloundec-7-ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-Ci -6 -alkyl-pyridine, a 2,4,6-tri-Ci.6-alkyl-pyridine, and mixtures thereof.
  • the non-nucleophilic base is triethylamine or 1 ,8- diazabicycloundec-7-ene. In a second sub-aspect, the non-nucleophilic base is triethylamine.
  • the non-nucleophilic base is present in an amount that ranges from about 0.01 equivalents mol to about 10 mol equivalents, and all mole equivalents in between, relative to the total mole amount of i?P-II-l and Sp-II-1.
  • the non-nucleophilic base is present in an amount that ranges from about 0.1 mol equivalents to about 1 mol equivalents, and all mole equivalents in between, relative to the total mole amount of i?p-II-l and Sp- II-l.
  • the solubility of Rp-II-1 is less than the solubility of Sp-II-1 in the liquid composition or vice versa.
  • the liquid composition comprises at least one of a solvent and an anti-solvent.
  • the liquid composition comprises at least one of a C ⁇ to C 8 alcohol, a C 2 to C 8 ether, a C 3 to C 7 ketone, a C 3 to C 7 ester, a Cj to C 2 chlorocarbon, a C 2 to C 7 nitrile, a C 5 to Cj 2 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
  • the liquid composition comprises at least one of a C 2 to C 8 ether, a C 3 to C 7 ester, a C 5 to C 12 saturated hydrocarbon, and a C 6 to C 12 aromatic hydrocarbon.
  • the liquid composition comprises at least one of a C 2 to Cg ether, a C 3 to C 7 ester, and a C 5 to C 12 saturated hydrocarbon.
  • the liquid composition comprises at least one of ethyl acetate, t-butyl-methylether, and hexane.
  • the liquid composition comprises ethyl acetate and hexane.
  • the liquid composition comprises t-butyl-methylether and hexane.
  • the amount of liquid composition ranges from about 1 mL to about 10 mL for every gram of the first composition and all mL/g values in between.
  • An eleventh aspect of the eighth embodiment further comprises adding crystalline i?p-II-l or Sp-II-l to the composition.
  • a first sub-aspect further comprises adding about 0.1 to about 1 wt. %, and all wt. % values in between, of crystalline Rp-II-1 or Sp-II-l to the first composition.
  • the invention is for the treatment and/or prophylaxis of a disease state by administering a therapeutically effective amount of compound I or compound III to a host in need thereof.
  • Selected disease states include, but are not limited to, cancer or a diseased state that may arise form the introduction of a viral agent to a host.
  • a diseased state that may arise form the introduction of a viral agent to a host.
  • nucleoside, nucleoside-analog, and non- nucleoside actives depicted above have been approved by the FDA for the treatment of at least one diseased state.
  • compound I or compound III would likewise be useful for the treatment of at least one diseased state, the treatment of which has been approved by the FDA. It is contemplated that the process disclosed herein will afford enantiomers or diastereomers of compound I or compound III that will have improved pharmacokinetic parameters relative to the active itself.
  • a diseased state may arise from the introduction of a viral agent to a host.
  • the compound I or compound III can be used for the treatment and/or prophylaxis of a viral agent.
  • Possible viral agents include, but are not limited to: HIV-1, HIV-2, herpes type 1, herpes type 2, HSV, influenza, HPV, ebolla, XMRV, CMV, RSV, rhinovirus, hepatitis C virus, hepatitis B virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, bovine viral diarrhea virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St.
  • An aspect of this embodiment is directed to a composition for the treatment of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, and equivalent medium and compound I or compound III.
  • Compound I or compound III may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.
  • Compound I or compound III is efficacious when administered by suppository administration, among other routes of administration.
  • the most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.
  • Compound I or compound III, as well as its salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of
  • suppositories for rectal or vaginal administration.
  • a typical preparation will contain from about 0.1% to about 99% active compound or compounds (w/w).
  • Compound I or compound III can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable salt form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the
  • Solid form preparations include, for example, powders, tablets, pills, capsules, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, , talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Examples of solid formulations are exemplified in EP 0524579; US 2002/0142050; US 2004/0224917; US 2005/0048116; US
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Examples of liquid formulation are exemplified in U.S. Patent Nos. 3,994,974; 5,695,784; and 6,977,257.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins,
  • methylcellulose sodium carboxymethylcellulose, and other well known suspending agents.
  • Compound I or compound III may be independently formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • Compound I or compound III may be independently formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Certain of these formulations may also be used in conjunction with a condom with or without a spermicidal agent.
  • compound I may be independently formulated in conjunction with liposomes or micelles.
  • liposomes it is contemplated that the purified compounds can be formulated in a manner as disclosed in U.S. Patent Nos.
  • the purified compounds can be formulated in a manner as disclosed in U.S. Patent Nos. 5,091,188 and 5,145,684 both of which are incorporated by reference.
  • a tenth embodiment is directed to a use of compound I or compound III in the manufacture of a medicament for the treatment of any one of the diseased states contemplated herein.
  • the term “medicament” means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising compound I or compound III. It is contemplated that the use of compound I or compound III in the manufacture of a medicament, for the treatment of any one of the diseased states contemplated herein.
  • a medicament includes, but is not limited to, any one of the compositions contemplated by the ninth embodiment of the present invention.
  • An eleventh embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective amount of compound I or compound III to the subject for the treatment of any one of the diseased states contemplated herein.
  • a subject in need thereof is one that has any diseased state disclosed herein, which may be the result of an infection by any of the viral agents disclosed herein, which includes, but is not limited to, HIV-1, HIV-2, herpes type 1, herpes type 2, HSV, influenza, HPV, ebolla, XMRV, CMV, RSV, rhinovirus, hepatitis C virus, hepatitus B virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, bovine viral diarrhea virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.
  • the viral agents disclosed herein includes, but is not limited to, HIV-1, HIV-2, herpes type 1, herpes type 2, HSV, influenza, HPV, ebolla, XMRV, C
  • subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the fifth embodiment can be compound I or compound III, either alone or in combination with another compound falling within the scope of compound I or compound III.
  • terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
  • the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • a daily dosage of between about 0.001 and about 10 g including all values in between, such as 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.050, 0.075, 0.1 , 0.125, 0.150, 0.175, 0.2, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should be appropriate in monotherapy and/or in combination therapy.
  • a particular daily dosage is between about 0.01 and about 1 g per day, including all incremental values of 0.01 g (i.e., 10 mg) in between, a preferred daily dosage about 0.01 and about 0.8 g per day, more preferably about 0.01 and about 0.6 g per day, and most preferably about 0.01 and about 0.25 g per day, each of which including all incremental values of 0.01 g in between.
  • treatment is initiated with a large initial "loading dose" to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection.
  • One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
  • Therapeutic efficacy can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively the therapeutic effectiveness may be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized.
  • serum proteins e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleos
  • a first aspect of the eleventh embodiment is directed to a method for the treatment of any one of the diseased states contemplated herein by administering to a subject (or host) in need thereof said method comprises administering to the subject a therapeutically effective amount of compound I or compound III and a therapeutically effective amount of another antiviral agent; wherein the
  • administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any subrange in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
  • another antiviral agent examples include, but are not limited to: HCV
  • HCV NS5B Inhibitors see US 2004229840, US 2005/0098125, US 2005154056, US 20060194749, US 20060241064, US 20060293306, US 2006040890, US 2006040927, US 2006166964, US 2007275947, US 6784166, US20072759300, WO 2002057287, WO 2002057425, WO
  • HCV NS4 Inhibitors see WO 2005067900 and WO 2007070556
  • HCV NS5a Inhibitors see US 2006276511, WO 2006035061, WO 2006100310, WO 2006120251, WO 2006120252
  • Toll-like receptor agonists see WO 2007093901
  • other inhibitors see WO 2000006529, WO 2010006529, WO 2010006529
  • antiviral agents that can be used in combination with compound I or compound III include, but are not limited to the following:
  • Invirase® (Saquinavir), Fortovase® (Saquinavir), Norvir® (Ritonavir), Crixivan® (Indinavir), Viracept® (Nelfmavir), Agenerase® (Amprenavir), Kaletra®
  • Concurrent administration as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
  • treatment also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
  • the specifically identified actives may be commercially available.
  • the specifically identified actives can be prepared according to procedures known in the art, as illustrated by the following information.
  • Z H, but for illustrative purposes, Z can also be a blocking group(c compounds 91-94)), one could take advantage of an advanced tribenzoylated cytidine intermediate (107) in the synthesis of certain 3',5'-diacylated analogs (108) of 23 (see below) already produced efficiently on a pilot plant scale (see WO 2006/031725 or US
  • 3',5'-O-dibenozyl-2'-deoxy-2'-fiuoro-2 , -C-methyl-N 4 -benzoylcytidine (107) is obtained by a method disclosed in WO 2006/031725 (US 2006/0122146) and WO 2008/045419 (US 2008/0139802) the subject matter of which is hereby incorporated by reference in its entirety.
  • 107 is treated with 70% aqueous acetic acid to form
  • the benzoyl esters can be hydrolyzed by a number of methods as well, e.g., alkoxides in alcoholic solvent, such as sodium methoxide in methanol, potassium carbonate in methanol, or ethanol analogs, alkylamines such as methylamine in methanol, butylamine etc. Methanolic ammonia was chosen for the larger scale work.
  • the uridine product (23) can be purified by crystallization to afford a 70% yield from the tribenzoylated cytidine (107).
  • This dibenzoyluridine intermediate, 108 was used directly in the next step by adding it all to freshly prepared methanolic ammonia (5.4 L, ca 25%) at 0°C. This temperature was maintained for 3 h and then allowed to warm to 15°C for 24 h. TLC indicated a complete reaction (Rf 0.4 in 10% methanol in DCM). The reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give the crude product (216 g). The crude product was stirred with ethyl acetate (325 mL) for 3 h at ambient temperature. The resulting solid was collected by filtration and washed with ethyl acetate (216 mL).
  • Rotation frames were integrated using SAINT (Bruker (2009) SAINT.
  • Figure 1A ORTEP drawing of molecule no. 1 109 of the asymmetric unit with 30% probability thermal ellipsoids.
  • Figure IB ORTEP drawing of molecule no. 2 109 of the asymmetric unit with 30% probability thermal ellipsoids. Table 1. Summary of Structure Determination of 109
  • a solution of sodium sulfite was prepared by adding Na 2 S 2 0 3 (1.51 g) and Na 2 S 2 0 5 (0.57 g) in water (25 mL). To a solution of the levulinate (113, 250 mg, 0.40 mmol) in anhydrous THF (2.5 mL) was added 1.0 ml of the sodium sulfite solution. This was allowed to stir at room temperature for 4 h. The reaction mixture was poured in to water (15 mL) and extracted with ethyl acetate (3x25 mL) dried and evaporated to give quantitatively a white solid product with about 97% P chiral purity which matched the physical and spectral properties of 110 produced directly from the unprotected nucleoside.
  • nucleoside 114 (2.52 g, 2.75 mmol) in anhydrous DCM (8 mL) was added DMAP (1.01 g, 8.2 mmol) and the solution was cooled at 0°C in an ice-water bath.
  • Cbz-Cl (0.77 g, 4.2 mmol) was added via a syringe to the mixture and resulted in a cloudy reaction mixture.
  • the mixture was stirred at room temperature for 24 hours and sat. NaHC0 3 (10 mL) was added.
  • the mixture was partitioned in DCM and water. The organic layer was dried over Na 2 S0 4 and concentrated to a white foam solid. The residue was purified via column
  • NMR and P-NMR and ratio of two isomers was ca. 17 : 1 favored the desired Sp isomer (117) and also matched the Sp isomer by thin layer chromatography. 31 P- NMR (DMSO-d 6 ): 6 4.91.
  • the white solid residue (31 g) was triturated in a mixture of EtOAc and hexanes (150 mL, 20:80, v/v) at RT for 17 h allowing time for dynamic resolution of the less soluble Sp-diastereomer.
  • the white slurry was filtered and solid was rinsed with 20% EtOAc in hexanes (2x 25 mL).
  • the solid (22.58 g) was checked by ⁇ -NMR and 31 P-NMR and it contained product as one isomer contaminated with triethylamine hydrochloride salt.
  • the solid was dissolved and partitioned in 310 mL of EtOAc and 100 mL of water.
  • the reaction was quenched by adding 20 mL of sat NH 4 C1 at 0 °C.
  • the mixture was diluted with 100 mL of ethyl acetate.
  • Two layers were separated and aqueous layer was extracted with 50 mL of ethyl acetate.
  • Organic layer was combined and washed with water (60 mL), sat sodium bicarbonate (2 x 60 mL), water (60 mL), brine (40 mL), and dried over sodium sulfate.
  • Solvent was removed under reduced pressure to afford an amorphous solid residue.
  • Example 7 Synthesis 117 by reaction with 118 and 9a and isolation by crystallization only.
  • To a 250 mL of dry three-necked round flask were loaded 5 g (15.96 mmol) of the nucleoside (9a) and 40 mL of anhydrous THF.
  • the suspension was cooled in an ice-water bath and 20 mL of the Grignard reagent (1 M solution in THF, 20 mmol) was added via a syringe over 10 minutes.
  • the clear reaction mixture was stirred at 0 °C for half hour and then a solution of the phosphorus reagent (118) in 40 mL of THF was added via an addition funnel in 2 hours. The reaction was allowed to warm up to ambient temperature slowly and stirred for overnight.
  • Phenyl phosphorodichloridate (10.0 g, 47.4 mmol) was dissolved in 60 mL of dry DCM and subsequently cooled to -78 °C.
  • a premixed solution of 2,4- dinitrophenol (8.72 g, 47.4 mmol) and triethylamine (7.27 mL, 52.1 mmol) in 20 mL of DCM was slowly added at -78 °C over a period of 30 min. The reaction was brought to 0 °C and stirred for 2.5 h at this temperature before (L)-alanine isopropyl ester (7.95 g, 47.4 mmol) was added as a solid in one batch.
  • the reaction was quenched by adding sat NH 4 C1 after one and half hour.
  • the mixture was diluted with 20 mL of ethyl acetate.
  • Organic layer was separated and aqueous layer was extracted with ethyl acetate (20 mL).
  • the combined organic layer was washed with water (50 mL), sat sodium bicarbonate (2 x 40 mL), sat sodium carbonate (40 mL), water (40 mL), and brine (30 mL).
  • the light yellow color organic layer was dried over sodium sulfate.
  • the solution was concentrated under reduced pressure and an amorphous solid residue resulted was purified via column chromatography.
  • the bis-phosphoramidate by-product was eluted out at 1 % methanol in DCM as a foam solid (32.4 mg) and 117 was eluted out at 3% methanol in DCM (74 mg, 0.127 mmol, 49.6%).
  • Phenyl phosphorodichloridate (10.0 g, 47.4 mmol) was dissolved in 60 mL of dry DCM and subsequently cooled to -78 °C. Slow addition of a preformed mixture of 2,4-dichlorophenol (7.73 g, 47.4 mmol) and triethylamine (7.27 mL, 52.1 mmol) in 20 mL of DCM was followed by stirring at above temperature for 30 min.
  • Phenyl phosphorodichloridate (10.0 g, 47.3 mmol) was dissolved in 50 mL of dry DCM and subsequently cooled to 0 °C. After addition of solid (L)-alanine isopropyl ester HCl salt (7.94 g, 47.3 mmol), the reaction mixture was cooled to -70 °C and then treated with triethylamine (13.8 mL, 94.6 mmol) dissolved in 50 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C.
  • the reaction was quenched by addition of sat NH 4 CI (5 mL) and diluted with 20 mL of ethyl acetate and 10 mL of water. Two layers were separated and aqueous layer was extracted with 20 mL of EtOAc. Organic layer was washed with water (20 mL), sat sodium bicarbonate (2 x 30 mL), 5% sodium carbonate (30 mL), water (20 mL), and brine (20 mL). Organic solution was dried over sodium sulfate and concentrated to a yellow color solid residue. The residue was purified via column chromatography (silica gel, 3% methanol in DCM) to afford 279 mg (0.48 mmol, 83%) of 120.
  • Phenyl phosphorodichloridate (6.37 g, 30.19 mmol) was dissolved in 40 mL of dry DCM and subsequently cooled to 0 °C. After addition of solid (L)-alanine isopropyl ester (5.06 g, 30.19 mmol), the reaction mixture was cooled to -78 °C and then treated with triethylamine (8.84 mL, 63.3 mmol) dissolved in 20 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C.
  • Tr CPh 3 ( ⁇ )-128
  • Example 14 the S-(2-hydroxyethyl) 3-hydroxy-2,2- dimethylpropanethioate is protected with a trityl (-CPh 3 ) protecting group. It is contemplated that the reaction can be conducted without a protecting group, as shown in the following equation.
  • reaction mixture was quenched with methanol (1 mL), solvent was evaporated under reduced pressure and the residue was chromatogrpahed using 0-5% methanol/DCM gradient to give pure product (130a) as a foamy solid (240mg, 59% yield).
  • cerium(III)chloride heptahydrate (154mg, 0.414mmol) and sodium iodide (41mg, 0.276mmol) at room temperature (21 °C). The mixture was heated at 85 °C for 6h. The solvent was evaporated and the residue was chromatographed using 0-15% methanol/dichloromethane gradient to give pure product 134 as a white solid (55mg, 35% yield).
  • Compound 44 is a non-nucleoside NS5B inhibitor of Hepatitis C with a free primary hydroxyl.
  • a chiral phosphoramidate has the advantage of making a single enantiomer and uniform physical properties to aid in development.
  • Compound 44 itself was prepared by literature methods (WO 2004/041201 ; US 7,265,152).
  • a-Naphthyl phosphorodichloridate (10.0 g, 38.46 mmol) was dissolved in 40 mL of dry dichloromethane and subsequently cooled to 0 °C.
  • solid (L)-alanine neopentyl ester />-toluenesulfonic acid salt (12.7 g, 38.46 mmol)
  • the reaction mixture was cooled to -70 °C and then treated with triethylamine (11.2 mL, 77.0 mmol) dissolved in 50 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C.
  • the bottom aqueous layer was extracted with 2 mL of EtOAc and the combined organic layers were washed with water (1 x 2 mL), saturated NaHC0 3 (2 x 1.5 mL), 1 M Na 2 C0 3 (2 x 1.5 mL), and water (2 x 2.0 mL).
  • the reaction was allowed to warm up to 20 °C and stirred at 20 °C for 2 hours at which point HPLC indicated complete consumption of 136.
  • the reaction was quenched by the addition of 1 mL of 1 N HC1 followed by removing THF by rotary evaporation.
  • the mixture was diluted with 9 mL of EtOAc and 2 mL of water and transferred to a seperatory funnel.
  • the bottom aqueous layer was extracted with 2 mL of EtOAc and the combined organic layers were washed with water (1 x 2 mL), saturated NaHC0 3 (2 x 1.5 mL), 1 M Na 2 C0 3 (2 x 1.5 mL), and water (2 x 2.0 mL).
  • nucleoside 138 prepared as disclosed in US 6,777,395
  • nucleoside 138 100 mg, 0.36 mmol
  • THF anhydrous THF
  • the reaction was allowed to warm up to 20 °C and stirred at 20 °C for 4 hours at which point HPLC indicated complete consumption of 136.
  • the reaction was quenched by the addition of 20 mL of 1 N HC1 followed by removing THF by rotary evaporation.
  • the mixture was diluted with 100 mL of EtOAc and 12 mL of water and transferred to a seperatory funnel.
  • the bottom aqueous layer was extracted with 12 mL of EtOAc and the combined organic layers were washed with water (1 x 24 mL), saturated NaHC0 3 (2 x 20 mL), 1 M Na 2 C0 3 (3 x 20 mL), and water (2 x 20 mL).
  • compositions containing enantiomerically- or diastereomerically-enriched compositions comprised of a compound of formula I, a compound of formula II, or a compound of formula III can be modified by one of ordinary skill without undue experimentation in order to obtain compositions containing enantiomerically- or diastereomerically-enriched compositions comprised of a compound of formula I or a compound of formula III where the active is comprised of any one of the compounds 1-90 (less one or more hydrogen atoms).
  • HCV inhibition assay Clone A or ET-lunet cells were seeded at a density of 1500 or 3000 cells per well in a 96-well plate, respectively. Test compounds serially diluted in culture medium without G418 were added to cells so that the final DM SO concentration was 0.5%. Plates were incubated at 37°C in a 5% C0 2 atmosphere for 4 days. Inhibition of HCV RNA replication was determined by real time PCR (RT-PCR) or by measuring the levels of luminescence expressed via the luciferase reporter gene encoded within the ET replicon.
  • RT-PCR real time PCR
  • % (l-(2 "AACt )) x 100.
  • luminescence was measured by using a Victor3 plate reader (Perkin-Elmer, Boston, MA) following the addition of Bright-Glo reagent as recommended by the manufacturer (Promega, Madison, WI).
  • Percent inhibition of HCV replication was determined by comparing the change in luminescence of the drug treated wells versus the DMSO cell controls. EC 50 and EC 90 values, the concentrations at which 50% and 90% inhibition were achieved, were determined using the GraphPad Prism software (San Diego, CA).
  • the absorbance at 490 nm was read with a Victor3 plate reader (Perkin Elmer) using the medium only control wells as blanks.
  • the 50% inhibition value (CC 50 ) was determined by comparing the absorbance in wells containing cells and test compound to untreated cell control wells.

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Abstract

Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same. A process for preparing a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I is disclosed: 1 which comprises a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a diastereomerically enriched compound of formula II wherein Group is as defined herein, W is an aryl or -CCH2)nSC(O)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3, and LG is a leaving group; b) optionally deprotecting the compound obtained in step a) and c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the active.

Description

STEREOSELECTIVE SYNTHESIS OF
PHOSPHORUS CONTAINING ACTIVES
Priority
This application claims priority to US 61/319,513, filed on March 31, 2010 and US 61/319,548, filed on March 31, 2010, the subject matter of which is incorporated by reference in its entirety.
Field of the Invention
Disclosed herein are phosphorus-containing actives, their use as actives for treating diseases, and a stereoselective process for preparing the same. Also disclosed herein are useful synthetic intermediates and processes for preparing the same.
Background of the Invention
The liver is a vital organ whose functions include, among other things, detoxification, protein synthesis, maintaining an adequate supply of glucose and lipids to the surrounding tissues. R. Kahl's Chapter 13 entitled "The Liver," pp. 273- 296 in H. Marquardt's Toxicology (1999): Academic Press, San Diego, CA. Chronic liver diseases such as hepatitis B virus and hepatitis C virus, liver cancer and certain metabolic diseases can seriously injure the liver. Serious liver injury can give rise to a loss of any one of certain liver functions, which in turn can lead to liver failure and death of the organism. Certain drugs that may be effective for treating identified liver diseases may cause unwanted and even serious side-effects that limit the drug's usefulness. Therefore, specific liver-targeting is an important consideration in developing a particular drug substance designed to combat certain liver diseases.
M. D. Erion in "Prodrugs for Liver-targeted Drug Delivery," Biotechnology Pharmaceutical Aspects, 1, Volume V, Prodrugs, Part II, Part 5, Pages 541-572, explains that liver- utilization of certain nucleosides and/or nucleoside-analogs can be hampered if the drug substance is a poor substrate for certain phosphorylating enzymes generally known as kinases. The biological activity of some
pharmaceutically active agents may be hampered by poor substrate characteristics for one or more of the kinases needed to convert it to the active triphosphate form or alternatively for introduction into a cell that requires treatment. Formation of the monophosphate by a nucleoside kinase is generally viewed as the rate limiting step of the three phosphorylation events. To circumvent the need for the initial phosphorylation step in the metabolism of an active to the triphosphate analog, the preparation of stable phosphate prodrugs has been reported. Nucleoside
phosphoramidate prodrugs have been shown to be precursors of the active nucleoside triphosphate and to inhibit viral replication when administered to viral infected whole cells (McGuigan, C, et al, J Med. Chem., 1996, 39, 1748-1753; Valette, G., et al, J. Med. Chem., 1996, 39, 1981-1990; Balzarini, J., et al, Proc.
National Acad Sci USA, 1996, 93, 7295-7299; Siddiqui, A. Q., et al, J. Med. Chem., 1999, 42, 4122-4128; Eisenberg, E. J., et al, Nucleosides, Nucleotides and Nucleic Acids, 2001 , 20, 1091-1098; Lee, W.A., et al, Antimicrobial Agents and
Chemotherapy, 2005, 49, 1898; Mehellou, Y., et al ChemMedChem., 2009, 4, 1779-1791); US 2006/0241064; and WO 2007/095269. Erion further proposes strategies for circumventing the kinase-associated problems. For instance, Erion identifies a prodrug variant of adefovir, which is designated chemically as (2R,4S)- 2-(2-(6-amino-9H-purin-9-yl)ethoxy)-4-(3-chlorophenyl)-l,3,2-dioxaphosphinane 2- oxide, was designed to deliver an adefovir containing a phosphorus moiety to the liver. Erion discloses other strategies for delivering nucleosides and nucleoside- analogs to the liver, but does not disclose or suggest the phosphorus-containing actives.
Also limiting the utility of actives as viable therapeutic agents is their sometimes poor physicochemical and pharmacokinetic properties. These poor properties can limit the intestinal absorption of an agent and limit uptake into the target tissue or cell. To improve on their properties prodrugs of actives have been employed. It has been demonstrated in certain instances that preparation of nucleoside phosphoramidates improves the systemic absorption of a nucleoside and furthermore, the phosphoramidate moiety of these "pronucleotides" is masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the nucleoside monophosphate analog relative to administering the parent nucleoside alone. Enzyme-mediated hydrolysis of the phosphate ester moiety produces a nucleoside monophosphate wherein the rate limiting initial phosphorylation is unnecessary. This concept has been demonstrated for certain compounds disclosed in US 2010/0016251. There, certain 2'-deoxy-2'-a-F-2'-p-C-methyluridine phosphoramidates are capable of being absorbed through the intestinal tract, and then, delivered to the liver where the phosphoramidate moiety is cleaved to produce a 2'-deoxy-2'-a-F-2'- -C-methyluridine monophosphate. It is conceivable that the liver-directed phosphoramidate approach can be applied to actives other than the above-mentioned 2'-deoxy-2'-a-F-2'-P-C-methyluridine phosphoramidates. Such an approach would leverage the ability of the liver to metabolize the phosphoramidate moiety to the monophosphate and in the case of a non-nucleoside to lose the phosphate group ultimately releasing the active agent.
However, a potential complicating factor is that asymmetrically-substituted phosphoramidates can exist as either enantiomeric or diastereomeric mixtures.
These mixtures may be purified to afford enantiomerically- or diastereomerically- enriched compositions, but the additional purification can increase overall costs for production of the phosphoramidate-derivatized active. In an effort to reduce and/or eliminate the potential complicating factor, a methology has been developed to prepare enantiomerically- or diastereomerically-enriched phosphoramidate reagents, which may then be used as useful starting materials for the preparation of enantiomerically- or diastereomerically-enriched phosphoramidate-containing actives.
Summary of the Invention
Disclosed herein is a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
O II *
Active p— Group
I
ow
I
which comprises reacting a protected or unprotected active with a composition comprising an enantiomerically- or a diastereomerically-enriched compound of formula II: O
LG— P— Group
OW
II
in the presence of a base; wherein Active comprises a functional group capable of forming a bond to P; Group, W, and LG are as defined herein.
Also disclosed herein is a composition comprising an enantiomerically- or diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
0
Active p II—* Group
I
OW
I
wherein Active comprises a functional group capable of forming a bond to P; Group and W are as defined herein.
Also disclosed herein is a process for preparing an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III:
O
Active P— Group
III
which comprises reacting a protected or unprotected active with a compound of formula IV:
O
LG— P— Group
LG'
IV
in the presence of a base
wherein Active comprises at least two functional groups capable of forming a bond to P; Group is as defined herein; and each of LG and LG', independent of one another, is a leaving group.
Disclosed herein is a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III: O
Active P— Group
III
wherein Active comprises at least two functional groups capable of forming a bond to P; and Group is as defined herein.
Also disclosed herein is a composition comprising an enantiomerically- or a diasteromerically-enriched compound, hydrate, solvate, salt, or combinations thereof, represented by the formula II:
O
II *
LG— P— Group
I
ow
II
wherein LG, Group, and W are as defined herein. Detailed Description of the Invention
Definitions
The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.
The terms "optional" or "optionally" as used herein means that a
subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
The term "about" (also represented by ~) means that the recited numerical value is part of a range that varies within standard experimental error.
The term "P*" means that the phosphorus atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R" or "S" which have their accepted plain meanings.
The terms "enantiomerically-enriched" and "diastereomerically-enriched," as used herein refer to an instance where, due to the chirality at phosphorus, the mole amount of one enantiomer or diastereomer (Rp or Sp) exceeds the mole amount of the other enantiomer or disasteremoer (_¾> or RP). Recognizing that the phosphorus atom in a compound of formula I, a compound of formula II, a compound of formula III is chiral, one of ordinary skill will understand that a composition, comprised of a compound of formula I, a compound of formula II or a compound of formula III, comprises a mixture of enantiomers (when the substituents
Active/Group, ArO, and LG lack chirality) or a mixture of diastereomers (when at least one substituent Active/Group, ArO, and LG possesses chirality).
Thus, "enantiomerically-enriched" or "diastereomerically-enriched" as used herein, embraces a composition having at least about 51 mol% of one enantiomer or one diastereomer (Rp or S?) and at most about 49 mol% of the other enantiomer or the other diastereomer (<¾ or RP). Within this meaning, "enantiomerically-enriched" or "diastereomerically-enriched" includes a composition comprised of about 51 mol% to about 100 mol%, and all integers inbetween, of one enantiomer or one diastereomer (Rp or SP) and about 49 mol% to about 0 mol%, and all integers inbetween, of the other enantiomer or the other diastereomer (Sp or RP). Also within this meaning, "enantiomerically-enriched" or "diastereomerically-enriched" includes a composition comprised of about at least about 60 mol% of one enantiomer or one diastereomer to about 40 mol% of the other enantiomer or the other diastereomer, about 70 mol% of one enantiomer or one diastereomer to about 30 mol% of the other enantiomer or the other diastereomer, about 80 mol% of one enantiomer or one diastereomer to about 20 mol% of the other enantiomer or the other diastereomer, about 90 mol% of one enantiomer or one diastereomer to about 10 mol% of the other enantiomer or the other diastereomer, about 95 mol% of one enantiomer or one diastereomer to about 5 mol% of the other enantiomer or the other diastereomer, about 96 mol% of one enantiomer or one diastereomer to about 4 mol% of the other enantiomer or the other diastereomer, about 97 mol% of one enantiomer or one diastereomer to about 3 mol% of the other enantiomer or the other diastereomer, about 98 mol% of one enantiomer or one diastereomer to about 2 mol% of the other enantiomer or the other diatereomer, about 99 mol% of one enantiomer or one diastereomer to about 1 mol% of the other enantiomer or the other diastereomer, about 99.5 mol% of one enantiomer or one diastereomer to about 0.5 mol% of the other enantiomer or the other diastereomer, about 99.8 mol% of one enantiomer or one diastereomer to about 0.2 mol% of the other enantiomer or the other
diastereomer, about 99.9 mol% of one enantiomer or one diastereomer to about 0.1 mol% of the other enantiomer or the other diastereomer, and about 99.99 mol% of one enantiomer or one diastereomer to about 0.01 mol% of the other enantiomer or the other diastereomer.
The term "purified," as described herein, refers to the purity of a given compound. For example, a compound is "purified" when the given compound is a major component of the composition, i.e., at least 50% w/w pure. Thus, "purified" embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at least 80%) purity, at least 85%> purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96%) purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein "substantially pure" embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity.
The term "substantially anhydrous" means that a substance contains at most 10%) by weight of water, at most 1% by weight of water, at most 0.5% by weight of water, or at most 0.1% by weight of water.
The term "halo" or "halogen" as used herein, includes chloro, bromo, iodo and fluoro.
The term "blocking group" or "protecting group" which is derived from a "protecting compound," refers to a chemical protecting group which has its plain and ordinary meaning, i.e., at least one protecting or blocking group is bound to at least one functional group (e.g., -OH, -NH2, etc.) that allows chemical modification of an unprotected part of a compound. The group must react selectively in good yield to give a protected substrate that is stable to the projected reactions (see Protective Groups in Organic Synthesis, 3nd ed. T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, N.Y., 1999). Examples of groups include, but are not limited to: benzoyl, acetyl, phenyl-substituted benzoyl, tetrahydropyranyl, trityl, DMT (4,4'-dimethoxytrityl), MMT (4-monomethoxytrityl), trimethoxytrityl, pixyl (9- phenylxanthen-9-yl) group, thiopixyl (9-phenylthioxanthen-9-yl) or 9-(p- methoxyphenyl)xanthine-9-yl (MOX), etc.; C(0)-alkyl, C(0)Ph, C(0)aryl,
C(0)0(C1-6alkyl), C(0)0(Ci-6alkylene)aryl (e.g.,
-C(0)OCH2Ph), C(0)Oaryl, CH20-alkyl, C¾0-aryl, S02-alkyl, S02-aryl, a protecting group comprising at least one silicon atom, such as, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, Si(Ci-6alkyl)20Si(Ci-6alkyl)20H (such as, -Si('Pr)20Si Pr)20H). Acetals, such as MOM or THP and the like are considered possible groups. Fluorinated compounds are also contemplated insofar that they can be attached to the compound and can be selectively removed by passing through a fluorous solid phase extraction media (e.g., FluoroFlash®). A specific example includes a fluorinated trityl analog, trityl analog l-[4- (lH,lH,2H,2H-perfluorodecyl)phenyl)-l ,l-diphenylmethanol. Other fluorinated analogs of trityl, BOC, FMOC, CBz, etc. are also contemplated. Sulfonyl chlorides like p-toluenesulfonyl chloride can react selectively on the 5' position. Esters could be formed selectively such as acetates and benzoates. Dicarboxylic anhydrides such as succinic anhydride and its derivatives can be used to generate an ester linkage with a free carboxylic acid, such examples include, but are not limited to oxalyl, malonyl, succinyl, glutaryl, adipyl, pimelyl, superyl, azelayl, sebacyl, phthalyl, isophthalyl, terephthalyl, etc. The free carboxylic acid increases the polarity dramatically and can also be used as a handle to extract the reaction product into mildly basic aqueous phases such as sodium bicarbonate solutions. The
phosphoramidate group is relatively stable in acidic media, so groups requiring acidic reaction conditions, such as, tetrahydropyranyl, could also be used.
The term "protecting compound," as used herein and unless otherwise defined, refers to a compound that contains a "protecting group" and that is capable of reacting with a compound that contains functional groups that are capable of being protected.
The term "leaving group", as used herein, has the same meaning to the skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure- Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351-357) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (with for example a nucleophile), the leaving group is then displaced. Examples of leaving groups include, but are not limited to: halogen (F, CI, Br, and I), CI, Br, or I; tosylate, mesylate, triflate, acetate, trifluoromethylacetate, camphorsulfonate, 2- thioxobenzo[d]thiazol-3(2H)-yl, aryloxide, and aryloxide substituted with at least one electron withdrawing group. The term "electron withdrawing group" is accorded its plain meaning. Examples of an aryloxide substituted with at least one electron withdrawing group include, but are not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide, etc. Examples of electron withdrawing groups include, but are not limited to, a halogen (F, CI, Br, or I), -N02, -CN, -C(0)(C1-6alkyl), -C(0)(aryl), -C(0)0(Ci-6alkyl), - C(0)0(aryl), etc.
The term "base" embraces the term "basic reagent" and is meant to be a compound that is capable of deprotonating a proton-containing compound, e.g., a Bransted base. In addition to the examples recited above, further examples of a base include, but are not limited to pyridine, collidine, 2,6-(Ci-6alkyl)-pyridine, dimethyl- aniline, imidazole, N-methyl-imidazole, pyrazole, N-methyl-pyrazole, triethylamine, di-isopropylethylamine, etc.
The term "basic reagent", as used herein, means a compound that is capable of deprotonating a hydroxyl group or an amino group. Examples of basic reagents include, but are not limited to, a (Ci_6alkyl)oxide ((Ci-6alkyl)OM) in combination with an alcoholic solvent, where (Ci-6alkyl)oxides include, but are not limited to, MeO", EtO", "PrO", 'PrO", ¾uO", 'AmO- (iso-amyloxide), etc., and where M is an alkali metal cation, such as Li+, Na+, +, etc. Alcoholic solvents include (Ci.
6alkyl)OH, such as, for example, MeOH, EtOH, "PrOH, 'PrOH, ¾uOH, 'AmOH, etc. Non-alkoxy bases can also be used such as sodium hydride, sodium
hexamethyldisilazane, lithium hexamethyldisilazane, lithium diisopropylamide, calcium hydride, sodium carbonate, potassium carbonate, cesium carbonate, DBU, DBN, Grignard reagents, such as (Ci-6alkyl)Mg(halogen), which include but are not limited to MeMgCl, MeMgBr, 'BuMgCl, 'BuMgBr, etc.
The term "non-nucleophilic base" means a compound that is capable of acting as a Bransted base, but has low nucleophilicity. Examples of non- nucleophilic bases include, but are not limited to, potassium carbonate, cesium carbonate, di-isopropylamine, di-isopropylethylamine, triethylamine, quinuclidine, naphthalene-1 ,8-diamine, 2,2,6,6-tetramethylpiperidine, 1 ,8-diazabicycloundec-7- ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-Cl-6-alkyl -pyridine, a 2,4,6-tri- Cl-6-alkyl-pyridine, l,5-diazabicyclo[4.3.0]non-5-ene, and 1,4- diazabicyclo[2.2.2]octane.
The term "alkyl" refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term "C\. alkyl" refers to an alkyl comprising 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. The term "C1-20alkyl" as used herein refers to an alkyl comprising 1 to 20 carbon atoms. The term "Cj-ioalkyl" as used herein refers to an alkyl comprising 1 to 10 carbons. The term "C]-6alkyl" denotes a straight or branched chain hydrocarbon residue comprising 1 to 6 carbon atoms. Examples of Ci-6alkyl groups include, but are not limited to, methyl, ethyl, propyl, z- propyl, n-butyl, z'-butyl, /-butyl or pentyl, isopentyl, neopentyl, and hexyl. The term "C]-4alkyl" refers to an alkyl containing 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, z'-propyl, n-butyl, z'- butyl, /-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The term (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group is optionally substituted by an aryl or a heteroaryl group respectively.
The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent, such as benzyl. The term "Ci-6alkaryl" or "Ci-6alkylaryl" refer to a C]. 6alkyl group with an aryl substituent, such as benzyl. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent, such as tolyl, xylyl, mesityl, etc.
The term "cycloalkyl" refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms; 3 to 8 carbon atoms
(C3-8cycloalkyl); 3 to 7 carbon atoms (C3-7cycloalkyl); 3 to 6 carbon atoms(C3- 6cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or cyclooctyl. Examples of a C3-7cycloalkyl and a C3-6cycloalkyl include, but are not limited to, cyclopropyl (cPr), 2-methyl-cyclopropyl, etc., cyclobutyl (cBu), 2-methyl- cyclobutyl, 3-methyl-cyclobutyl, etc., cyclopentyl (cPn), 2-methyl-cyclopentyl, 3- methyl-cyclopentyl, 4-methyl-cyclopentyl, etc., cyclohexyl (cHx), cycloheptyl (cHp)etc.
The term "alkenyl" refers to an unsubstituted hydrocarbon chain radical having from 2 to 10 carbon atoms having one or two olefinic double bonds, preferably one olefmic double bond. The term "C2-N alkenyl" refers to an alkenyl comprising 2 to N carbon atoms, where N is an integer having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term "C2-ioalkenyl" refers to an alkenyl comprising 2 to 10 carbon atoms. The term "C2-4alkenyl" refers to an alkenyl comprising 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, 2- propenyl (allyl) or 2-butenyl (crotyl). The term "aryl," as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl. The aryl group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, amino, alkyl, cycloalkyl, alkylamino, arylamino, alkoxy, alkenyl, aryl, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.
The term "aryloxide" ("-OAr") as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenoxide (PhO-), p-phenyl- phenoxide
(p-Ph-PhO-), or naphthoxide, preferably the term aryloxide refers to substituted or unsubstituted phenoxide. The aryloxide group can be substituted with one or more moieties selected from among hydroxyl, F, CI, Br, I, -C(0)(Ci-6alkyl),
-C(0)0(Ci-6alkyl), amino, alkyl, cycloalkyl, alkylamino, arylamino, alkoxy, alkenyl, aryl, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T.W. Greene and P.G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999.
The term "Active" as used herein refers to a compound capable of eliciting a biological response, which comprises at least one functional group capable of forming a bond to P. Examples of Actives include, but are not limited to, nucleosides, nucleoside-analogs, and non-nucleoside compounds.
Examples of nucleoside and nucleoside-analog actives include, but are not limited to:
Figure imgf000012_0001
Figure imgf000013_0001

Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000014_0004
Figure imgf000014_0005
a: R = H; X = CH b:R=CN;X = CH c: R = H; X = N d: R = CN; X = N
Figure imgf000015_0001

Figure imgf000016_0001

Figure imgf000017_0001

Figure imgf000018_0001

Figure imgf000019_0001
85 86
Figure imgf000019_0002
The term "protected active" as used herein refers to an active that comprises a blocking (or protecting) group. As a "protected active" is useful for preparing compound I or compound II, it is contemplated that said protected active is an embodiment of the disclosed invention and that said embodiment covers at least the following compounds.
Figure imgf000020_0001
91: Z = -C(0)CH2CH2C(0)CH3 95: Z = -C(0)CH2CH2C(0)CH3
92: Z = -C(0)OCH2Ph 96: Z = -C(0)OCH2Ph
93: Z = -Si(Me)2'Bu 97: Z = -Si(Me)2'Bu
94: Z = -Si(iPr) OSi('Pr)2OH 98: Z = -Si('Pr)2OSi Pr)2OH
Figure imgf000020_0002
99: Z = -C(0)CH2CH2C(0)CH3 103: Z = -C(0)CH2CH2C(0)CH3
100: Z = -C(0)OCH2Ph 104: Z = -C(0)OCH2Ph
101: Z = -Si(Me)2'Bu 105: Z = -Si(Me)2'Bu
102: Z = -Si('Pr)2OSi('Pr)2OH 106: Z = -SiC'Pr^OSi Pr^OH
The term "Group" as defined herein is hydrolyzable group meaning that when compound I or compound II is ingested the group is hydrolyzed, either enzymatically or non-enzymatically. The term "group precursor" as used herein is a parent compound, existing as its salt, hydrate, or salt/hydrate thereof, of the Group. Examples of a Group include, but are not limited to, a radical comprising an amine (e.g., benzylamine) or an amine further comprising a chiral center, which includes, but is not limited to an amino acid or an R- or S-a-methylbenzylamine.
The term "amino acid" includes naturally occurring and synthetic α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a certain embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β- threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β- glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the alkyl, cycloalkyl, or alkaryl esters of α, β, γ, or δ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the D and L-configurations, as well as acid-addition salts. For example, reference to L-alanine is a specific and independent disclosure not only of the free acid, but of alkyl, cycloalkyl, or alkaryl esters of L-alanine or its acid-addition salts, as well as C]-6alkyl, C3-7cycloalkyl, and Cj-6alkaryl esters of L-alanine or its acid addition salts.
A solvent or anti-solvent (as used in reactions, crystallization, etc. or lattice and/or adsorbed solvents) includes at least one of a Ci to C8 alcohol, a C2 to C8 ether, a C3 to C7 ketone, a C3 to C7 ester, a Cj to C2 chlorocarbon, a C2 to C7 nitrile, a miscellaneous solvent, a C5 to CJ2 saturated hydrocarbon, and a C6 to Cj2 aromatic hydrocarbon.
The Ci to C8 alcohol refers to a straight/branched and/or cyclic/acyclic alcohol having such number of carbons. The C\ to C8 alcohol includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, isobutanol, hexanol, and cyclohexanol.
The C2 to C8 ether refers to a straight/branched and/or cyclic/acyclic ether having such number of carbons. The C2 to C8 ether includes, but is not limited to, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, methyl-t-butyl ether (MTBE), tetrahydrofuran, and dioxane
The C3 to C7 ketone refers to a straight/branched and/or cyclic/acyclic ketone having such number of carbons. The C3 to C7 ketone includes, but is not limited to, acetone, methyl ethyl ketone, propanone, butanone, methyl isobutyl ketone, methyl butyl ketone, and cyclohexanone.
The C3 to C7 ester refers to a straight/branched and/or cyclic/acyclic ester having such number of carbons. The C3 to C7 ester includes, but is not limited to, ethyl acetate, propyl acetate, n-butyl acetate, etc.
The C1 to C2 chlorocarbon refers to a chlorocarbon having such number of carbons. The Ci to C2 chlorocarbon includes, but is not limited to, chloroform, methylene chloride (DCM), carbon tetrachloride, 1 ,2-dichloroethane, and
tetrachloroethane.
A C2 to C7 nitrile refers to a nitrile have such number of carbons. The C2 to C7 nitrile includes, but is not limited to, acetonitrile, propionitrile, etc.
A miscellaneous solvent refers to a solvent commonly employed in organic chemistry, which includes, but is not limited to, diethylene glycol, diglyme
(diethylene glycol dimethyl ether), 1 ,2-dimethoxy-ethane, dimethylformamide, dimethylsulfoxide, ethylene glycol, glycerin, hexamethylphsphoramide,
hexamethylphosphorous triame, N-methyl-2-pyrrolidinone, nitromethane, pyridine, triethyl amine, and acetic acid.
The term C5 to Q2 saturated hydrocarbon refers to a straight/branched and/or cyclic/acyclic hydrocarbon. The C5 to C12 saturated hydrocarbon includes, but is not limited to, n-pentane, petroleum ether (ligroine), n-hexane, n-heptane, cyclohexane, and cycloheptane.
The term C6 to Cj2 aromatic refers to substituted and unsubstituted hydrocarbons having a phenyl group as their backbone. The term C6 to C12 aromatic includes, but is not limited to, benzene, xylene, toluene, chlorobenzene, o-xylene, m- xylene, p-xylene, xylenes, mesitylene, etc.
The term "salts," as described herein, refers to a compound comprising a cation and an anion, which can produced by the protonation of a proton-accepting moiety and/or deprotonation of a proton-donating moiety. It should be noted that protonation of the proton-accepting moiety results in the formation of a cationic species in which the charge is balanced by the presence of a physiological anion, whereas deprotonation of the proton-donating moiety results in the formation of an anionic species in which the charge is balanced by the presence of a physiological cation.
The term "HX," as used herein, refers a Bronsted acid in the form of an acid addition salt to a synthetic reagent. Examples of HX include, but are not limited to, HC1, HBr, p-toluenesulfonic acid, methanesulfonic acid, triflic acid, trifluoroacetic acid, etc.
The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, K+, Mg2+, Ca2+, NHgR 4-g +, in which R is a Ci_3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the desired dose and pharmacokinetic parameters.
The term "excipient" as used herein refers to a compound that is used to prepare a pharmaceutical composition, and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
Embodiments
A first embodiment is directed to a composition comprising an
enantiomerically- or a diastereomerically-enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
O
Active p II—* Group
O I W
I
wherein Active comprises a functional group capable of forming a bond to P; Group is as defined herein; and W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3. A first aspect of the first embodiment is directed to a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
Figure imgf000024_0001
1
wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside compound; Group is as defined herein; and W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3.
A second aspect of the first embodiment is directed to a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
O II *
Active p— Group
I
OW
I
wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside and Group is an N-amino-acyl having the following structure
R
H I *
-N— C - -COOR'
H
and W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3.
A third aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l:
Figure imgf000024_0002
Rp-I-1 Sp-I-l wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a substituent for an amino acid as defined herein; and R' is an alkyl or a cycloalkyl. Here, for purposes of illustration, it is assumed that the order of priority from highest to lowest is Active > ArO > P=0 > NHCH(R)C(0)OR'.
A fourth aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?P-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; R is an alkyl; and R' is an alkyl or a cycloalkyl.
A fifth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Ci-6alkyl; and R' is a Ci-6alkyl or a C3-7cycloalkyl.
A sixth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non-nucleoside; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Ci_6alkyl; and R' is a Cj-6alkyl or a C3-7cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
A seventh aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
An eighth aspect of the first embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-1, wherein Active comprises a nucleoside, nucleoside-analog, or non- nucleoside; W is a phenyl naphthalen-1 -yl, or -(CH2)2SC(0)C(CH3)2(CH2OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. A ninth aspect of the first embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula i?p-I-l or Sp-I-l, wherein Active comprised of a nucleoside selected from among compounds 1-8, 10- 13, 15-20, 22, 24-26, 28-32, 39, and 41-43, a nucleoside-analog selected from among compounds 33-38 and 40, or non-nucleoside compound selected from among compounds 44-90; W is a phenyl naphthalen-l-yl, or - (CH2)2SC(0)C(CH3)2(CH2OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a Ci^alkyl or a C3-7 cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
A tenth aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000026_0001
An eleventh aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000026_0002
A twelfth aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000026_0003
wherein Np represents naphthalen-l-yl.
A thirteenth aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000027_0001
wherein Np represents naphthalen-l-yl.
A fourteenth aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000027_0002
wherein R is a Ci-6alkyl or a C3-7cycloalkyl.
A fifteenth aspect of the first embodiment is directed to a compound having the structure:
Figure imgf000027_0003
wherein R is a Ci-6alkyl or a C3-7cycloalkyl.
A second embodiment is directed to a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula I: O
Active p— Group
I
OW
I
which comprises
a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or
diastereomerically-enriched compound of formula II
Figure imgf000028_0001
II
wherein Group is as defined herein, W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3, and LG is a leaving group;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound.
A first aspect of the second embodiment is directed to a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
O
Active p II*— Group
I
OW
I
which comprises
a) reacting a protected or unprotected Active with a basic reagent to form a salt of said active and then reacting said salt with a compound of formula II
O
LG— P II—* Group
I
OW II wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside; Group is as defined herein; W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; and LG is a leaving group;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound.
A second aspect of the second embodiment is directed to a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I:
O
Active p II—* Group
OW
I
which comprises
a) reacting a protected or unprotected Active with a basic reagent to form a salt of said active and then reacting said salt with a compound of formula II
Figure imgf000029_0001
II
wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside; Group is as defined herein; W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; and LG is a leaving group;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound;
d) obtaining the compound of formula II
Figure imgf000030_0001
II
by a process that comprises:
1 ) reacting (LG)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
(i) a Group-precursor, as defined herein, and a first base to obtain (LG)P(0)(LG')(Group) followed by reacting
(LG)P(0)(LG')(Group) with HOW and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different,
(ii) HOW and a first base to obtain (LG)P(0)(LG')(OW) followed by reacting (LG)P(0)(LG')(OW) with a Group-precursor and a second base to obtain a mixture comprising
(LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different,
(iii) combining a Group, HOW, and at least one base to obtain a mixture comprising (LG)P(0)(OW)(Group); or
2) reacting (WO)P(0)(LG')2, wherein LG' is a leaving group, with
(i) a Group-precursor and a first base to obtain
(WO)P(0)(LG')(Group) followed by reacting
(WO)P(0)(LG')(Group) with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different, e) subjecting the mixture comprising (LG)P(0)(OW)(Group) to
chromatography, extraction, or crystallization to obtain compound II.
Recognizing that the phosphorus atom in (LG)P(0)(OW)(Group) is chiral, one of ordinary skill will understand that the mixture comprising
(LG)P(0)(OW)(Group), which is represented by the following structures, comprises a mixture of enantiomers (when the substituents Group, WO, and LG lack chirality) or a mixture of diastereomers (when at least one substituent Group, WO, and LG possesses chirality).
Figure imgf000031_0001
RP-II SP-ll
Here, for purposes of assignment of the Cahn-Ingold-Prelog ("CIP") designation of RP or Sp, it is assumed that the order of priority from highest to lowest is LG > WO > P=0 > Group. It is expected that one of ordinary skill would be able to deduce the chirality, and thus the CIP designation of R or Sp, of the phosphorus atom according to the CIP rules based on the particular identity of the functional groups bound to the phosphorus atom. A utility of the disclosed process is that a compound represented by formula II is sufficiently stable so as to allow one to obtain the enantiomeric or diastereomeric mixture of II, and then isolate the desired stereoisomer of II depending on which stereoisomer of I is sought, viz.
Figure imgf000031_0002
A third aspect of the second embodiment is a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-l:
0 R
I H I *
Active p — C— COOR'
1 H
ow
I-l
which comprises
a) reacting a protected or unprotected Active with a basic reagent to form a salt of said active and then reacting said salt with a compound of formula II- 1
0 R
IU H I*
LG— P N— C— COOR'
1 H
OW Π-1 wherein
the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside compound; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy-proline where the fragment N-C-R forms a ring-system, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain compound II- 1.
A fourth aspect of the second embodiment is a process for preparing a composition comprising an enantiomerically- or a diastereomerically enriched phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula I-l:
Figure imgf000032_0001
I-l
which comprises
a) reacting a protected or unprotected Active with a basic reagent to form a salt of said active and then reacting said salt with a compound of formula II-l
Figure imgf000032_0002
II-l
wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside compound; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH20H)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3;
LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the desired compound said aspect further comprising
d) obtaining the compound of formula II- 1
Figure imgf000033_0001
II I
by a process that comprises:
1) reacting (LG)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
(i) R'02CCHRNH2 »HX and a first base to obtain
(LG)P(0)LG'(NHCHRC02R') followed by reacting (LG)P(0)(LG')(NHCHRC02R') with HOW and a second base to obtain a mixture comprising (LG)P(0)(OW)(NHCHRC02R'), wherein the first base and the second base are the same or different,
(ii) HOW and a first base to obtain (LG)P(0)(LG')(OW) followed by reacting (LG)P(0)(LG')(OW) with RO2CCHRNH2 »HX and a second base to obtain a mixture comprising
(LG)P(0)(OW)(NHCHRC02R'), wherein the first base and the second base are the same or different, or (iii) combining R'02CCHRNH2 «HX, HOW, and at least one base to obtain a mixture comprising (LG)P(0)(OW)(NHCHRC02R'); or
2) reacting (WO)P(0)(LG')2, wherein LG' is a leaving group, with
(i) RO2CCHRNH2-HX and a first base to obtain
(WO)P(0)(LG')(NHCHRC02R') followed by reacting (WO)P(0)(LG')(NHCHRC02R') with a leaving group precursor and a second base to obtain a mixture comprising
(LG)P(0)(OW)(NHCHRC02R'), wherein the first base and the second base are the same or different,
e) subjecting the mixture comprising (LG)P(0)(OW)(NHCHRC02R') to chromatography or crystallizing the mixture to obtain compound II-l.
For the first aspect of the second embodiment, the leaving groups (either LG or LG') are as defined above. In a first sub-aspect, LG is an aryloxide substituted with at least one electron withdrawing group. In a second sub-aspect, LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide,
pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6- trichlorophenoxide. In a third sub-aspect, W is an aryl or - (CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; R is a Ci- 6alkyl; and R' is a Ci-6alkyl or a C3..7cycloalkyl. In a fourth sub-aspect, W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; R is a C1-6alkyl; and R is a Ci-6alkyl or a C3-7cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a fifth sub-aspect, W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a sixth sub-aspect, W is a phenyl naphthalen-l-yl, or
-(CH2)2SC(0)C(CH3)2(CH2OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a seventh sub-aspect, R'02CCHRNH2'HX is substantially anhydrous. In an eighth sub-aspect, R is methyl and R' is isopropyl. In a ninth sub-aspect, R is methyl, R' is isopropyl, HX is HC1.
A fifth aspect of the second embodiment is directed to a process for preparing a compound having the structure:
Figure imgf000035_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000035_0002
with a basic reagent to form a salt of the first compound, where Z' is hydrogen or a protecting group and Y is =0 or -OCj-6alkyl, with proviso that is a single bond and n is 1 when Y is =0, and is a double bond and n = 0 when Y is -OCi-6alkyl;
b) reacting the salt of the first compound with a second compound having the structure,
Figure imgf000035_0003
where LG is a leaving group, Z is hydrogen or a protecting group, and Bn is -CH2Ph; and
c) optionally deprotecting. In a first sub-aspect, Z is hydrogen and Z' is hydrogen. In a second sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a third sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a fourth sub-aspect, the basic reagent is a Grignard reagent. In a fifth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a sixth sub-aspect, the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
the discussion for formula II above, recognizing that the phosphorus atom in (LG)P(0)(OW)(NHCHRC02R') is chiral, one of ordinary skill will understand that the mixture comprising (LG)P(0)(OW)(NHCHRC02R'), which is represented by the following structures, comprises a mixture of enantiomers (when the substituents NHCHRC02R', WO, and LG lack asymmetry thus imparting chirality to said substituent) or a mixture of diastereomers (when at least one substituent NHCHRC02R, WO, and LG possesses asymmetry thus imparting chirality to said substituent).
Figure imgf000036_0001
Rp-ll-l Sp-II-l
Here, for purposes of illustration, it is assumed that the order of priority from highest to lowest is LG > WO > P=0 > NHCHRC02R'.
A sixth aspect of the second embodiment is directed to a process for preparing a compound having the structure
Figure imgf000036_0002
which comprises: a) reacting a first compound having the structure
Figure imgf000037_0001
with a basic reagent to form a salt of the first compound, where Z' is hydrogen or a protecting group and Y is =0 or -OCi-6alkyl, with proviso that is a single bond and n is 1 when Y is =0, and is a double bond and n = 0 when Y is -OCi-6alkyl;
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000037_0002
where LG is a leaving group, Z is hydrogen or a protecting group, and Bn is -CH2Ph; and
c) optionally deprotecting. In a first sub-aspect, Z is hydrogen and Z' is hydrogen. In a second sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a third sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a fourth sub-aspect, the basic reagent is a Grignard reagent. In a fifth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a sixth sub-aspect, the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t-butylmagnesium halide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In an eighth sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
A seventh aspect of the second embodiment is directed to a process for preparing a compound having the structure
Figure imgf000038_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000038_0002
with a basic reagent to form a salt of the first compound, where Z' is hydrogen or a protecting group;
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000038_0003
where LG is a leaving group and Np is naphthalen-l-yl; and
c) optionally deprotecting. In a first sub-aspect, Z' is hydrogen. In a second sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a third sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a fourth sub-aspect, the basic reagent is a Grignard reagent. In a fifth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a sixth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In an eighth sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
An eighth aspect of the second embodiment is directed to a process for preparing a compound having the structure
Figure imgf000039_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000039_0002
with a basic reagent to form a salt of the first compound,
where Z' is hydrogen or a protecting group;
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000039_0003
where LG is a leaving group and Np is naphthalen-l-yl; and c) optionally deprotecting. In a first sub-aspect, Z' is hydrogen. In a second sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a third sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a fourth sub-aspect, the basic reagent is a Grignard reagent. In a fifth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a sixth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1 , about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In an eighth sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
A ninth aspect of the second embodiment is directed to a process for preparing a compound having the structure
Figure imgf000040_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000041_0001
with a basic reagent to form a salt of the first compound,
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000041_0002
where LG is a leaving group and R is a Ci-6alkyl or a C3-7 cycloalkyl. In a first sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a second sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a third sub-aspect, the basic reagent is a Grignard reagent. In a fourth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a fifth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a sixth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1 , about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
A tenth aspect of the second embodiment is directed to a process for preparing a compound having the structure
Figure imgf000042_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000042_0002
with a basic reagent to form a salt of the first compound,
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000042_0003
where LG is a leaving group and R is a Ci-6alkyl or a C3-7 cycloalkyl. In a first sub-aspect, LG is an aryloxide having at least one electron withdrawing group. In a second sub-aspect, LG is an aryloxide selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide; 2,4-dichlorophenoxide; and 2,4,6-trichlorophenoxide. In a third sub-aspect, the basic reagent is a Grignard reagent. In a fourth sub-aspect, the basic reagent is a t-butylmagnesium halide. In a fifth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to the first compound. In a sixth sub-aspect, the basic reagent is a t- butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound. In a seventh sub-aspect, the basic reagent is a t-butylmagnesium bromide is present in a mole equivalent amount of about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to the first compound.
A third embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III:
O
Active P !l—* Group
III
wherein
Active comprises at least two functional groups capable of forming a bond to P; and Group is as defined herein.
A first aspect of the third embodiment is directed to a phosphorus-containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active comprises at least two functional groups capable of forming a bond to P and Group is an amino acid.
A second aspect of the third embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active is a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P and Group is an amino acid. Examples of a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P include, but are not limited to compounds 2, 3, 4, 5, 7, 8, 9a, 9b, 9c, 13, 14, 15-23, 26, 28-32, 34a, 34b, 34c, 34d, 35, 37-39, 41-43, 49-51, 56-57, 59-62, and 79.
A fourth embodiment is directed to a process for preparing a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III:
O
Active P— Group
III
which comprises reacting a protected or unprotected active with a basic reagent to form a salt of said active and then react said salt with a compound of formula IV: O
LG— P II—* Group
I
LG'
IV
wherein
Active comprises at least two functional groups capable of forming a bond to
P;
Group is as defined herein;
and
each of LG and LG', independent of one another, is a leaving group.
A first aspect of the fourth embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active comprises at least two functional groups capable of forming a bond to P and Group is an amino acid.
A second aspect of the fourth embodiment is directed to a phosphorus- containing active, salt, or pharmaceutically acceptable salt thereof, of formula III, wherein Active is a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P and Group is an amino acid. Examples of a nucleoside, nucleoside-analog, or non-nucleoside compound comprising at least two functional groups capable of forming a bond to P include, but are not limited to compounds 2, 3, 4, 5, 7, 8, 9a, 9b, 9c, 13, 14, 15-23, 26, 28-32, 34a, 34b, 34c, 34d, 35, 37-39, 41-43, 49-51, 56-57, 59-62, and 79.
A fifth embodiment is directed to a composition comprising an
enantiomerically- or diasteromerically-enriched compound, hydrate, solvate, salt, or combinations thereof, represented by the formula II:
O
LG— P II—* Group
I
OW II
where LG is a leaving group, group is as defined herein, and -W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3.
A first aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combinations thereof, represented by the formula i?p-II or Sp-II.
Figure imgf000045_0001
Λρ-ΙΙ Sp-U
Here, for purposes of assignment of the Cahn-Ingold-Prelog ("CIP") designation of R? or S?, it is assumed that the order of priority from highest to lowest is LG > WO > P=0 > Group. It is expected that one of ordinary skill would be able to deduce the chirality, and thus the CIP designation of Rp or Sp, of the phosphorus atom according to the CIP rules based on the particular identity of the functional groups bound to the phosphorus atom. A utility of the a compound represented by formula Rp-II or Sp-II is that it is sufficiently stable, yet adequately reactive, so as to allow one to obtain the enantiomeric or diastereomeric I or III in substantially pure form by reaction of i?p-II or Sp-H with a protected or unprotected active, as disclosed herein.
A second aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l
Figure imgf000045_0002
Λρ-11-l Sp-II-l wherein W is an aryl or -(CH2)nSC(0)C(CH3)m(CH20H)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3; LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy-proline where the fragment N-C-R forms a ring-systemor R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl. A third aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
A third aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide.
A fourth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is an alkyl; and R' is an alkyl or a cycloalkyl.
A fifth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Ci-6alkyl; and R' is a Ci-i0alkyl or a C3-8cycloalkyl.
A sixth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4- dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a C1-6alkyl; and R' is a Q. 6alkyl or a C3- cycloalkyl. A seventh aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or £p-II-l wherein LG is an aryloxide or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a C\. 6alkyl; and R' is a
Ci-6alkyl or a C3-7cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
An eighth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or Sp-II-l wherein LG is an aryloxide substituted with at least one electron
withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
A ninth embodiment is directed to a a compound, hydrate, solvate, salt, or combinations thereof, represented by the formula II:
O II *
LG— P— Group
OAr
II
where LG is a leaving group, group is as defined herein, and Ar is an aryl. A tenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combinations thereof, represented by the formula i?P-II or Sp-II.
Figure imgf000047_0001
RP-II Sp-II Here, for purposes of assignment of the Cahn-Ingold-Prelog ("CIP") designation of Rp or Sp, it is assumed that the order of priority from highest to lowest is LG > ArO > P=0 > Group. It is expected that one of ordinary skill would be able to deduce the chirality, and thus the CIP designation of R or Sp, of the phosphorus atom according to the CIP rules based on the particular identity of the functional groups bound to the phosphorus atom. A utility of the a compound represented by formula Rp-II or Sp-II is that it is sufficiently stable, yet adequately reactive, so as to allow one to obtain the enantiomeric or diastereomeric I or III in substantially pure form by reaction of Rp-II or Sp-II with a protected or unprotected active, as disclosed herein.
An eleventh aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1
Figure imgf000048_0001
Rp-ll-l Sp-II-l wherein Ar is an aryl; LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, which includes proline or hydroxy- proline where the fragment N-C-R forms a ring-system, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R' is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl.
A twelfth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide. A thirteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?P-II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
A fourteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is an alkyl; and R' is an alkyl or a cycloalkyl.
A fifteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or ■Sp-II-1 wherein LG is an aryloxide or an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Cj. 6alkyl; and R' is a
C1-10alkyl or a C3-7cycloalkyl.
A sixteenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or SP-II-1 wherein LG is an aryloxide substituted with at least one electron
withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Cj. 6alkyl; and R' is a
Ci-6alkyl or a C3-7cycloalkyl.
A seventeenth aspect of the fifth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula i?p-II-l or Sp-II-1 wherein LG is aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4- dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is a Ci-6alkyl; and R' is a C\. 6alkyl or a C3-7cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
An eighth aspect of the sixth embodiment is directed to a compound, its hydrate, solvate, salt, or combination thereof, represented by the formula Rp-II-1 or Sp-II-l wherein LG is an aryloxide substituted with at least one electron withdrawing group, which includes, but is not limited to, 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid.
A sixth embodiment is directed to a process for preparing compound of formula II
O II *
LG— P— Group
I
ow
II
wherein Group is as defined herein, W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3, and LG is a leaving group;
by a process that comprises:
a) reacting (LG)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
1) a Group-precursor and a first base to obtain
(LG)P(0)(LG')(Group) followed by reacting (LG)P(0)(LG')(Group) with HOW and a second base to obtain a mixture comprising
(LG)P(0)(OW)(Group), where the first base and the second base are the same or different,
2) HOW and a first base to obtain (LG)P(0)(LG')(OW) followed by reacting (LG)P(0)(LG')(OW) with a Group and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), where the first base and the second base are the same or different, 3) combining a Group, HOW, and at least one base to obtain a mixture comprising (LG)P(0)(OW)(Group); or
b) reacting (WO)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
1) a Group-precursor and a first base to obtain
(WO)P(0)(LG')(Group) followed by reacting (WO)P(0)(LG')(Group) with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), where the first base and the second base are the same or different, and
c) subjecting the mixture comprising (LG)P(0)(OW)(Group) to
chromatography, extraction, crystallization to obtain compound II.
In a first aspect of the sixth embodiment, LG' is chloride or bromide.
In a second aspect of the sixth embodiment, LG is chloride.
In a third aspect of the sixth embodiment, LG is an aryloxide substituted with at least one electron withdrawing group.
In a fourth aspect of the sixth embodiment, LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
A fifth aspect of the sixth embodiment is directed to a process for preparing compound of formula II by a process that comprises:
b) reacting (WO)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with a Group-precursor and a first base to obtain (WO)P(0)(LG')(Group) followed by reacting (WO)P(0)(LG')(Group) with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), where the first base and the second base are the same or different, and
c) subjecting the mixture comprising (LG)P(0)(OW)(Group) to
chromatography, extraction, crystallization to obtain compound II. In a first sub- aspect, LG' is chloride or bromide. In a second sub-aspect, LG' is chloride. In a third sub-aspect, LG is an aryloxide substituted with at least one electron
withdrawing group. In a fourth sub-aspect, LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide. In a fifth sub-aspect, W is aryl or
-(CH2)2SC(0)C(CH3)2(CH2OH). In a sixth sub-aspect, W is phenyl. A seventh embodiment is directed to a process for preparing compound of formula II-l
Figure imgf000052_0001
II-l
by a process that comprises:
a) reacting (LG)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
1) R'02CCHRNH2 »HX and a first base to obtain
(LG)P(0)LG'(NHCHRC02R') followed by reacting
(LG)P(0)(LG')(NHCHRC02R') with HOW and a second base to obtain a mixture comprising (LG)P(0)(OW)(NHCHRC02R), where the first base and the second base are the same or different
2) HOW and a first base to obtain (LG)P(0)(LG')(OW) followed by reacting (LG)P(0)(LG')(OW) with R'02CCHRNH2 «HX and a second base to obtain a mixture comprising (LG)P(0)(OW)( NHCHRC02R'), where the first base and the second base are the same or different or
3) combining R'02CCHRNH2 »HX, HOW, and at least one base to obtain a mixture comprising (LG)P(0)(OW)(NHCHRC02R); or
b) reacting (WO)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
1 ) R'02CCHRNH2 «HX and a first base to obtain
(WO)P(0)(LG')(NHCHRC02R') followed by reacting
(WO)P(0)(LG')(NHCHRC02R') with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(NHCHRC02R'), e) subjecting the mixture comprising (LG)P(0)(OW)(NHCHRC02R) to chromatography or crystallizing the mixture to obtain compound II-l.
For the first aspect of the seventh embodiment, the leaving groups (either LG or LG') are as defined above. In a first sub-aspect, LG is an aryloxide substituted with at least one electron withdrawing group. In a second sub-aspect, LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide,
pentafluorophenoxide, 2-chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6- trichlorophenoxide. In a third sub-aspect, W is an aryl or -
(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Cj. 6alkyl; and R' is a Ci-6alkyl or a C3-7cycloalkyl. In a fourth sub-aspect, W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a C1-6alkyl; and R' is a Ci-6alkyl or a C3-7cycloalkyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a fifth sub-aspect, W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a sixth sub-aspect, W is a phenyl naphthalen-l-yl, or
-(CH2)2SC(0)C(CH3)2(CH2OH); R is selected from among methyl, ethyl, and isopropyl; and R' is a selected from among, methyl, ethyl, isopropyl, neopentyl, cyclobutyl, cyclopentyl, and cyclohexyl; and wherein the stereochemistry of C-R is the same as a naturally occurring amino acid. In a seventh sub-aspect,
R'02CCHRNH2 HX is substantially anhydrous. In an eighth sub-aspect, R is methyl and R' is isopropyl. In a ninth sub-aspect, R is methyl, R' is isopropyl, HX is HC1.
One of ordinary skill will appreciate that the compounds disclosed herein, such as, I, II, or III, can be separated by traditional extraction, traditional crystallization or traditional chromatographic techniques. Traditional
• chromatographic techniques include, but are not limited to, chromatography on silica gel (using, e.g., 3-5% methanol in DCM or 4-6% isopropanol in DCM) to produce enhanced levels of one isomer (50-100%) and then crystallize it, if possible. Alternatively, one could use reversed phase chromatography (using, e.g., 1-30% acetonitrile-aqueous mobile phase). Furthermore the compounds can be isolated by supercritical fluid chromatography SFC with carbon dioxide as the main solvent and alcohols such as methanol as a modifier, preferably using the appropriate chiral media, such as, Daicel Chiralpack IA. Alternatively, SMB chromatography may be employed using the appropriate chiral media, such as, Daicel ChiralPack IA, using a mixture of solvents such as hexanes/isopropanol or single solvents such as ethyl acetate. Furthermore, the compound represented by formula II may be purified by crystallization induced dynamic resolution, which is contemplated by the following embodiment. An eighth embodiment is directed to a process for preparing a compound of formul -II-1 or 5p-II-l represented by the structures
Figure imgf000054_0001
RP-II-I Sp-Il-1 said process comprising:
crystallizing the compound of formula i?P-II-l or Sp-II-l from a
composition, comprising
a) a first composition;
b) a leaving group precursor;
c) a non-nucleophilic base; and
d) a liquid composition;
wherein the first composition comprises both i?p-II-l or Sp-II-1; and wherein LG is a leaving group, W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; R is a Ci-6alkyl, and R' is a Ci-6alkyl or a C3-7cycloalkyl.
In a first aspect of the eighth embodiment, the mole amount of i?p-II-l and the mole amount of Sp-II-1 are the same or different.
In a second aspect of the eighth embodiment, the mole amount of i?p-II-l is greater than the mole amount of 5p-II-l or vice versa.
In a third aspect of the eighth embodiment, the leaving group precursor is 2,4-dinitrophenol, 4-nitrophenol, 2-nitrophenol, 2-chloro-4-nitrophenol, 2,4- dichlorophenol, or pentafluorophenol.
In a fourth aspect of the eighth embodiment, LG is 2-nitrophenoxide, 4- nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, or 2,4,6-trichlorophenoxide.
In a fifth aspect of the eighth embodiment, LG is pentafluorophenoxide. In a first sub-aspect, the second leaving group precursor is pentafluorophenol. In a second sub-aspect, the amount of pentafluorophenol ranges from about 0.01 mole equivalents to about 10 mole equivalents relative to the mole amount of i?p-II-l and Sp-II-1 and all mole equivalents in between. In a third sub-aspect, the amount of pentafluorophenol ranges from about 0.1 mole equivalents to about 1 mole equivalents relative to the mole amount of Rp-II-1 and Sp-II-l and all mole equivalents in between.
In a fifth aspect of the eighth embodiment, the crystallizing occurs at a temperature that ranges from about -10°C to about +40°C and all temperature values in between. In a first sub-aspect, the crystallizing occurs at about room temperature.
In a sixth aspect of the eighth embodiment, the non-nucleophilic base is selected from among potassium carbonate, cesium carbonate, di-isopropylamine, di- isopropylethylamine, triethylamine, quinuclidine, naphthalene- 1 ,8-diamine, 2,2,6,6- tetramethylpiperidine, l ,8-diazabicycloundec-7-ene, 4-dimethylamino-pyridine, pyridine, a 2,6-di-Ci-6-alkyl-pyridine, a 2,4,6-tri-Ci.6-alkyl-pyridine, and mixtures thereof. In a first sub-aspect, the non-nucleophilic base is triethylamine or 1 ,8- diazabicycloundec-7-ene. In a second sub-aspect, the non-nucleophilic base is triethylamine.
In a seventh aspect of the eighth embodiment, the non-nucleophilic base is present in an amount that ranges from about 0.01 equivalents mol to about 10 mol equivalents, and all mole equivalents in between, relative to the total mole amount of i?P-II-l and Sp-II-1. In a first sub-aspect, the non-nucleophilic base is present in an amount that ranges from about 0.1 mol equivalents to about 1 mol equivalents, and all mole equivalents in between, relative to the total mole amount of i?p-II-l and Sp- II-l.
In an eighth aspect of the eighth embodiment, the solubility of Rp-II-1 is less than the solubility of Sp-II-1 in the liquid composition or vice versa.
In a ninth aspect of the eighth embodiment, the liquid composition comprises at least one of a solvent and an anti-solvent. In a first sub-aspect, the liquid composition comprises at least one of a C\ to C8 alcohol, a C2 to C8 ether, a C3 to C7 ketone, a C3 to C7 ester, a Cj to C2 chlorocarbon, a C2 to C7 nitrile, a C5 to Cj2 saturated hydrocarbon, and a C6 to C12 aromatic hydrocarbon. In a second sub- aspect, the liquid composition comprises at least one of a C2 to C8 ether, a C3 to C7 ester, a C5 to C12 saturated hydrocarbon, and a C6 to C12 aromatic hydrocarbon. In a third sub-aspect, the liquid composition comprises at least one of a C2 to Cg ether, a C3 to C7 ester, and a C5 to C12 saturated hydrocarbon. In a fourth sub-aspect, the liquid composition comprises at least one of ethyl acetate, t-butyl-methylether, and hexane. In a fifth sub-aspect, the liquid composition comprises ethyl acetate and hexane. In a sixth sub-aspect, the liquid composition comprises t-butyl-methylether and hexane.
In a tenth aspect of the eighth embodiment, the amount of liquid composition ranges from about 1 mL to about 10 mL for every gram of the first composition and all mL/g values in between.
An eleventh aspect of the eighth embodiment further comprises adding crystalline i?p-II-l or Sp-II-l to the composition. A first sub-aspect further comprises adding about 0.1 to about 1 wt. %, and all wt. % values in between, of crystalline Rp-II-1 or Sp-II-l to the first composition.
Dosage, Administration, and Use
In a ninth embodiment, the invention is for the treatment and/or prophylaxis of a disease state by administering a therapeutically effective amount of compound I or compound III to a host in need thereof.
Selected disease states include, but are not limited to, cancer or a diseased state that may arise form the introduction of a viral agent to a host. For instance, one of ordinary skill will recognize that the nucleoside, nucleoside-analog, and non- nucleoside actives depicted above, have been approved by the FDA for the treatment of at least one diseased state. It is contemplated that compound I or compound III would likewise be useful for the treatment of at least one diseased state, the treatment of which has been approved by the FDA. It is contemplated that the process disclosed herein will afford enantiomers or diastereomers of compound I or compound III that will have improved pharmacokinetic parameters relative to the active itself.
It is contemplated that a diseased state may arise from the introduction of a viral agent to a host. Thus, it is contemplated that the compound I or compound III can be used for the treatment and/or prophylaxis of a viral agent. Possible viral agents include, but are not limited to: HIV-1, HIV-2, herpes type 1, herpes type 2, HSV, influenza, HPV, ebolla, XMRV, CMV, RSV, rhinovirus, hepatitis C virus, hepatitis B virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, bovine viral diarrhea virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses. An aspect of this embodiment is directed to a composition for the treatment of any of the viral agents disclosed herein said composition comprising a pharmaceutically acceptable medium selected from among an excipient, carrier, diluent, and equivalent medium and compound I or compound III.
Compound I or compound III may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions. Compound I or compound III is efficacious when administered by suppository administration, among other routes of administration. The most convenient manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the severity of the disease and the patient's response to the antiviral medication.
Compound I or compound III, as well as its salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in
conventional proportions, with or without additional active compounds and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as suspensions, emulsions, or filled capsules for oral use; or in the form of
suppositories for rectal or vaginal administration. A typical preparation will contain from about 0.1% to about 99% active compound or compounds (w/w).
Compound I or compound III can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
A pharmaceutically acceptable salt form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the
pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. Solid form preparations include, for example, powders, tablets, pills, capsules, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, , talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Examples of solid formulations are exemplified in EP 0524579; US 2002/0142050; US 2004/0224917; US 2005/0048116; US
2005/0058710; US 2006/0034937; US 2006/0057196; US 2006/0188570; US 2007/0026073; US 2007/0059360; US 2007/0077295; US 2007/0099902; US 2008/0014228; US 6,267,985; US 6,294,192; US 6,383,471 ; US 6,395,300; US 6,569,463; US 6,635,278; US 6,645,528; US 6,923,988; US 6,932,983; US
7,060,294; and US 7,462,608, each of which is incorporated by reference.
Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs and aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Examples of liquid formulation are exemplified in U.S. Patent Nos. 3,994,974; 5,695,784; and 6,977,257. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
Compound I or compound III may be independently formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
Compound I or compound III may be independently formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Certain of these formulations may also be used in conjunction with a condom with or without a spermicidal agent.
Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,
Pennsylvania, which is hereby incorporated by reference. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
Additionally, compound I may be independently formulated in conjunction with liposomes or micelles. As to liposomes, it is contemplated that the purified compounds can be formulated in a manner as disclosed in U.S. Patent Nos.
4,797,285; 5,013,556; 5,077,056; 5,077,057; 5,154,930; 5,192,549; 5,213,804; 5,225,212; 5,277,914; 5,316,771 ; 5,376,380; 5,549,910; 5,567,434; 5,736,155;
5,827,533; 5,882,679; 5,891,468; 6,060,080; 6,132,763; 6,143,321 ; 6,180,134;
6,200,598; 6,214,375; 6,224,903; 6,296,870; 6,653,455; 6,680,068; 6,726,925;
7,060,689; and 7,070,801, each of which is incorporated by reference. As to micelles, it is contemplated that the purified compounds can be formulated in a manner as disclosed in U.S. Patent Nos. 5,091,188 and 5,145,684 both of which are incorporated by reference.
A tenth embodiment is directed to a use of compound I or compound III in the manufacture of a medicament for the treatment of any one of the diseased states contemplated herein.
The term "medicament" means a substance used in a method of treatment and/or prophylaxis of a subject in need thereof, wherein the substance includes, but is not limited to, a composition, a formulation, a dosage form, and the like, comprising compound I or compound III. It is contemplated that the use of compound I or compound III in the manufacture of a medicament, for the treatment of any one of the diseased states contemplated herein. A medicament includes, but is not limited to, any one of the compositions contemplated by the ninth embodiment of the present invention.
An eleventh embodiment is directed to a method of treatment and/or prophylaxis in a subject in need thereof said method comprises administering a therapeutically effective amount of compound I or compound III to the subject for the treatment of any one of the diseased states contemplated herein.
It is intended that a subject in need thereof is one that has any diseased state disclosed herein, which may be the result of an infection by any of the viral agents disclosed herein, which includes, but is not limited to, HIV-1, HIV-2, herpes type 1, herpes type 2, HSV, influenza, HPV, ebolla, XMRV, CMV, RSV, rhinovirus, hepatitis C virus, hepatitus B virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, bovine viral diarrhea virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, or those viruses belonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses or a viral agent causing symptoms equivalent or comparable to any of the above-listed viruses.
The term "subject" means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs, cats, and humans, preferably the subject is a human. It is contemplated that in the method of treating a subject thereof of the fifth embodiment can be compound I or compound III, either alone or in combination with another compound falling within the scope of compound I or compound III.
The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.001 and about 10 g, including all values in between, such as 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.050, 0.075, 0.1 , 0.125, 0.150, 0.175, 0.2, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should be appropriate in monotherapy and/or in combination therapy. A particular daily dosage is between about 0.01 and about 1 g per day, including all incremental values of 0.01 g (i.e., 10 mg) in between, a preferred daily dosage about 0.01 and about 0.8 g per day, more preferably about 0.01 and about 0.6 g per day, and most preferably about 0.01 and about 0.25 g per day, each of which including all incremental values of 0.01 g in between. Generally, treatment is initiated with a large initial "loading dose" to rapidly reduce or eliminate the virus following by a decreasing the dose to a level sufficient to prevent resurgence of the infection. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
Therapeutic efficacy can be ascertained from tests of liver function including, but not limited to protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism. Alternatively the therapeutic effectiveness may be monitored by measuring HCV-RNA. The results of these tests will allow the dose to be optimized.
A first aspect of the eleventh embodiment is directed to a method for the treatment of any one of the diseased states contemplated herein by administering to a subject (or host) in need thereof said method comprises administering to the subject a therapeutically effective amount of compound I or compound III and a therapeutically effective amount of another antiviral agent; wherein the
administration is concurrent or alternative. It is understood that the time between alternative administration can range between 1-24 hours, which includes any subrange in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.
Examples of "another antiviral agent" include, but are not limited to: HCV
NS3 protease inhibitors (see EP 1881001, US 2003187018, US 2005267018, WO 2003006490, WO 200364456, WO 2004094452, WO 2005028502, WO
2005037214, WO 2005095403, WO 2007014920, WO 2007014921, WO
2007014922, WO 2007014925, WO 2007014926, WO 2007015824, WO 2008010921, and WO 2008010921); HCV NS5B Inhibitors (see US 2004229840, US 2005/0098125, US 2005154056, US 20060194749, US 20060241064, US 20060293306, US 2006040890, US 2006040927, US 2006166964, US 2007275947, US 6784166, US20072759300, WO 2002057287, WO 2002057425, WO
2003010141 , WO 2003037895, WO 2003105770, WO 2004000858, WO
2004002940, WO 2004002944, WO 2004002977, WO 2004003138, WO
2004041201, WO 2004065367, WO 2004096210, WO 2005021568, WO
2005103045, WO 2005123087, WO 2006012078, WO 2006020082, WO
2006065335, WO 2006065590, WO 2006093801, WO 200702602, WO
2007039142, WO 2007039145, WO 2007076034, WO 2007088148, WO
2007092000, and WO2007095269); HCV NS4 Inhibitors (see WO 2005067900 and WO 2007070556); HCV NS5a Inhibitors (see US 2006276511, WO 2006035061, WO 2006100310, WO 2006120251, WO 2006120252); Toll-like receptor agonists (see WO 2007093901); and other inhibitors (see WO 2000006529, WO
2003101993, WO 2004009020, WO 2004014313, WO 2004014852, and WO
2004035571); and compounds disclosed in U.S. Patent Application No. 12/053,015, filed March 21 , 2008 (US 2010-0016251 the contents of which are incorporated by reference), interferon-a, interferon-β, pegylated interferon-a, ribavirin, levovirin, viramidine, another nucleoside HCV polymerase inhibitor, a HCV non-nucleoside polymerase inhibitor, a HCV protease inhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor.
In contemplated applications where HIV is the viral agent to be treated, nonlimiting examples of antiviral agents that can be used in combination with compound I or compound III include, but are not limited to the following:
Invirase® (Saquinavir), Fortovase® (Saquinavir), Norvir® (Ritonavir), Crixivan® (Indinavir), Viracept® (Nelfmavir), Agenerase® (Amprenavir), Kaletra®
(Lopinavir), Retrovir® (Zidovudine), Epivir® (Lamivudine), Combivir®
(lamivudine and zidovudine), Triazivir® (abacavir sulfate, lamivudine, and zidovudine), Ziagen® (Abacavir), Hivid® (Zalcitabine), Videx® (Didanosine), Videx® EC, Zerit® (Stavudine), Viread® (Tenofovir), Covincil tm, Viramune® (Nevirapine), Rescriptor® (Delavirdine), Sustiva® (Efavirenz), Droxia®
(hydroxyurea), Fuzeon® (Enfuvirtide), Atazanavir® (Atazanavir), Proleukin® (Interleukin-2), Remune® (HIV-1 Immunogen), Procrit® (Erythropoietin),
Darunavir® (Darunavir), and Serostim® (synthetic growth hormone). When compound I or compound III is administered in combination with another antiviral agent the activity may be increased over the parent compound. When the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives. "Concurrent administration" as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more agents at the same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.
It will be understood that references herein to treatment extend to
prophylaxis as well as to the treatment of existing conditions. Furthermore, the term "treatment" of a HCV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HCV infection, or the clinical symptoms thereof.
Examples
The specifically identified actives may be commercially available.
Alternatively, the specifically identified actives can be prepared according to procedures known in the art, as illustrated by the following information.
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
improved yield.
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Org. Chem. (1982), 47(18), 3457-3464.
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Not to be limited by way of example, the following examples serve to facilitate a better understanding of the claimed invention.
P.D. Howes et al. Nucleosides, Nucleotides & Nucleic Acids 2003, Vol. 22, Nos. 5-8, pp. 687-689 ("Howes") discloses 2'- and 5'-phosphoramidates obtained by a reaction with t-butylmagnesium chloride. There, Howes discloses that when a 3'- deoxy-cytidine nucleoside is reacted with (S)-2-[chloro-phenoxy-phosphorylamino] propionic acid methyl ester in the presence of 1.2 equivalents of t-butylmagnesium chloride, selective phosphorylation on the 2'-position occurred, but that with an additional equivalent of t-butylmagnesium chloride selective phosphorylation on the 5 '-position occurred. This disclosure should be contrasted to that which is disclosed in Howes' Scheme 1. Generally, a compound of formula I, derived, e.g., from any of the actives disclosed herein, can be obtained upon reaction with a compound of formula II. The following examples, are not intended to limit the scope of the disclosed and claimed subject matter, but serve only to better illustrate the embodiments disclosed herein.
Preparation of a Phosphoramidate Nucleotide.
Figure imgf000089_0001
In order to prepare the uridine nucleoside shown above (Z = H, but for illustrative purposes, Z can also be a blocking group(c compounds 91-94)), one could take advantage of an advanced tribenzoylated cytidine intermediate (107) in the synthesis of certain 3',5'-diacylated analogs (108) of 23 (see below) already produced efficiently on a pilot plant scale (see WO 2006/031725 or US
2006/0122146, both of which are incorporated by reference in their entirety). The following method was found to be scalable and cost-efficient.
3',5'-O-dibenozyl-2'-deoxy-2'-fiuoro-2,-C-methyl-N4-benzoylcytidine (107) is obtained by a method disclosed in WO 2006/031725 (US 2006/0122146) and WO 2008/045419 (US 2008/0139802) the subject matter of which is hereby incorporated by reference in its entirety. 107 is treated with 70% aqueous acetic acid to form
3',5'-0-dibenozyl-2,-deoxy-2'-fluoro-2'-C-methyl-uridine (108). The benzoyl esters can be hydrolyzed by a number of methods as well, e.g., alkoxides in alcoholic solvent, such as sodium methoxide in methanol, potassium carbonate in methanol, or ethanol analogs, alkylamines such as methylamine in methanol, butylamine etc. Methanolic ammonia was chosen for the larger scale work. The uridine product (23) can be purified by crystallization to afford a 70% yield from the tribenzoylated cytidine (107).
Figure imgf000090_0001
107 108
Example 1. Preparation of 2'-deoxy-2'-fluoro-2'-C-methyluridine (23)
In a 10 L flask, was added 3', 5'-0-dibenozyl-2'-deoxy-2'-fluoro-2'-C-methyl- N4-benzoylcytidine 107 (500 g, 0.874 mol) and 70% aqueous acetic acid (7.5 L). The solution was heated to reflux (110°C) for 20 h. TLC indicated a complete reaction (Rf 0.6 in 5% methanol in dichloromethane (DCM)). The mixture was cooled to ambient temperature and diluted with water (2 L). After stirring for 2 h, the resulting precipitate was collected by filtration and the solid was rinsed with water (5 L) and dried in the atmosphere at ambient temperature for 12 h to afford 360 g (88%). This dibenzoyluridine intermediate, 108, was used directly in the next step by adding it all to freshly prepared methanolic ammonia (5.4 L, ca 25%) at 0°C. This temperature was maintained for 3 h and then allowed to warm to 15°C for 24 h. TLC indicated a complete reaction (Rf 0.4 in 10% methanol in DCM). The reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give the crude product (216 g). The crude product was stirred with ethyl acetate (325 mL) for 3 h at ambient temperature. The resulting solid was collected by filtration and washed with ethyl acetate (216 mL). The solid was dried under vacuum at ambient temperature for 4h to afford 160 g (78%) of the desired product, 23, in 98.7% HPLC purity. 1H-NMR (DMSO- 6) δ 1 1.44 (br s, 1H, NH), 7.95 (d, 1H, C-6H), 5.97 (d, 1H, C-l'H), 5.64 (d, 1H, C-5H), 3.84-3.77 (m, 3H, C-5'-Ha, C- 3Ή. C-4'H), 3.63-3.60 (m, 1H, C5'-Hb), 1.23 (d, 3H, C-2'-CH3). ES-MS M-l 259.
Example 2. Preparation
Figure imgf000090_0002
23 109 110 To a stirred solution of l -((2R,3R,4R,5R)-3-Fluoro-4-hydroxy-5- hydroxymethyl-3 -methyl -tetrahydro-furan-2-yl) -lH-pyrimidine-2,4-dione 23
(32mg, 0.12mmol) in dry THF (lmL) was added a 1M solution of tButylmagnesium chloride (0.26mL, 0.26mmol, 2.1 equiv)) at room temperature over a period of 3min. After 30min, a solution of (S)-2-[(R)-(4-nitro-phenoxy)-phenoxy-phosphorylamino] propionic acid isopropyl ester (109) in THF (0.5mL) was added drop wise over a period of 3min. The mixture was allowed to stir at room temperature for 42h and then quenched with saturated aqueous NH4C1 (l OmL). The mixture was partitioned between ethyl acetate and water. The combined organic extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed using 0-4% methanol/dichloromethane gradient to give 110 as foamy solid (29mg, 44.5%yield).
110 Data: 1H-NMR (CDC13) δ 8.63 (br s, 1H, NH), 7.47 (d, 1H, C6-H), 7.30 (m, 2H, o-aromatic ), 7.26-7.18 (m, 3H, ^ -aromatic), 6.18 (br d, 1H, Cl '-H), 5.70 (d, 1H, C5-H), 5.02 (sept, CH-(CH3)2), 4.53 (m, 2H, C-5'-H2), 4.1 1 (d, 1H, C3'-H), 3.97 (m, 3H, C3'-OH, C4'-H, ala-CH-CH3), 3.77 (br s, 1H, ala-NH), 1.39 (d, 3H,C2'- CH3), 1.37 (d, 3H, ala-CH3), 1.24 (d, 6H, CH-(CH3)2). Example 3. Preparation of (S)-2-[(4-nitro-phenoxy)-phenoxy- phosphorylamino] propionic acid isopropyl ester:
Figure imgf000091_0001
To a stirred solution of 4-nitrophenyl phoshorodichloridate 12.8g, 50mmol) in dichloromethane (lOOmL) was added a solution of phenol and triethylamine (7.7mL, 55mmol) in dichloromethane (lOOmL) at -78°C over a period of 20min. The mixture was stirred at this temperature for 30min and then transferred to another round bottom flask containing L-alanine isopropyl ester hydrochloride (8.38g, 50mmol) in dichloromethane (lOOmL) at 0°C. To the mixture was added second lot of triethylamine (14.6mL, 105mmol) over a period of 15min. The mixture was stirred at 0°C for lh and then the solvent was evaporated. The residue was triturated with ethyl acetate (150mL) and the white solid was filtered off. The filtrate was concentrated under reduced pressure to give pale yellow oil. The crude compound was chromatographed using 0-20% ethyl acetate/hexanes gradient to give product (17g, 83 %yield) as a mixture of diastereomers in about 1 :1 ratio. P NMR (162 MHz, CDCI3): δ -2.05, -2.10; 1H NMR (400 MHz, CDC13): δ 8.22 (d, J=9.2Hz, 2H), 7.41-7.33(m, 4H), 7.26-7.18(m, 3H), 5.05-4.96(m, 1H), 4.14-4.05(m, 1H), 3.93-3.88(m, 1H), 1.38(d, J=6.8Hz, 3H), 1.22 (dd, J=6.2 & 3.0Hz, 6H); MS (ESI) m/z 407 (M-l)+.
Crystallization of (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy-phosphorylamino] propionic acid isopropyl ester (109):
Figure imgf000092_0001
°Y O"¾"^° IPE/hexanes ^ O^ ^0
109
(S)-2-[(4-Nitro-phenoxy)-phenoxy-phosphorylamino]-propionic acid isopropyl ester (3.4g) was dissolved in IPE (6mL). To the above solution were added hexanes (lmL) while hand shaking until the solution was turbid. Few drops of IPE were then added to the mixture to get a clear solution. The mixture was gently stirred at room temperature for 20h. A white and fine crystalline solid obtained was filtered, washed with 1 : 1 mixture of IPE/hexanes and dried to give white fluffy solid (820mg, 24% yield) mp 52 (shrinks) 62-66 (melts). 31P NMR (162 MHz, CDC13): δ -2.05; 1H NMR (400 MHz, CDC13): δ 8.22 (d, J=9.2Hz, 2H), 7.41-7.33(m, 4H), 7.26-7.18(m, 3H), 5.05-4.96(m, 1H), 4.14-4.05(m, 1H), 3.93-3.88(m, 1H), 1.38(d, J=6.8Hz, 3H), 1.22 (dd, J=6.2 & 3.0Hz, 6H); MS (ESI) m/z 407 (M-l)+. The stereochemistry of 109 has been confirmed by single crystal X-ray crystallography, as evidenced by the ORTEP representation presented below (where P=0 projects away from the viewer). X-Ray Crystallography of 109
109, Ci8H21N2P07, crystallizes in the monoclinic space group P2i
(systematic absences OkO: k=odd) with a=5.3312(4)A, b=15.3388(8)A,
c=23.7807(13)A, β=92.891(3)°, V=1942.2(2)A3, Z=4, and dcaic=1.397 g/cm3. X-ray intensity data were collected on a Bruker APEXII CCD area detector employing graphite-monochromated Μο-Κα radiation (λ=0.71073 A) at a temperature of 100(1)K. Preliminary indexing was performed from a series of thirty-six 0.5° rotation frames with exposures of 30 seconds. A total of 3608 frames were collected with a crystal to detector distance of 70.00 mm, rotation widths of 0.5° and exposures of 20 seconds: scan type 2Θ ω φ X frames
Φ -35.50 279.40 27.32 48.96 725 φ 24.50 22.31 35.56 69.08 692 ω -13.00 321.68 247.79 69.08 95
Φ 34.50 204.08 28.21 -92.80 293 φ -30.50 310.60 214.10 54.21 361 φ 32.00 304.67 24.47 50.72 722 φ -35.50 122.14 316.59 -78.84 720 Rotation frames were integrated using SAINT (Bruker (2009) SAINT.
Bruker AXS Inc., Madison, Wisconsin, USA.) producing a listing of unaveraged F2 and a(F2) values which were then passed to the SHELXTL (Bruker (2009)
SHELXTL. Bruker AXS Inc., Madison, Wisconsin, USA.) program package for further processing and structure solution on a Dell Pentium 4 computer. A total of 6909 reflections were measured over the ranges 1.58 < Θ < 25.09°, -6 < h < 6, -18 < k < 18, -28 < 1 < 28 yielding 6909 unique reflections (Rint = 0.0581). The intensity data were corrected for Lorentz and polarization effects and for absorption using SADABS (Sheldrick, G.M. (2007) SADABS. University of Gottingen, Germany.) (minimum and maximum transmission 0.6093, 0.7452).
The structure was solved by direct methods (SHELXS-97 (Sheldrick, G.M.
(2008) Acta Cryst. A64, 1 12-122.)). Refinement was by full-matrix least squares based on F2 using SHELXL-97 (Sheldrick, G.M. (2008) Acta Cryst. A64, 112- 122.). All reflections were used during refinement. The weighting scheme used was w=l/[a2(Fo2 )+ (0.0000P)2 + 14.0738P] where P = (F0 + 2F0 2)/3. Non-hydrogen atoms were refined anisotropically and hydrogen atoms were refined using a riding model. Refinement converged to Rl = 0.0847 and wR2 = 0.1899 for 6173 observed reflections for which F > 4o(F) and Rl=0.0963 and wR2=0.1963 and GOF =1.1 19 for all 6909 unique, non-zero reflections and 512 variables (Rl =∑||F0| - |FC|| /∑ |F0|; wR2 = [∑w(F0 2 - Fc 2)2/∑w(F0 2)2]½; GOF = [∑w(F0 2 - Fc 2)2/(n - p)]½; where n = the number of reflections and p = the number of parameters refined). The maximum A/a in the final cycle of least squares was 0.000 and the two most prominent peaks in the final difference Fourier were +0.402 and -0.559 e/A3. Table 1 lists cell information, data collection parameters, and refinement data. Final positional parameters are given in Tables 2 and 3. Figures 1 A and IB are ORTEP ("ORTEP-II: A Fortran Thermal Ellipsoid Plot Program for Crystal Structure Illustrations". C.K. Johnson (1976) ORNL-5138.) representations of the two molecules in the asymmetric unit with 30% probability thermal ellipsoids displayed.
Figure imgf000094_0001
Figure 1A. ORTEP drawing of molecule no. 1 109 of the asymmetric unit with 30% probability thermal ellipsoids.
Figure imgf000095_0001
Figure IB. ORTEP drawing of molecule no. 2 109 of the asymmetric unit with 30% probability thermal ellipsoids. Table 1. Summary of Structure Determination of 109
Figure imgf000095_0002
Theta range for data collection 1.58 to 25.09°
Index ranges -6 < h < 6, -18 < k < 18, -28≤ 1≤ 28
Reflections collected 6909
Independent reflections 6909 [R(int) = 0.0581]
Completeness to theta = 25.09° 99.6 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7452 and 0.6093
Refinement method Full-matrix least-squares on F^
Data / restraints / parameters 6909 / 1 / 512
Goodness-of-fit on 1.119
Final R indices [I>2sigma(I)] Rl = 0.0847, wR2 = 0.1899
R indices (all data) Rl = 0.0963, wR2 = 0.1963
Absolute structure parameter 0.1(2)
Largest diff. peak and hole 0.402 and -0.559 e.A"3
Example 4. Preparation of 110 with 91 as a Synthetic Intermediate.
Figure imgf000096_0001
113
Figure imgf000097_0001
110
a) Synthesis of 5'-0-tert-Butyldimethylsilyl-2'-deoxy-2'-fluoro-2'-C- methyluridine (111): To a stirred solution of 2'-deoxy-2,-fluoro-2'-C-methyluridine (23, 81.1 g,
312 mmol) in dry pyridine (750 mL) was added drop-wise a solution of TBDMSC1 (103.19 g, 685.6 mmol) in dry pyridine (500 mL) over a period of 45 min at ambient temperature. The reaction was allowed to stir at ambient temperature for 24 h.
Methanol (85 mL) was added to the reaction mixture and it was allowed to stir for 10 min and then the solvents were distilled off under reduced pressure. Hot water (45 °C) (1 L) was added to the reaction mass and the mixture extracted with ethyl acetate (2 x 500 mL), washed with water (1 x 500 mL). The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off and the residue obtained was co-evaporated with toluene (2 x 500 mL) to give crude 111 as a white foam. Yield = 116.9 g (quantitative).
1H NMR : CDC13 (300 MHz): δ 0.1 (s,6H), 0.91 (s, 9H), 1.22 (d, 3H, J = 21 Hz), 2.50 (s, 2H), 3.75-4.05 (m,4H), 5.54 (d, 1H, J = 9 Hz), 5.73 (s, 1H), 6.0 (d, 1H, J = 18 Hz), 7.81 (d, lH, J = 9 Hz), 8.57 (br, s, 1H), 1 1.1 (s, 1H). b) Synthesis of 5'-0 -( tert -Butyldimethylsilyl)-3'-0-levuIinyl-2!-deoxy-2'- fiuoro 2'-C-methyl-uridine (112):
To a stirred solution of nucleoside 111 (1 16.9 g, 312.1 mmol) in DCM (1 L) was added DMAP (30.5 g, 249.7 mmol) and this was allowed to stir at RT for 20 min. A soln. of levulinic anhydride (133.6 g, 642.3 mmol) in DCM (200 mL) was added to the mixture and allowed to stir for 24 h. TLC of the mixture indicated completion of reaction. Cold water (500 mL) was added and the mixture stirred for 20 min. Layers were separated and the organic layer was washed with sat. sodium bicarbonate solution (2 x 250 mL), dried over anhydrous sodium sulfate and then the solvent was distilled under reduced pressure to give yellow oil. Crude yield: 197.6 g (135 %). The material was used as is for the next step.
112 Data: 1H NMR : CDC13 (300 MHz) δ 0.11 (s, 6H), 0.94 (s, 9H), 1.34 (d, 3H, J = 21 Hz), 2.22 (s, 3H), 2.6-2.89 (m, 4H), 3.72 (m, IH), 4.01 (d, IH, J = 12 Hz), 4.23 (d, IH, J = 9 Hz), 5.33 (dd, IH, J = 15 Hz), 5.73 (d, IH, J = 6 Hz), 6.26 (d, IH, J = 15 Hz), 8.12 (d, IH, J = 12 Hz), 8.72 (br, s, IH). c) Synthesis of 3'-0-levulinyl-2'-deoxy-2'-fluoro 2'-C-methyl-uridine (91):
Crude 112 (197.6 g, 312.1 mmol -assumed) was dissolved in DCM (1 L) to which was added TEA.3HF (50.3 g, 312.1 mmol) and allowed to stir overnight at ambient temperature. TLC of the mixture indicated about 50 % completion of reaction. Another equivalent of TEA.3HF (50.3 g, 312.1 mmol) was added and the reaction mixture was allowed to stir for 6 h. TLC at this point indicated about 10 % of unreacted starting material. Another 0.25 eq of TEA.3HF (12.5 g, 78.0 mmol) was added and the reaction mixture was allowed to stir overnight. Reaction mixture was concentrated to dryness to give yellow oil. Crude from all the batches was purified by column chromatography on silica gel (0-2% MeOH in DCM) to give 124.1 g of 3'-levulinate as a white foam solid (90% purified yield over three steps from2'-deoxy-2'-fluoro-2'-C-methyluridine) .
91 Data: !H NMR: CDC13 (400 MHz) δ 1.55 (d, 3H, CH3, J = 20 Hz), 2.36 (s, 3H, CH3), 2.8-3.03 (m, 5H, CH2CH3), 3.91-3.96 (dd, IH, CH"), 4.2-4.25 (m, IH, CH*), 4.34 (dd, IH, CH, J = 8 Hz), 5.25 (dd, IH, J = 16 Hz), 5.93 (d, IH, J = 8 Hz), 8.20 (d, IH, J = 8 Hz), 9.18 (s, IH). d) Stereoselective synthesis of (S)-2-{[(lR,4R,5R)-5-(2,4-Dioxo-3,4-dihydro- 2H-pyrimidin-l-yI)-4-(R)-fluoro-3-(4-oxopentanoyl)-4-methyl- tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryIamino}-propionic acid (S)-isopropyl ester (113): (Synonym: (2R,3R,4R,5R)-5-(2,4-dioxo- 3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-2-((((R)-(((S)-l-isopropoxy-l- oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4- methyItetrahydrofuran-3-yl 4-oxopentanoate) :
e)
To a solution of the nucleoside (91, 1.00 mmol, 358 mg) in 5 ml anhydrous THF that was cooled to 0°C was added tBuMgCl (1.7 M in THF, 2 eq) and allowed it to warm to ambient temperature and stirred for half hour. To this mixture was added the reagent (ca 97% chiral purity) (S)-2-[(S)-(4-nitro-phenoxy)-phenoxy- phosphorylamino] propionic acid isopropyl ester (109) (408 mg, 1.00 mmol, 1.00 eq.) in one lot and allowed it to stir at ambient temperature. After 16 h, there was -30% starting material left. The reaction mixture was quenched with saturated NH4CI solution 10 ml, and the aqueous phase was extracted with ethyl acetate (3 x25 ml). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate and evaporated to dryness to give a pale yellow foam (500 mg). This was purified by silica gel chromatography using 2-5% methanol in methylene chloride to give the product as a white foam (275 mg) of about 97% P chiral purity and unreacted starting material (162 mg). Based on consumed starting material, the yield was 76 %.
113 Data: 31P NMR (162 MHz): 3.7 ppm; 1H NMR (400 MHz): δ 1.22 (dd, 6H, J = 6.4 Hz), 1.37 (s, 3H), 1.58 (s, 3H), 2.18 (s, 3H), 2.63-2.9 (m, 4H), 4.0 (d, 1H, J = 8 Hz), 4.2-4.33 (m, 1H), 4.57 (d, 1H, J = 8Hz), 4.96-5.00 (sept, 1H), 5.2 (dd, 1H, J = 9 Hz), 5.42 (d, 1H, J = 8Hz), 6.19 (d, 1H, J = 18Hz), 7.15-7.35 (m, 5H), 7.5 (d, 1H, J = 5.6 Hz), 8.2 (br, s, 1H). e) Synthesis of (S)-2-{[(lR,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin- l-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]- phenoxy-phosphoryIamino}-propionic acid (S)-isopropyl ester (110)
A solution of sodium sulfite was prepared by adding Na2S203 (1.51 g) and Na2S205 (0.57 g) in water (25 mL). To a solution of the levulinate (113, 250 mg, 0.40 mmol) in anhydrous THF (2.5 mL) was added 1.0 ml of the sodium sulfite solution. This was allowed to stir at room temperature for 4 h. The reaction mixture was poured in to water (15 mL) and extracted with ethyl acetate (3x25 mL) dried and evaporated to give quantitatively a white solid product with about 97% P chiral purity which matched the physical and spectral properties of 110 produced directly from the unprotected nucleoside.
Example 5. Preparation of 117 with 96 as a Synthetic Intermediate
Figure imgf000099_0001
9a 114 115
TFA
CH2C1:
Figure imgf000100_0001
Figure imgf000100_0002
117
a) Synthesis of (2R,3R,4R,5R)-2-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-((bis(4- methoxyphenyl)(phenyl)methyl)amino)-6-methoxy-9H-purin-9-yl)-4- fluoro-4-methyltetrahydrofuran-3-ol (114):
To a solution of (2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4- fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (9a, 4 g, 12.8 mmol) in anhydrous pyridine (100 mL) cooled at 0°C was added DMT-Cl portion- wise under nitrogen. The brown solution was stirred at ambient temperature for 24 hours. The mixture was concentrated under reduced pressure to remove most of solvent and sat. NaHC03 (20 mL) was added. The mixture was diluted with water. (150 mL) and EtOAc (120 mL). The organic layer was separated and washed with water (5x 120 mL), brine and dried over Na2S04. After removal of solvent, the residue was purified via column chromatography (20% EA in hexanes to 80%) EA in hexanes) to afford 11.6 g of product, 114, as a white foam solid (quantitative yield).
114 Data: Ή-NMR (DMSO-d6): δ 7.94 (s, 1 H), 7.39-7.37 (m, 3 H), 7.26-7.14 (m, 17 H), 6.84-6.80 (m, 8 H), 5.58 (s, 1 H), 4.04 (br, 1 H), 3.71-3.70 (m, 14 H), 3.68 (m, 1 H), 3.48 (br, 2 H), 3.20 (d, 1 H), 0.88 (br, 3 H). b) Synthesis of benzyl ((2R,3R,4R,5R)-2-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-((bis(4- methoxyphenyl)(phenyl)methyl)amino)-6-methoxy-9H-purin-9-yl)-4- fluoro-4-methyltetrahydrofuran-3-yl) carbonate (115):
To a solution of nucleoside 114 (2.52 g, 2.75 mmol) in anhydrous DCM (8 mL) was added DMAP (1.01 g, 8.2 mmol) and the solution was cooled at 0°C in an ice-water bath. Cbz-Cl (0.77 g, 4.2 mmol) was added via a syringe to the mixture and resulted in a cloudy reaction mixture. The mixture was stirred at room temperature for 24 hours and sat. NaHC03 (10 mL) was added. The mixture was partitioned in DCM and water. The organic layer was dried over Na2S04 and concentrated to a white foam solid. The residue was purified via column
chromatography (10-60% EtOAc in hexanes) to afford 2.74 g product, 115, as a white foam solid (yield, 95%).
115 Data: Ή-NMR (CDC13):5 7.87 (s, 1 H), 7.41-7.16 (m, 24 H), 6.79-6.75 (m 8 H), 6.28 (s, 1 H), 5.65 (br, 1 H), 5.15 (s, 2 H), 4.28 (d, 1 H), 3.79-3.71 (m, 15 H), 3.55-3.52 (m, 1 H), 3.39-3.36 (m, 1 H), 0.93 (br, 3 H). c) Synthesis of (2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4- fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-yl benzyl carbonate (96):
A 1 voP/o of TFA solution in DCM (50 mL) was added to a flask loaded with 115 (2.69 g, 2.56 mmol). The mixture was stirred at room temperature for 2 h and it was complete. Sat. NaHC03 (20 mL) was added and the mixture was partitioned in water and DCM. The organic layer was concentrated and solid residue was purified by column chromatography (silica gel, 0-5% 2-PrOH in DCM) to afford 1.01 g of product, 96, as a white foam solid (yield 88%).
96 Data: Ή-NMR (CDC13):5 7.82 (s, 1 H), 7.39-7.33 (m, 5 H), 6.02 (d, 1 H, J = 19.2 Hz), 5.77 (dd, 1 H, J= 20.8, 8.8 Hz), 5.32-5.30 (m, 1 H), 5.20 (s, 2 H), 5.04 (s, 2 H), 4.34 (d, 1 H, J= 8.8 Hz), 4.15 (m, 1 H), 4.04 (s, 3 H), 3.85-3.79 (m, 1 H), 1.21 (d, 3 H, J = 22.8 Hz). d) Synthesis of SP-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2-amino-6- methoxy-9H-purin-9-yl)-3-(((benzyloxy)carbonyl)oxy)-4-fluoro-4- methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (116): To a solution of the nucleoside 96 (150 mg, 0.34 mmol) in 1.5 mL of anhydrous THF was added a solution of t-BuMgCl in THF (1.0 M, 0.41 mL) at 0 °C. The cloudy mixture was stirred at ambient temperature for 1 h and then a solution of phosphoramidate reagent (ca 95% chiral purity) (S)-2-[(S)-(4- nitrophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester (109) (162 mg, 0.4 mmol) in 1.5 mL of THF was added to the mixture via a syringe drop-wise. The mixture was stirred at ambient temperature for 20 h and ca 29% of starting material remained. The reaction was quenched by adding sat. NH4C1 (4 mL) and 20 mL of EtOAc was added. After separation, organic layer was washed with water (3x 25 mL), brine and dried over Na2S04. After removal of solvent, the oil residue was checked by 'H-NIVIR and 31P-NMR. The ratio of two isomers was ca. 12.5 : 1. The major isomer, 1H-NMR (CDC13): δ 7.73 (s, 1 H); 31P-NMR (CDC13): δ 4.02. e) Synthesis of SP-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2-amino-6- methoxy-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (117):
To a solution of crude phosphoramidate 116 in MeOH (2.5 mL) was added 5% Pd on charcoal (40 mg). The atmosphere in the flask was exchanged with hydrogen twice. The mixture was stirred at ambient temperature under one atmosphere of hydrogen for 1 h. The mixture was filtered through a short pad of Celite and the filtrate was concentrated. The crude residue was checked by Ή-
31
NMR and P-NMR and ratio of two isomers was ca. 17 : 1 favored the desired Sp isomer (117) and also matched the Sp isomer by thin layer chromatography. 31P- NMR (DMSO-d6): 6 4.91.
The following exemplified embodiments are directed to various
phosphoramidate reagents having differing leaving groups. Example 6. Synthesis of (S)-2-{(S)-[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin- 9-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]- phenoxy-phosphorylamino}-propionic acid isopropyl ester monohydrate (117) via (S)-isopropyl 2-(((S)-
(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (118) and isolation by chromatography and crystallization.
Figure imgf000103_0001
9a Ar = -C6F5 117 a) Preparation of (S)-2-[(2,3?4,5,6-pentafIuoro-phenoxy)-phenoxy- phosphorylamino] propionic acid isopropyl ester and isolation of (S)-2- [(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino] propionic acid isopropyl ester (118) via crystallization-induced dynamic resolution in a single crop.
To a 1 L of dry three-necked flask fitted with a low-temperature thermometer and a mechanical stirrer was loaded phenyl phosphorodichloridate (25 g, 1 18.5 mmol). Anhydrous dichloromethane (125 mL) was added and the solution was cooled to 0°C. The alanine ester salt (oven dried) (19.86 g, 1 eq) was added quickly under N2 while agitated. The solution was cooled to ca -50°C (internal temperature (in an acetone/dry ice bath under N2). A solution of triethylamine (25.2 g, 2.1 eq) in DCM (125 mL) was added dropwise via an addition funnel over 0.5 h at -50°C and the resulting white slurry was stirred at about -50°C for 0.5 h. The mixture was allowed to warm up to 0°C over 1.5 h and then a pre-mixed cooled solution of pentafluorophenol (21.82 g, 1 eq) and TEA (13.2 g, 1.1 eq) (caution: heat released while mixing pentafluorophenol and TEA) in 75 mL of DCM was added over 0.5 h at 0°C via an addition funnel. The mixture was stirred at 0°C for additional 4 h.
The mixture was filtered through a Buchner funnel and the collected solid triethylamine hydrochloride was rinsed with DCM (3 x 40 mL). The filtrate was checked by 31P-NMR (ratio ca 1.14: 1 favored the Sp-diastereomer (118) - downfield peak) and was divided into two parts of equal weight. One of them was
concentrated under reduced pressure. The white solid residue (31 g) was triturated in a mixture of EtOAc and hexanes (150 mL, 20:80, v/v) at RT for 17 h allowing time for dynamic resolution of the less soluble Sp-diastereomer. The white slurry was filtered and solid was rinsed with 20% EtOAc in hexanes (2x 25 mL). The solid (22.58 g) was checked by Ή-NMR and 31P-NMR and it contained product as one isomer contaminated with triethylamine hydrochloride salt. The solid was dissolved and partitioned in 310 mL of EtOAc and 100 mL of water. After separation of the organic layer, the aqueous layer was back-extracted with EtOAc (50 mL). The combined organic layer was washed with water (3x 80 mL), brine (50 mL) and dried over MgS04. The solution was concentrated under reduced pressure and then dried under high vacuum at RT to a constant weight to furnish 17.36 g of product as a white solid from the one half of the reaction.. The yield is 64%. The mother liquor from above was concentrated to a gummy residue (7.89 g) that contained the reagents with a ratio of 1 : 1.2 (118/i?p-diastereomer) based on 31P-NMR. (The absolute structure of 118 was confirmed by single crystal X-ray crystallography. b) Preparation of 117 from 118 and 9a
To a 250 mL of dry three-necked round flask was added 5.06 g (16.15 mmol) of the purine nucleoside (9a). The solid was suspended in 40 mL of anhydrous THF and cooled in an ice-water bath. The Grignard reagent (1 M solution in THF) was added dropwise via a syringe and a clear solution was formed. The mixture was stirred at 0 °C for 30 minutes and a solution of 118 (8.32 g, 18.35 mmol) in 40 mL of THF was added via an addition funnel over 50 minutes. After finishing addition, the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding 20 mL of sat NH4C1 at 0 °C. The mixture was diluted with 100 mL of ethyl acetate. Two layers were separated and aqueous layer was extracted with 50 mL of ethyl acetate. Organic layer was combined and washed with water (60 mL), sat sodium bicarbonate (2 x 60 mL), water (60 mL), brine (40 mL), and dried over sodium sulfate. Solvent was removed under reduced pressure to afford an amorphous solid residue.
To the crude residue 7 mL of ethyl acetate was added and followed by 26 mL of anisole. The mixture was stirred until a solution was formed. Water (320 mg) was added and 20 mg of crystal seeds of product (117) was added. The mixture was cooled at -5 °C overnight. White solid was formed and collected by filtration. Solid was rinsed with pre-cooled mixture of heptane and TBME (1 :1, 3 x 2 mL) and weighed 3.3 g after drying. The mother liquor was concentrated under reduced pressure and the residue was purified via column chromatography (5-7% 2-propanol in DCM). Product was obtained as a white amorphous solid (4.5 g).
Solids from above were combined (7.8 g) and mixed with 7.7 mL of ethyl acetate. To the slurry, 31 mL of anisole was added and the mixture was stirred until a uniformed solution was formed. To the solution 160 mg of water was added and followed by 20 mg of crystal seeds of product (117). The mixture was stirred slowly at room temperature and white solid precipitated. The mixture was kept at -5 °C for 2 hours and solid was collected via filtration. Solid was rinsed with pre-cooled mixture of heptane and TBME (1 :1, 4 x 5 mL) and dried in vacuo. Product weighed 6.69 g (69% yield).
Example 7. Synthesis 117 by reaction with 118 and 9a and isolation by crystallization only. To a 250 mL of dry three-necked round flask were loaded 5 g (15.96 mmol) of the nucleoside (9a) and 40 mL of anhydrous THF. The suspension was cooled in an ice-water bath and 20 mL of the Grignard reagent (1 M solution in THF, 20 mmol) was added via a syringe over 10 minutes. The clear reaction mixture was stirred at 0 °C for half hour and then a solution of the phosphorus reagent (118) in 40 mL of THF was added via an addition funnel in 2 hours. The reaction was allowed to warm up to ambient temperature slowly and stirred for overnight. The mixture was cooled to 0 °C and 50 mL of 1 N diluted HC1 was added. Most of THF was removed under reduced pressure and the mixture was diluted with 200 mL of ethyl acetate. The organic layer was separated and aqueous layer was extracted with 30 mL of ethyl acetate. The combined organic layer was washed with water (60 mL), sat'd. sodium bicarbonate (2 x 50 mL), 5% sodium carbonate (70 mL), water (50 mL), and brine (50 mL). Organic solution was dried over magnesium sulfate and solvent was removed under reduced pressure to afford an amorphous solid residue.
The crude residue was dissolved in 41 mL of anisole at room temperature.
To the solution, 24 mL of xylenes was added and followed by 410 mg of water. The mixture was stirred slowly at room temperature and crystal seeds of 117 (10 mg) were added. White solid precipitated and the mixture was kept at -5 °C for 2 hours. Solid was collected via filtration and rinsed with a pre-cooled mixture of heptane and TBME (1 :1, 3 2 mL). Solid weighed 5.83 g after drying. The mother liquor was concentrated to dryness under reduced pressure. The residue was dissolved in 7.2 mL of anisole and 10.7 mL of xylenes was added. To the solution, 178 mg of water was added and 5 mg of crystal seeds of 117 were added. The mixture was slowly stirred at room temperature for overnight. White solid was formed and collected via filtration. Solid was rinsed with a pre-cooled mixture of heptane and HBME (1 : 1. 3 x 1 mL) and weighed 1.17 g.
Solids obtained above were combined (7.0 g) and added 7 mL of ethyl acetate. After addition of 27 mL of anisole, a clear solution was formed. To the solution, 200 mg of water was added and then added 5 mg of crystal seeds of 117. The mixture was stirred at ambient temperature and white solid precipitated. The mixture was kept at -5 °C for overnight. Crystalline solid was collected by filtration and rinsed with a pre-cooled mixture of heptane and TBME (1 : 1 , 3 x 5 mL). The resultant product (117) weighed 5.66 g with purity of 98.3% by HPLC.
The above solid was purified again via crystallization from a combination of 5.6 mL ethyl acetate and 22.6 mL of anisole. After filtration and drying, 4.48 g
(47%) of product was obtained and purity was 99.18% by HPLC. Spectral(Ή- and 31P-NMPv, MS) and physical properties (HPLC retention, melting point and appearance) matched an authentic sample. Example 8. Synthesis of (S)-2-{(S)-[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin- 9-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]- phenoxy-phosphorylamino}-propionic acid isopropyl ester (117) via (S)- isopropyl 2-(((S)-(2,4-dinitrophenoxy)(phenoxy)phosphoryI)amino)propanoate
(119)
Figure imgf000106_0001
Preparation of (2S)-isopropyl 2-(((2,4- dinitrophenoxy)(phenoxy)phosphoryl)amino)propanoate diastereomeric mixture and isolation of the single isomer (2S)-isopropyl 2-(((S)-(2,4- dinitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (119) by crystallization
Figure imgf000107_0001
Phenyl phosphorodichloridate (10.0 g, 47.4 mmol) was dissolved in 60 mL of dry DCM and subsequently cooled to -78 °C. A premixed solution of 2,4- dinitrophenol (8.72 g, 47.4 mmol) and triethylamine (7.27 mL, 52.1 mmol) in 20 mL of DCM was slowly added at -78 °C over a period of 30 min. The reaction was brought to 0 °C and stirred for 2.5 h at this temperature before (L)-alanine isopropyl ester (7.95 g, 47.4 mmol) was added as a solid in one batch. Stirring for 40 min at 0 °C was then followed by addition of more triethylamine (13.9 mL, 99.54 mmol) and additional stirring for 3 h at 0 °C or until judged complete by TLC (ethyl acetate/hexane = 1/3). The reaction mixture was subsequently evaporated under reduced pressure, residue redissolved in MTBE (100 mL), solids filtered off and filtrate evaporated to dryness to give yellow syrup. NMR of the crude sample indicated mixture of 2 isomers in the ratio of 1 :1. A mixture of EtOAc: Hexanes (1 : 1) (50 ml) was added and mixture allowed to stir for 15h. The white solid thus formed was filtered off and rinsed with EtOAc:Hexanes (1 : 1) (20 mL) and dried under vacuum to give 6.0 g (28 %) of 119 a single isomer.
119 Data: 1H NMR (CDC13, 400 MHz) δ: 8.82-8.81 (m, 1 H), 8.43-8.40 (m, 1 H), 7.89-7.86 (m, 1 H), 7.36-7.32 (m, 2 H), 7.23-7.19 (m, 3 H), 4.96 (hepta, 1 H), 4.19- 4.08 (m, 2 H), 1.42 (d, 3 H), 1.20 (d, 6 H). 31P NMR (CDC13, 162 MHz) δ: -1.82. b) Preparation of 117 from 119 and 9a
To a 50 mL of dry round-bottomed flask were added 80 mg (0.255 mmol) of 9a and 1 mL of anhydrous THF. The suspension was cooled in an ice water bath and 0.33 mL of Grignard reagent was added via a syringe under nitrogen. A clear solution was formed and stirred at 0 °C for half hour. A solution of ll9 (133 mg, 0.294 mmol) in 1.5 mL of THF was added via a syringe. The orange-colored, clear, reaction mixture was checked by TLC in 20 minutes at 0 °C and the reaction was almost complete. Product was formed as well as the 3',5'-bisphosphoramidate by- product. The reaction was quenched by adding sat NH4C1 after one and half hour. The mixture was diluted with 20 mL of ethyl acetate. Organic layer was separated and aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed with water (50 mL), sat sodium bicarbonate (2 x 40 mL), sat sodium carbonate (40 mL), water (40 mL), and brine (30 mL). The light yellow color organic layer was dried over sodium sulfate. The solution was concentrated under reduced pressure and an amorphous solid residue resulted was purified via column chromatography. The bis-phosphoramidate by-product was eluted out at 1 % methanol in DCM as a foam solid (32.4 mg) and 117 was eluted out at 3% methanol in DCM (74 mg, 0.127 mmol, 49.6%).
Example 9. Synthesis of (S)-2-{[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin-9- yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy- phosphorylamino}-propionic acid isopropyl ester diastereomeric mixture (120) via (2S)-isopropyl 2-(((2- nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (121)
Figure imgf000108_0001
a) Preparation of 121
To a solution of phenyl phosphorodichloridate (30 g, 142.2 mmol) in dichloromethane (150 mL) at - 70°C under nitrogen atmosphere was added drop wise a pre-prepared mixture of o-Nitro phenol (19.76 g, 142.2 mmol) and triethylamine (19.8 mL, 142.2 mmol) in dichloromethane (150 mL) through addition funnel for lh at above temperature. Stirring was continued for additional 2h and was slowly brought to 0 °C. L-alanine isopropyl ester hydrochloride salt (26.2 g, 156.3 mmol) was added as solid and then followed by triethylamine (43.7 mL, 313.4 mmol) in dichloromethane (150 mL) drop wise at 0 °C for 20 min. and the reaction mass was continued stirring at the same temperature for additional one hour. The reaction mixture was filtered and concentrated and was finally purified by column chromatography (20 % EtOAc/hexanes) on a silica gel to yield 121 as
diastereomeric mixture (14.4 g, 25%).
121 Data: 1H NMR (CDC13, 400 MHz) 5: 7.94-7.90 (m, 1 H), 7.67-7.63 (m, 1 H), 7.57-7.54 (m, 1 H), 7.33-7.26 (m, 3 H), 7.23-7.14 (m, 3 H), 5.04-4.89 (m, 1 H), 4.21-4.04 (m, 2 H), 1.38 (d, 3 H, isomer I), 1.33 (d, 3 H, isomer II), 1.23-1.17 (m, 6 H). 3IP NMR (CDC13, 162 MHz) 5: -1.55 (isomer I), -1.76 (isomer II). b) Preparation of 120 from 121 and 9a To a 50 mL of dry round-bottomed flask were added 80 mg (0.255 mmol) of
9a and 1 mL of anhydrous tetrahydrofuran. The suspension was cooled in an ice- water bath and a solution of Grignard reagent (1 M in THF, 0.32 mmol) was added via a syringe. The clear solution thus formed was stirred at 0 °C for half hour and then a solution of 121 (120 mg, 0.296 mmol, mixture of isomers) in 1 mL of THF was added dropwise at 0 °C. The mixture was stirred at room temperature for 44 hours and quenched by addition of 1 N diluted HC1. After aqueous work-up as usual, the crude residue was purified via column chromatography (silica gel, 3% methanol in DCM) to afford 33.9 mg (0.058 mmol, 22.8%) of 120 as a 1 : 1 mixture of two isomers.
Example 10. Synthesis of (S)-2-{[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin-9- yI)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy- phosphorylamino}-propionic acid isopropyl ester diastereomeric mixture (120) via diastereomeric mixture of (2S)-isopropyl 2-(((2,4- dich!orophenoxy)(phenoxy)phosphoryl)amino)propanoate (122)
Figure imgf000109_0001
a) Preparation of (2S)-isopropyl 2-(((2,4- dichlorophenoxy)(phenoxy)phosphoryI)amino)propanoate
diastereomeric mixture (122)
Figure imgf000110_0001
Phenyl phosphorodichloridate (10.0 g, 47.4 mmol) was dissolved in 60 mL of dry DCM and subsequently cooled to -78 °C. Slow addition of a preformed mixture of 2,4-dichlorophenol (7.73 g, 47.4 mmol) and triethylamine (7.27 mL, 52.1 mmol) in 20 mL of DCM was followed by stirring at above temperature for 30 min.
The reaction was brought to 0 °C and stirred for 2.5 h at this temperature before (L)- alanine isopropyl ester (7.95 g, 47.4 mmol) was added as a solid in one batch.
Stirring for 40 min at 0 °C was then followed by addition of more triethylamine (13.9 mL, 99.54 mmol) and additional stirring for 3 h at 0 °C or until judged complete by TLC (ethyl acetate/hexane = 1/3). The reaction mixture was subsequently evaporated under reduced pressure and finally submitted to column chromatography (ethyl acetate in hexane) on silica gel to yield the product 122
(mixture of two isomers) in 66% yield (13.6 g) as viscous colorless oil.
122 Data: 1H NMR (CDC13, 400 MHz) δ: 7.47-7.44 (m, 1 H), 7.42-7.39 (m, 1 H), 7.35-7.30 (m, 2 H), 7.24-7.15 (m, 3 H), 5.05-4.94 (m, 1 H), 4.19-4.08 (m, 1 H), 3.96-3.89 (m, 1 H), 1.41-1.35 (m, 1 H), 1.24-1.19 (m, 6 H). 3 IP NMR (CDC13, 162 MHz) δ: -1.52 (one isomer), -1.54 (the other isomer). b) Preparation of Diastereomeric Mixture of 120 from 122 and 9a
To a dry 50 mL of round-bottomed flask were added 181 mg (0.58 mmol) of 9a and 1.5 mL of anhydrous THF. The suspension was cooled in an ice-water bath. Grignard reagent (1 M solution in THF, 0.72 mmol) was added via a syringe dropwise over 5 minutes at 0 °C. The clear solution was stirred at room temperature for half hour before a solution of 122 (276 mg, 0.66 mmol) in 1.5 mL of THF was added over 10 minutes. The reaction was allowed to warm up to ambient temperature and stirred for 22 hours. Reaction was not complete and less than half of starting material was consumed. The reaction was quenched after additional three days by adding sat NH4C1 (5 mL). The mixture was diluted with 20 mL of ethyl acetate. After work-up, the residue was purified via column chromatography (silica gel, 4% 2-propanol in DCM) to afford 63.1 mg (0.108 mmol, 19%) of 120 as a mixture of two diastereomers. From column, 29.6 mg (0.094 mmol) of starting nucleoside was recovered. Example 11. Synthesis of (S)-2-{[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin-9- yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy- phosphorylamino}-propionic acid isopropyl ester diastereomeric mixture (120) via (2S)-isopropyl 2-(((2-chloro-4- nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (123)
Figure imgf000111_0001
a) Preparation of 123 and isolation of (124, Sp-diastereomer) and 125 (i?p diastereomer))
Figure imgf000111_0002
123 124 125
Phenyl phosphorodichloridate (10.0 g, 47.3 mmol) was dissolved in 50 mL of dry DCM and subsequently cooled to 0 °C. After addition of solid (L)-alanine isopropyl ester HCl salt (7.94 g, 47.3 mmol), the reaction mixture was cooled to -70 °C and then treated with triethylamine (13.8 mL, 94.6 mmol) dissolved in 50 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C. Subsequently, a preformed solution of 2-chloro-4- nitrophenol (8.2 g, 47.3 mmol) and triethylamine (6.6 mL, 47.3 mmol) dissolved in 20 mL of dry DCM was added over 5-10 min and was continued stirring for additional 2h. The solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in 50 mL of TBME and stirred for 10 min at room temperature. Subsequent filtration removed more triethylamine hydrochloride and yielded a filtrate that was again stripped of its solvent under reduce pressure. Column chromatography (dichloromethane) yielded the desired product (12.2 g, 27.6 mmol) as solid. The product was recrystallized using EtOAc/hexane (2:3) for two times to isolate 125 (5.2 g, 25% yield) and upon cooling the mother liquor to -5 °C 124 was obtained (1.5 g, 7% yield).
124 Data: Ή NMR (CDC13, 400 MHz) δ: 8.33 (m, 1 H), 8.13-8.10 (m, 1 H), 7.73- 7.71 (m, 1 H), 7.36-7.33 (m, 2 H), 7.25-7.18 (m, 3 H), 5.00 (hepta, 1 H), 4.19-4.10 (m, 1 H), 4.02-3.97 (m, 1 H), 1.43 (d, 3 H), 1.23-1.21 (m, 6 H).
31P NMR (CDCI3, 162 MHz) δ: -1.97.
125 Data: 1H NMR (CDCI3, 400 MHz) δ: 8.32-8.31 (m, 1H), 8.13-8.10 (m, 1 H), 7.73-7.71 (m, 1 H), 7.38-7.34 (m, 2 H), 7.28-7.19 (m, 3 H), 5.02 (hepta, 1 H), 4.21- 4.1 1 (m, 1 H), 4.01-3.95 (m, 1 H), 1.40 (d, 3 H), 1.25-1.22 (m, 6 H).
31P NMR (CDCI3, 162 MHz) 5: -2.02. b) Preparation of 120 from 123 and 9a
To a dry 50 mL of round-bottomed flask were added 181 mg (0.58 mmol) of 9a and 1.5 mL of anhydrous THF. The suspension was cooled in an ice-water bath under nitrogen. Grignard reagent (1 M solution in THF, 0.72 mmol) was added via a syringe and a clear solution was formed. The mixture was stirred at ambient temperature for half hour and then cooled to 0 °C again. A solution of 123 (292 mg, 0.66 mmol) in 1.5 mL of THF was added via a syringe over 10 minutes at 0 °C. The resulting orange color reaction solution was stirred at room temperature for overnight (19 h) and reaction was almost complete as checked by TLC. The reaction was quenched by addition of sat NH4CI (5 mL) and diluted with 20 mL of ethyl acetate and 10 mL of water. Two layers were separated and aqueous layer was extracted with 20 mL of EtOAc. Organic layer was washed with water (20 mL), sat sodium bicarbonate (2 x 30 mL), 5% sodium carbonate (30 mL), water (20 mL), and brine (20 mL). Organic solution was dried over sodium sulfate and concentrated to a yellow color solid residue. The residue was purified via column chromatography (silica gel, 3% methanol in DCM) to afford 279 mg (0.48 mmol, 83%) of 120.
I l l Example 12. Synthesis of (S)-2-{(R)-[(lR,4R,5R)-5-(2-Amino-6-methoxy- 9-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]- phenoxy-phosphorylamino}-propionic acid isopropyl ester (126) via (2S)- isopropyl 2-(((R)-(2-chloro-4- nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (125) and 9a
Figure imgf000113_0001
To a 50 mL of dry round-bottomed flask were charged 70 mg (0.223 mmol) of 9a and 1 mL of anhydrous THF. The flask was cooled in an ice-water bath and Grignard reagent (1 M solution in THF, 0.32 mL) was added dropwise at 0 °C. After stirred at 0 °C for half hour, a solution of the (125) (129 mg, 0.29 mmol) in 1 mL of THF was added via a syringe. A clear brown color solution was formed and gradually warmed up to ambient temperature. After overnight (19 h) at room temperature, the reaction was quenched by adding 1 N of diluted HC1 at 0 °C. The mixture was diluted with ethyl acetate (20 mL) and water (10 mL). After separation of two layers, aqueous layer was extracted with EtOAc (10 mL). Organic layer was washed with water (10 mL), sat sodium bicarbonate (3 15 mL), water (10 mL), brine (10 mL), and dried over sodium sulfate. After concentration, the solid residue was purified via column chromatography (silica gel, 3% methanol in DCM) to afford 100 mg (0.17 mmol, 77%) of 126 as a white solid and single isomer.
Example 13. Synthesis of (S)-2-{[(lR,4R,5R)-5-(2-Amino-6-methoxy-purin-9- yI)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy- phosphorylamino}-propionic acid isopropyl ester diastereomeric mixture (120) via diastereomeric mixture (2S)-isopropyl 2-((phenoxy(2- thioxobenzo[d]thiazoI-3(2H)-yl)phosphoryl)amino)propanoate (127).
Figure imgf000114_0001
9a Ar = S= "" f 1 120 ί
a) Preparation of 127
Figure imgf000114_0002
Phenyl phosphorodichloridate (6.37 g, 30.19 mmol) was dissolved in 40 mL of dry DCM and subsequently cooled to 0 °C. After addition of solid (L)-alanine isopropyl ester (5.06 g, 30.19 mmol), the reaction mixture was cooled to -78 °C and then treated with triethylamine (8.84 mL, 63.3 mmol) dissolved in 20 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C. Subsequently, a preformed solution of benzo[d]thiazole- 2(3H)-thione (5.05 g, 30.19 mmol) and triethylamine (4.63 mL, 33.21 mmol) dissolved in 20 mL of dry DCM was added over 5-10 min whereupon the mixture was allowed to warm to RT over night. The cloudy mixture was then cooled back to 0 °C and filtered to remove all solids. The filtrate was stripped of all solvent under reduced pressure. The resulting residue was suspended in 50 mL of TBME and stirred for 1 h at- RT. Subsequent filtration removed more triethylamine
hydrochloride and yielded a filtrate that was again stripped of its solvent under reduce pressure. Column chromatography (DCM) yielded 127 (3: 1, isomer I/isomer II) in 15% (1.97 g) yield as viscous oil.
127 Data: Ή NMR (CDC13, 300 MHz) 6: 8.63-8.59 (m, 1 H), 7.37-7.27 (m, 7 H), 7.18-7.14 (m, 1 H), 6.05-5.97 (m, 1 H), 5.04 (hepta, 1 H, isomer II), 4.91 (hepta, 1 H, isomer I), 4.37-4.24 (m, 1 H), 1.45-1.42 (d, 3 H, isomer I), 1.41-1.39 (d, 3 H, isomer II), 1.26-1.22 (m, 6 H), 1.09-1.02 (m, 6 H). 31P NMR (CDC13, 121 MHz) δ: - 0.43 (isomer I), -1.29 (isomer II). b) Preparation of 120 from 127 and 9a
To a dry round-bottomed flask were added 120 mg (0.38 mmol) of 9a and
I .5 mL of anhydrous THF. The mixture was cooled to 0 °C and 0.5 mL of Grignard reagent (0.5 mmol) was added dropwise. The clear solution was stirred at 0 °C for half hour. A solution of 127 (197 mg, 0.45 mmol) in 1.5 mL of THF was added via a syringe. The resulting mixture was allowed to warm up to room temperature and stirred for overnight (19 h). TLC showed reaction was not complete and product was found together with bis-phosphoramidate by-product. Reaction was quenched by addition of 1 N of diluted HC1 at 0 °C and mixture was diluted with 20 mL of ethyl acetate. After work-up, as noted above, an oily residue was obtained and it was purified via column chromatography (silica gel, 3% methanol in DCM) to afford 78.6 mg (0.13 mmol, 35%) of 120. From column, 36.4 mg of bis- phosphoramidate by-product was isolated.
Based on the results in the reactions for preparing compounds 117, 120, and 126, an unexpected correlation was observed between a lower pKa of the leaving group and increased reactivity. Increased reactivity was desirable in the sense that it allowed completion of the reaction in a shorter time period and usually in a higher yield, but very high reactivity also led to less discrimination of substitution on the desired 5'-hydroxyl versus continued reaction with the 3'-hydroxyl. For substrates not containing a competing secondary hydroxyl group or a protected secondary hydroxyl, this would not be a concern.
While this chiral phosphoramidate synthesis method was developed primarily for the Pharmasset nucleotide compounds, 110 and 117, it has broader utility. The methodology can be used to react with any primary or secondary hydroxyl to form chiral phosphoramidates. The examples that follow demonstrate this. Example 14. Synthesis of racemic S-(2-
(((benzylamino)(perfluorophenoxy)phosphoryl)oxy)ethyl)2,2-dimethyl-3- (trityloxy)-propanethioate (128):
Figure imgf000116_0001
Tr=CPh3 (±)-128
128a: fast-moving enantiomer Ar=C6F5
128b: slow-moving enantiomer
To a stirred solution of POCl3 (0.72 mL, 7.85mmol) in dichloromethane (24 mL) was added a solution of S-(2-hydroxyethyl) 2,2-dimethyl-3- (trityloxy)propanethioate ((±)-128, 3.3g, 7.85mmol) and triethylamine in
dichloromethane (16mL) at -30 °C, over a period of 35min. The mixture was stirred at this temperature for lh and then was added a solution of pentafluorophenol
(1.44g, 7.85mmol) and triethylamine in dichloromethane (16mL) over a period of 30min at -30 °C. The mixture was stirred at this temperature for 30min and then warmed to room temperature over 30min. After stirring for lh at room temperature the mixture was cooled to -30 °C, and then was added a solution of benzylamine
(BnN¾, 0.86mL, 7.85mmol) and triethylamine over a period of 5min. The mixture was stirred at this temperature for 30min and slowly allowed to warm to 0 °C over a period of 3h. The solvent was evaporated and the residue was suspended in ethyl acetate (50mL). The white solids were filtered, washed with ethyl acetate (lOmL) and the filtrate was concentrated under reduced pressure. The residue was
chromatographed using 0-30% EtOAc/hexanes gradient to give pure racemic
product (128) as colorless syrup (2.25g, 38% yield).
128 Data: 1H NMR (CDC13, 400 MHz): δ 7.42-7.39 (m, 6H), 7.31-7.28 (m, 10H), 7.23-7.19 (m, 4H), 4.26 (dd, J=14.8, 6.8 Hz, 2H), 4.20 (dd, J=10.4, 6.8 Hz, 2H),
3.28-3.19 (m, 3H), 3.16 (s, 2H), 1.21 (s, 3H), 1.20 (s, 3H). 31P NMR (CDC13, 162 MHz): 5 5.11 (using H3PO4 as external reference set to 0 ppm)
In Example 14, the S-(2-hydroxyethyl) 3-hydroxy-2,2- dimethylpropanethioate is protected with a trityl (-CPh3) protecting group. It is contemplated that the reaction can be conducted without a protecting group, as shown in the following equation.
Figure imgf000117_0001
Ar=C6F5
Example 15. Separation of the enantiomers of S-(2- (((benzyIamino)(perfluorophenoxy)phosphoryl)oxy) ethyl)2,2-dimethyl-3- (trityloxy)-propanethioate by SFC
1.9g of (±)-128 was subjected to SFC using a ChiralPak AS-H (2 15 cm) column and eluted with 45% 8:2 isopropanol:ethanol in carbon dioxide at 100 bar with a flow rate of 70mL/min (UV: 220 nm). An injection loading of 1.75 mL of sample at a concentration of 16 mg/mL in isopropanol was used. The two enantiomers were collected separately and the appropriate fractions of the multiple runs were combined and concentrated under reduced pressure to give 870 mg (100 % ee) of the fast moving enantiomer and 430mg (98.3 % ee) of slow moving enantiomer (Analytical method: ChiralPak AS-H (25 x 0.45 cm), Mobile phase: 40% 80:2 isopropanol :ethanol in carbon dioxide, Pressure: 100 bar, Flow rate: 3mL/min,
1 3 1
UV: 220 nm). The H and P NMR of the individual enantiomers were identical to the racemic sample. For fast moving enantiomer (128a): [α]ο25 (c=T .02 in MeOH): +6.9 ± 0.1. For slow moving enantiomer (128b): [a]D 25 (c=1.02 in MeOH): -7.0 ± 0.1. Absolute stereochemistry at phosphorous center was not determined.
Example 16. Synthesis of 131a and 132a from from 129 and 128a (fast-moving enantiomer)
Figure imgf000118_0001
132a 131a
Note: 129 was prepared according to literature procedures: Eldrup et al., J. Med Chem. 2004, 47, 2283. and McGuigan et al, J Med. Chem. 2010, 53, 4949.
a) Synthesis of 130a. To a stirred solution of 129 (172mg, 0.55mmol) in dry THF (5.6mL) was added a 1.7M solution of tert-butylmagnesium chloride in THF (1.OmL, 1.71mmol) over a period of 8 min at room temperature (23 °C). The white suspension was stirred at this temperature for 30min and then was added a solution of 128a (500mg, 0.66mmol) in THF (1.5mL) over a period of 5min. The mixture was stirred at this temperature for 18h. The reaction mixture was quenched with methanol (1 mL), solvent was evaporated under reduced pressure and the residue was chromatogrpahed using 0-5% methanol/DCM gradient to give pure product (130a) as a foamy solid (240mg, 59% yield).
130a Data: 1H NMR (CDC13, 400 MHz): δ 7.77 (s, 1H), 7.40-7.38 (m, 6H), 7.29- 7.18 (m, 14H), 5.95 (s, 1H), 5.26 (bs, 2H), 4.62 (bs, 1H), 4.50-4.45 (m, 1H), 4.43 (bs, 1H), 4.41 (bs, 1H), 4.32-4.26 (m, 1H), 4.21-4.17 (m, 1H), 4.13-3.95 (m, 4H), 4.02 (s, 3H), 3.58-3.50 (m, 1H), 3.17-3.08 (m, 2H), 3.14 (s, 2H), 1.18 (s, 3H), 1.17 (s, 3H), 0.96 (s, 3H). 31P NMR (CDC13, 162 MHz): δ 9.80 (using H3P04 as external reference set to 0 ppm). MS (ESI): m/z 883.0 [M + H]+. b) Synthesis of 131a: To a stirred solution of 130a (205mg, 0.23mmol) in methanol (2.0 mL) was added 95%> aqueous trifluoroacetic acid (0.5 mL) and the mixture was stirred at 40 °C for 6h. The solvent was evaporated and the residue was
chromatographed using 0-8%> methanol/CH2Cl2 gradient to give pure product (131a) as white foam (108 mg, 73% yield). 131a Data: 1H NMR (CD3OD, 400 MHz): δ 8.02 (s, IH), 7.32-7.25 (m, 4H), 7.21- 7.19 (m, IH), 5.97 (s, IH), 4.36-4.31 (m, 2H), 4.22 (d, J=8.8 Hz, IH), 4.16-4.14 (m, IH), 4.10-3.95 (m, 4H), 4.05 (s, 3H), 3.55 (s, 2H), 3.15 (dd, J=13.6, 6.8 Hz, IH), 3.07 (dd, J=14.0, 6.8 Hz, IH), 1.16 (s, 6H), 0.97 (s, 3H). 31P NMR (CD3OD, 162 MHz): δ 1 1.05 (using H3P04 as external reference set to 0 ppm). MS (ESI): m/z 641.0 [M + H]+. c) Synthesis of 132a. To a stirred solution of 131a (92 mg, 0.14 mmol) in acetonitrile (1.5mL) was added cerium trichloride heptahydrate (80 mg, 0.22 mmol) followed by sodium iodide (22 mg, 0.14 mmol) at room temperature. The mixture was heated at 85 °C for 6 h. The solvent was evaporated and the residue was chromatographed using 0-20% methanol/DCM gradient to give pure product (132a) as a white solid (76mg, 84 % yield).
132a Data: 1H NMR (CD3OD, 400 MHz): δ 8.01 (bs, IH), 7.45 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 7.22 (t, J=7.2 Hz, IH), 6.01 (bs, IH), 4.56-4.24 (m, 6H), 4.19 (bs, 2H), 3.54 (s, 2H), 3.24 (q, J=6.0 Hz, 2H), 1.16 (s, 6H), 1.08 (s, 3H). 31P NMR (CD3OD, 162 MHz): δ 14.94 (using H3P04 as external reference set to 0 ppm). MS (ESI): m/z 627.0 [M + H]+.
Example 17. Synthesis of 131b and 132b from from 129 and 128b (slow-moving enantiomer)
Figure imgf000119_0001
a) Synthesis of 130b. To a stirred solution of 129 (103 mg, 0.33 mmol) in dry THF (3.5 mL) was added a 1.7M solution of tert-butylmagnesium chloride in THF (0.602 mL, 1.02 mmol) over a period of 5 min at room temperature. The white suspension was stirred at this temperature for 30 min and then was added a solution of 128b (300 mg, 0.397 mmol) in THF (lmL) over a period of 5 min. The mixture was stirred at this temperature for 18 h. The reaction mixture was quenched with methanol, solvent was evaporated under reduced pressure and the residue was chromatogrpahed using 0-5% methanol/DCM gradient to give pure product (130b) as white foam (105 mg, 36 % yield).
130b Data: 1H NMR (CDC13, 400 MHz): δ 7.74 (s, 1H), 7.40-7.38 (m, 6H), 7.29- 7.18 (m, 14H), 5.94 (s, 1H), 5.35 (bs, 2H), 4.85 (bs, 1H), 4.55-4.45 (m, 2H), 4.28- 4.17 (m, 3H), 4.15-3.96 (m, 4H), 4.03 (s, 3H), 3.62-3.52 (m, 1H), 3.14 (s, 2H), 3.11 (d, J = 6.8 Hz, 2H), 1.18 (s, 6H), 0.94 (s, 3H). 31P NMR (CDC13, 162 MHz): δ 9.83 (using H3PO4 as external reference set to 0 ppm). MS (ESI): m/z 883.0 [M + H]+. b) Synthesis of 131b. To a stirred solution of 130b (85 mg, 0.10 mmol) in methanol
(1.0 mL) was added 95% aqueous trifluoroacetic acid (0.3 mL) and the mixture was stirred at 40 °C for 6h. The solvent was evaporated and the residue was
chromatographed using 0-8% methanol/CH2Cl2 gradient to give pure product (131b) as white solid (45 mg, 73 % yield).
131b Data: 1H NMR (CD3OD, 400 MHz): δ 7.98 (s, 1H), 7.33-7.30 (m, 2H), 7.27- 7.23 (m, 2H), 7.20-7.18 (m, 1H), 5.96 (s, 1H), 4.40 (ddd, J=1 1.6, 5.6, 2.2 Hz, 1H), 4.36-4.32 (m, 1H), 4.22-4.15 (m, 2H), 4.10-3.96 (m, 4H), 4.06 (s, 3H), 3.55 (s, 2H), 3.10 (t, J=6.6 Hz, 2H), 1.17 (s, 6H), 0.95 (s, 3H). 31P NMR (CD3OD, 162 MHz): δ 1 1.16 (using H3PO4 as external reference set to 0 ppm). MS (ESI): m/z 641.0 [M + H]+. c) Synthesis of 132b. To a stirred solution of 131b (36 mg, 0.056 mmol) in acetonitrile (lmL) was added cerium trichloride heptahydrate (31 mg, 0.084 mmol) followed by sodium iodide (8.4 mg, 0.056 mmol) at room temperature. The mixture was heated at 85 °C for 4h. The solvent was evaporated and the residue was chromatographed using 0-20% methanol/DCM gradient to give pure product (132b) as a white solid (32 mg, 91 % yield).
132b Data: 1H NMR (CD3OD, 400 MHz): δ 8.09 (bs, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28 (t, J=7.6 hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.02 (bs, 1H), 4.58-4.52 (m, 1H), 4.48- 4.42 (m, 1H), 4.36-4.18 (m, 6H), 3.55 (s, 2H), 3.21 (bt, J=6.0 Hz, 2H), 1.17 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H). 31P NMR (CD3OD, 162 MHz): δ 14.57 (using H3P04 as external reference set to 0 ppm). MS (ESI): m/z 627 [M + H]+. Example 18. Synthesis of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6- methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate(133).
Figure imgf000121_0001
129 118 133
To a stirred solution of 129 (208mg, 0.67mmol) in dry THF (4mL) was added a 1.7M solution of tert-butylmagnesium chloride in THF (1.22mL, 2.07mmol) over a period of 5min at 21 °C. The white suspension was stirred at this temperature for 30min and was added a solution of 118 (see Example 6) (360mg, 0.8mmol) in THF (5mL) over a period of 15min using a syringe pump. The mixture was stirred at 21 °C for 18h and then quenched with methanol. The solvent was evaporated and the residue was chromato graphed using 0-6% methanol/dichloromethane gradient to give pure product 133 as a white solid (196 mg, 51% yield).
133 Data: 1H NMR (DMSO- , 400 MHz): δ 7.93 (s, 1H), 7.34 (t, J=7.4Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 7.15(t, J=7.4Hz, 1H), 6.51 (s, 1H), 5.97 (dd, J=12.8, 10.0 Hz, 1H), 5.83 (s, 1H), 5.38-5.37 (m, 1H), 5.22 (s, 1H), 4.78 (septet, J=6.4Hz, 1H), 4.35 (dd, J=11.0, 6.2Hz, 1H), 4.26 (quintet, J 5.8Hz, 1H), 4.03 (bs, 2H), 3.94 (s, 3H), 3.80-3.74 (m, 1H), 1.19 (d, J=6.8, 3H), 1.09 (d, J=6.4Hz, 3H), 1.07 (d, J=6.4Hz, 3H),0.79 (s, 3H). MS (ESI): m/z 581.0 [M + H]+.
Example 19. Synthesis of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2-amino-6- oxo-lH-purin-9(6H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (134).
Figure imgf000121_0002
133 134
To a stirred solution of 133 (160mg, 0.28mmol) was added
cerium(III)chloride heptahydrate (154mg, 0.414mmol) and sodium iodide (41mg, 0.276mmol) at room temperature (21 °C). The mixture was heated at 85 °C for 6h. The solvent was evaporated and the residue was chromatographed using 0-15% methanol/dichloromethane gradient to give pure product 134 as a white solid (55mg, 35% yield).
134 Data: 1H NMR (DMSO-rf6, 400 MHz): δ 10.63 (bs, IH), 7.76 (s, IH), 7.34 (t, J=8.0Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 7.15 (t, J=7.2Hz, IH), 6.53 (bs, 2H), 5.99 (dd, J=12.8, 10.4Hz, IH), 5.73 (s, IH), 5.65 (d, J=6.4Hz, IH), 5.19 (s, IH), 4.79 (septet, J=6.4Hz, IH), 4.33 (dd, J=11.0, 6.4Hz, IH), 4.24 (quintet, J=5.8Hz, IH), 4.03-3.93 (m, 2H), 3.82-3.72 (m, IH), 1.19 (d, J=6.8Hz, 3H), 1.09 (t, J=10.8Hz, 6H), 0.80 (s, 3H). MS (ESI): m/z 566.9 [M + H]+.
Compound 44 is a non-nucleoside NS5B inhibitor of Hepatitis C with a free primary hydroxyl. A chiral phosphoramidate has the advantage of making a single enantiomer and uniform physical properties to aid in development. Compound 44 itself was prepared by literature methods (WO 2004/041201 ; US 7,265,152).
Example 20. HCV-796 chiral phosphoramidate derivative:
Synthesis of (S)-isopropyl 2-(((S)-(2-(N-(5-cyclopropyl-2~(4-fluorophenyl)-3-
Figure imgf000122_0001
44 118 135
To a dry 50 mL of round-bottomed flask were added 50 mg (0.1 1 mmol) of 44 and 1 mL of anhydrous tetrahydrofuran. The clear solution was cooled to 0°C in an ice-water bath. Grignard reagent (1 M solution in THF, 0.18 mmol) was added via a syringe slowly and the mixture was stirred at 0 °C for half hour. A solution of the 118 (71 mg, 0.16 mmol) in 1 mL of THF was added dropwise at 0 °C. The mixture was stirred at room temperature for 14 hours. The reaction was complete and sat'd NH4C1 was added. The mixture was diluted with ethyl acetate and water. Organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was washed with water (8 mL), sat. sodium bicarbonate (2 x 10 mL), 1 M sodium carbonate (8 mL), water (8 mL), brine (8 mL), and dried over sodium sulfate. After removal of solvent, the solid residue was purified via column chromatography (silica gel, 1% MeOH in DCM) to afford 76 mg (0.1 1 mmol, 95%) of product 135 as a white amorphous solid.
135 Data: Ή NMR (CDC13) 6 7.89-7.84 (m, 2 H), 7.54-7.50 (m, 1 H), 7.33-7.26 (m, 3 H), 7.22-7.1 1 (m, 5 H), 5.94-5.90 (m, 1 H), 4.98 (heptd, 1 H), 4.29-4.08 (m, 3 H), 4.00-3.75 (m, 2 H), 3.68-3.62 (m, 1 H), 3.05-3.01 (m, 3 H), 2.97 (d, 3 H), 2.28- 2.21 (m, 1 H), 1.32 (d, 3 H), 1.23-1.19 (m, 6 H), 1.05-1.01 (m, 2 H), 0.97-0.92 (m, 1 H), 0.65-0.61 (m, 1 H).
Example 21. Synthesis of (2S)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-6- methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(naphthalen-l-yloxy)phosphoryl)amino)propanoate
Figure imgf000123_0001
129 136 137
C5F6; Np = naphth a) Preparation of (2S)-neopentyl 2-(((naphthalen-l- yloxy)(perfluorophenoxy)phosphoryl)amino)propanoate (136), as its
diastereomeric mixture, chiral separation into two pure diastereomers 136a (fast-moving diastereomer) and 136b (slow-moving diastereomer)
Ar = C5
Figure imgf000123_0002
a-Naphthyl phosphorodichloridate (10.0 g, 38.46 mmol) was dissolved in 40 mL of dry dichloromethane and subsequently cooled to 0 °C. After addition of solid (L)-alanine neopentyl ester />-toluenesulfonic acid salt (12.7 g, 38.46 mmol), the reaction mixture was cooled to -70 °C and then treated with triethylamine (11.2 mL, 77.0 mmol) dissolved in 50 mL of dry DCM. The resulting mixture was stirred for 30 min at this temperature before being allowed to warm to 0 °C. Subsequently, a preformed solution of pentafluorophenol (7.07 g, 38.46 mmol) and triethylamine (5.9 mL, 42.32 mmol) dissolved in 20 mL of dry DCM was added over 5-10 min and was continued stirring for additional 2h. The solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in 50 mL of TBME and stirred for 10 min at room temperature.
Subsequent filtration removed more triethylamine hydrochloride and yielded a filtrate that was again stripped of its solvent under reduced pressure. Column chromatography (dichloromethane) yielded the desired product (14.7 g, 72% yield) as solid diastereomeric mixture.
136 Data: 1H NMR (CDC13, 400 MHz) δ: 8.13-8.10 (m, 1 H), 7.88-7.86 (m, 1 H), 7.72-7.70 (m, 1 H), 7.62-7.52 (m, 3 H), 7.44-7.40 (m, 1 H), 4.32-4.27 (m, 1 H), 4.14-4.09 (m, 1 H), 3.90-3.73 (m, 2 H), 1.47 (d, 3 H), 0.93 (s, 9 H, isomer I), 0.90 (s, 9 H, isomer II). 31P NMR (CDC13, 162 MHz) δ -0.54, -0.59.
1.9 g of 136 was separated by supercritical fluid chromatography (SFC) using a ChiralPak AD-H column (2 x 15 cm), and eluting with 20% isopropanol/C02, 100 bar, 65 mL/min, 220 nm, injection volume of 0.3 mL, 33 mg/mL methanol to yield 930 mg of 136a (fast-moving diastereomer) (> 99% ee) and 930 mg of 136b (slow- moving diastereomer) (> 99% ee).
136a NMR data: 1H NMR (CDC13, 400 MHz) 6, ppm: 8.12 (d, J = 8.0 Hz, 1H), 7.87 (d, J= 7.2 Hz), 7.71 (d, J= 8.0 Hz, 1H), 7.62-7.53 (m, 3H), 7.42 (t, J= 8.0 Hz, 1H), 4.35-4.20 (m, 2H), 3.89 (d, J= 10.4 Hz, 1H), 3.81 (d, J= 10.4 Hz, 1H), 1.47 (d, J= 6.9 Hz, 3H), 0.93 (s, 9H); 31P NMR (CDC13, 162 MHz) δ, ppm: 10.87 (s).
136b NMR data: 1H NMR (CDC13, 400 MHz) δ, ppm: 8.16 (d, J = 8.0 Hz, 1H), 7.87 (d, J= 7.2 Hz), 7.71 (d, J= 8.0 Hz, 1H), 7.62-7.53 (m, 3H), 7.40 (t, J= 8.0 Hz, 1H), 4.35-4.22 (m, 1H), 4.19-4.10 (m, 1H), 3.85 (d, J = 10.4 Hz, 1H), 3.78 (d, J= 10.4 Hz, 1H), 1.47 (d, J= 6.9 Hz, 3H), 0.93 (s, 9H); 31P NMR (CDC13, 162 MHz) 6, ppm: 10.91 (s). b) Preparation of 137a from 136a (fast-moving diastereomer) and 129. To a dry 10 mL one-neck round bottom flask equipped with an rubber septum, magnetic stir bar and nitrogen inlet/outlet was charged 0.1050 g of 129
(prepared based on an adaptation of literature methods; see Eldrup et al, J Med Chem. 2004, 47, 2283. and McGuigan et al., J. Med. Chem. 2010, 53, 4949.) and 1.6 mL of anhydrous THF under nitrogen. The slurry was cooled in to 0 °C. 1.0 mL of t-butyl magnesium chloride solution (1 M in THF) was added via a syringe over 2-3 mins. The slurry was stirred at 0-5 °C for 20 mins. To this was added a solution of 0.186 g of (2S)-neopentyl 2-(((naphthalen-l- yloxy)(perfluorophenoxy)phosphoryl)amino)-propanoate, 136b (fast-moving diastereomer) in 1 mL of anhydrous THF. The reaction was allowed to warm up to 20 °C and stirred at 20 °C for 2 hours at which point HPLC indicated complete consumption of 136. The reaction was quenched by the addition of 1 mL of 1 N HC1 followed by removing THF by rotary evaporation. The mixture was diluted with 9 mL of EtOAc and 2 mL of water and transferred to a seperatory funnel. The bottom aqueous layer was extracted with 2 mL of EtOAc and the combined organic layers were washed with water (1 x 2 mL), saturated NaHC03 (2 x 1.5 mL), 1 M Na2C03 (2 x 1.5 mL), and water (2 x 2.0 mL). The organic layer was dried over MgS04, filtered, and concentrated via rotary evaporation to furnish the crude product as a white foam, which was purified by flash column chromatography to yield 0.0808 grams (36% yield) of (S)-neopentyl 2- (((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4- methyltetrahydrofuran-2-yl)methoxy)(naphthalen-l-yloxy)phosphoryl)amino) propanoate, 137a, as a white foam.
137a Data: UPLC-MS: m + 1 = 659; 1H NMR (CDC13, 400 MHz) δ, ppm: 8.12- 8.10 (m, 1H), 7.80-7.79 (m, 1H), 7.64-7.62 (m, 2H), 7.62-7.46 (m, 2H), 7.35 (t, J= 8 Hz, 1H), 5.90 (s, 1H), 5.34 (br s, 2H), 4.87-4.82 (m, 2H), 4.49-4.42 (m, 2H), 4.40- 4.23 (m, 2H), 4.15-4.05 (m, 2H), 4.02 (s, 3H), 3.78 (d, J= 10 Hz, 1H), 3.64 (d, J = 10 Hz, 1H), 2.30 (br s), 2.09 (br s), 1.34 (d, J= 7.0 Hz, 3H), 0.89 (s, 3H), 0.85 (s, 9H); 31P NMR (CDC13> 162 MHz) δ, ppm: 4.09 (s). c) Preparation of 137b from 136b (slow-moving diastereomer) and 129.
To a dry 10 mL one-neck round bottom flask equipped with an rubber septum, magnetic stir bar and nitrogen inlet/outlet was charged 0.1079 g of 129 and 2.0 mL of anhydrous THF under nitrogen. The slurry was cooled in to 0 °C. 1.0 mL of t-butyl magnesium chloride solution (1 M in THF) was added via a syringe over 2-3 mins. The slurry was stirred at 0-5 °C for approx. 20 mins. To this was added a solution of 0.2642 g of 136b (slow-moving diastereomer) in 1.5 mL of anhydrous THF.
The reaction was allowed to warm up to 20 °C and stirred at 20 °C for 2 hours at which point HPLC indicated complete consumption of 136. The reaction was quenched by the addition of 1 mL of 1 N HC1 followed by removing THF by rotary evaporation. The mixture was diluted with 9 mL of EtOAc and 2 mL of water and transferred to a seperatory funnel. The bottom aqueous layer was extracted with 2 mL of EtOAc and the combined organic layers were washed with water (1 x 2 mL), saturated NaHC03 (2 x 1.5 mL), 1 M Na2C03 (2 x 1.5 mL), and water (2 x 2.0 mL). The organic layer was dried over MgS04, filtered, and concentrated via rotary evaporation to furnish the crude product as a white foam, which was purified by flash column chromatography to yield 0.0724 grams (32% yield) of 137b as a white foam. 137b Data: UPLC-MS: m + 1 = 659; 1H NMR (CDC13; 400 MHz) δ, ppm: 8.12- 8.10 (m, IH), 7.82-7.79 (m, IH), 7.70 (s, IH), 7.64-7.62 (m, IH), 7.61-7.46 (m, 2H), 7.38-7.33 (m, IH), 5.90 (s, IH), 5.32 (br s, 2H), 4.70-4.66 (m, 2H), 4.58 (br s, IH), 4.48-4.10 (m, 6H), 4.05 (s, 3H), 3.78 (d, J= 10 Hz, IH), 3.64 (d, J= 10 Hz, IH), 2.43 (br s), 2.12 (br s), 1.35 (d, J= 7.0 Hz, 3H), 0.89 (s, 3H), 0.85 (s, 9H); 31P NMR (CDC13,162 MHz) δ, ppm: 4.47 (s).
Example 22. Synthesis of (S)-2-{(S)-[(2R,3R,4R,5R)-5-(4-amino-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]- phenoxy-phosphorylamino}-propionic acid isopropyl ester (139)
Figure imgf000126_0001
138 118 139
To a 50 mL of dry round-bottemed flask were added the nucleoside 138 (prepared as disclosed in US 6,777,395) (100 mg, 0.36 mmol) and 1.5 mL of anhydrous THF. The white suspension was cooled to 0 °C in an ice-water bath.
Grignard reagent (1 M solution in THF, 1.2 mL) was added via a syringe dropwise.
The resulting cloudy mixture was stirred at 0 °C for 30 min before a solution of the phosphorus reagent in 1.5 mL of THF was added via a syringe drop wise at 0 °C. The resulting clear reaction solution was allowed to warm up to room temperature and stirred for 22 hours. The reaction was quenched by adding sat NH4C1. The mixture was diluted with ethyl acetate (40 mL). After separation of two layers, the aqueous layer was extracted with EtOAc (10 ML). Combined organic layer was washed with water (10 ML), sat NaHC03 (2 x 10 mL), brine (10 mL), and dried over Na2S04. Removal of solvent afforded a sticky oil residue. The residue was purified via column chromatography (silica gel, 5% MeOH in DCM) to furnish product as a white amorphous solid (129 mg, 0.23 mmol, 66%).
139 Data: 1H NMR (CDC13, 400 MHz) δ: 8.27 (s, 1 H), 7.30-7.22 (m, 4 H), 7.13- 7.08 (m, 2 H), 6.35 (d, 1 H), 6.31 (s, 1 H), 5.82 (s, 2 H), 4.96 (hepta, 1 H), 4.63-4.58 (m, 1 H), 4.54-4.50 (m, 1 H), 4.45-4.40 (m, 1 H), 4.23-4.21 (m, 1 H), 4.05-3.95 (m, 2 H), 1.33 (d, 3 H), 1.18-1.13 (m, 6 H), 0.74 (s, 3 H). J 1P NMR (CDC13, 162 MHz) 5: 4.14.
Example 23. Synthesis of (2S)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-6- methoxy-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(naphthalen-l-yloxy)phosphoryl)amino)propanoate (140)
Figure imgf000127_0001
Ar = C5F6; Np = naphth-l-yl To a dry 100 mL one-neck round bottom flask equipped with an rubber septum, magnetic stir bar and nitrogen inlet/outlet was charged 2.0 g of 9a and 12 mL of anhydrous THF under nitrogen. The slurry was cooled in to 0 °C. 8.0 mL of t-butyl magnesium chloride solution (1 M in THF) was added via a syringe over 10 mins. The slurry was stirred at 0-5 °C for 30 mins. To this was added a solution of 3.90 g of 136 in 20 mL of anhydrous THF.
The reaction was allowed to warm up to 20 °C and stirred at 20 °C for 4 hours at which point HPLC indicated complete consumption of 136. The reaction was quenched by the addition of 20 mL of 1 N HC1 followed by removing THF by rotary evaporation. The mixture was diluted with 100 mL of EtOAc and 12 mL of water and transferred to a seperatory funnel. The bottom aqueous layer was extracted with 12 mL of EtOAc and the combined organic layers were washed with water (1 x 24 mL), saturated NaHC03 (2 x 20 mL), 1 M Na2C03 (3 x 20 mL), and water (2 x 20 mL). The organic layer was dried over MgS04, filtered, and concentrated via rotary evaporation to furnish the crude product as a white foam, which was purified by flash column chromatography to yield 2.59 grams (63% yield) of (2S)-neopentyl 2-(((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9- yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-l- yloxy)phosphoryl)amino) propanoate (140) as an off-white foam.
140 Data: UPLC-MS: m + 1 = 661 ; 1H NMR (CDC13; 400 MHz) δ, ppm: 8.13-8.09 (m, 1H), 7.82-7.78 (m, 1H), 7.63-7.59 (m, 1H), 7.53-7'.46 (m, 3H), 7.37-7.32 (m, 1H), 6.00 (dd, J= 19, 6 Hz, 1H), 5.21 (br s, 2H), 4.86-4.78 (m, 1H), 4.74-4.65 (m, 1H), 4.52-4.46 (m, 1H), 4.30-4.20 (m, 1H), 4.12-4.06 (m, 1H), 4.02 (d, J= 3 Hz, 3H), 3.77 (dd, J= 6, 10 Hz, 1H), 3.63 (dd, J= 6, 10 Hz, 1H), 1.38 (t, J= 6 Hz, 3H), 19, 6 Hz, 3H), 0.85 (s, 9H); J 1P NMR (CDC13, 162 MHz) δ, ppm: 5.45
The above-recited examples can be modified by one of ordinary skill without undue experimentation in order to obtain compositions containing enantiomerically- or diastereomerically-enriched compositions comprised of a compound of formula I, a compound of formula II, or a compound of formula III. The above-recited examples can be modified by one of ordinary skill without undue experimentation in order to obtain compositions containing enantiomerically- or diastereomerically- enriched compositions comprised of a compound of formula I or a compound of formula III where the active is comprised of any one of the compounds 1-90 (less one or more hydrogen atoms).
Preparation of compounds falling within the scope of Compound III
It is contemplated that a compound represented by formula III can be prepared by the following scheme,
LG—
Figure imgf000128_0001
as disclosed in WO 2008/079206 (US 2010/0022468).
Biological Activity
HCV inhibition assay. Clone A or ET-lunet cells were seeded at a density of 1500 or 3000 cells per well in a 96-well plate, respectively. Test compounds serially diluted in culture medium without G418 were added to cells so that the final DM SO concentration was 0.5%. Plates were incubated at 37°C in a 5% C02 atmosphere for 4 days. Inhibition of HCV RNA replication was determined by real time PCR (RT-PCR) or by measuring the levels of luminescence expressed via the luciferase reporter gene encoded within the ET replicon. Briefly, for the RT-PCR assay, total RNA was extracted using the RNeasy-96 kit as recommended by the manufacturer (Qiagen, Valencia, CA), reversed transcribed into cDNA, and amplified using primer and probe mix for HCV 5'-NTR RNA and human ribosomal RNA (rR A) in a one-step RT-PCR reaction as described previously (Stuyver, L. J. et al. Antiviral Chem. Chemother. (2006) 17, 79-87). A relative quantification method was used to determine the extent of inhibition. The threshold cycle (Ct) of rRNA was subtracted from the Q of HCV RNA (ACt). The average AQ of the DMSO cell controls was then subtracted from the ACt of the compound treated sample (AACt). Percent inhibition was determined by using the following equation: % = (l-(2"AACt)) x 100. For the luciferase-based replicon assay, luminescence was measured by using a Victor3 plate reader (Perkin-Elmer, Boston, MA) following the addition of Bright-Glo reagent as recommended by the manufacturer (Promega, Madison, WI). Percent inhibition of HCV replication was determined by comparing the change in luminescence of the drug treated wells versus the DMSO cell controls. EC50 and EC90 values, the concentrations at which 50% and 90% inhibition were achieved, were determined using the GraphPad Prism software (San Diego, CA).
Cell cytotoxicity assays. Each compound (serially diluted from 100 μΜ) was added to Huh7 (2 x 103 cells/well), HepG2 (2 x 103 cells/well), BxPC3 (2 x 103 cells/well), or CEM (5 x 103 cells/well) cells and allowed to incubate for 8 days at 37°C. A medium only control was used to determine the minimum absorbance value and an untreated cell. At the end of the growth period, MTS dye from the CellTiter 96 Aqueous One Solution Cell Proliferation Assay kit (Promega) was added to each well and the plate was incubated for an additional 2 hours. The absorbance at 490 nm was read with a Victor3 plate reader (Perkin Elmer) using the medium only control wells as blanks. The 50% inhibition value (CC50) was determined by comparing the absorbance in wells containing cells and test compound to untreated cell control wells.
Compound EC90 (μΜ) CC50 (μΜ)
110 0.22 >20
117 0.13 >20
140 0.0035 >20
137 0.0017 >1
137a 0.0037 0.93
137b 0.0036 1.84
133 0.078 4.14
134 0.56 >20
132 0.30 >10
132a 0.30 >20 Compound EC90 (μΜ) CC50 (μΜ)
132b 0.35 >20
131a 0.093 >20
131b 0.186 >20
44 0.020 >10a
135 0.081 >20
138 5.56b 800a
139 0.020 >10
'MTT Assay; bPCR
This application claims priority to US 61/319,513, filed on March 31, 2010 and US 61/319,548, filed on March 31 , 2010, the subject matter of which is incorporated by reference in its entirety.
The subject matter of U.S. Patent Application Nos. 12/053,015 filed on
March 21, 2008; 12/783,680, filed May 20, 2010 is hereby incorporated by reference in its entirety. The subject matter of U.S. Provisional Patent Application No.
61/179,923, filed May 20, 2009, 61/319,513, filed March 31 , 2010, and 61/319,548, filed on March 31, 2010 is incorporated by reference in its entirety. The essential subject matter of all cited references is hereby incorporated by reference. In the event that the meaning of an incorporated term conflicts with the meaning of a term defined herein, the meaning of the term contained in the present disclosure controls over the meaning of the incorporated term.

Claims

Claims
1. A process for preparing a composition comprising an enantiomerically- or a diastereomerically-enriched phosphorus-containing active, salt, or
pharmaceutically acceptable salt thereof, of formula I:
O
Active p II*— Group
I
ow
I
which comprises
a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with an enantiomerically- or a
diastereomerically enriched compound of formula II
Figure imgf000131_0001
II
wherein Group is as defined herein, W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1 , 2, or 3, and LG is a leaving group;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain the active.
2. The process of claim 1, wherein the base is a basic reagent.
3. The process of claim 1 , wherein the Active is a nucleoside, a nucleoside- analog, or a non-nucleoside compound.
4. The process of claim 3, wherein the nucleoside is selected from among compounds 1-8, 10-13, 15-20, 22, 24-26, 28-32, 39, and 41-43.
5. The process of claim 3, wherein the nucleoside-analog is selected from among compounds 33-38 and 40.
6. The process of claim 3, wherein the non-nucleoside compound is selected from among compounds 44-90.
7. The process of claim 1, wherein the compound of formula II is obtained a process that comprises:
1 ) reacting (LG)P(0)(LG')2, wherein LG', independent of LG, is a leaving group, with
(i) a Group-precursor, as defined herein, and a first base to obtain (LG)P(0)(LG')(Group) followed by reacting
(LG)P(0)(LG')(Group) with HOW and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different,
(ii) HOW and a first base to obtain (LG)P(0)(LG')(OW) followed by reacting (LG)P(0)(LG')(OW) with a Group-precursor and a second base to obtain a mixture comprising
(LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different, or
(iii) combining a Group-precursor, HOW, and at least one base to obtain a mixture comprising (LG)P(0)(OW)(Group); or
2) reacting (WO)P(0)(LG')2, wherein LG' is a leaving group, with
(i) a Group-precursor and a first base to obtain
(WO)P(0)(LG')(Group) followed by reacting
(WO)P(0)(LG')(Group) with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different.
8. The process of claim 1, wherein the compound of formula II is obtained by a process that comprises:
reacting (WO)P(0)(LG')2, wherein LG' is a leaving group, with (i) a Group- precursor and a first base to obtain (WO)P(0)(LG')(Group) followed by reacting (WO)P(0)(LG')(Group) with a leaving group precursor and a second base to obtain a mixture comprising (LG)P(0)(OW)(Group), wherein the first base and the second base are the same or different.
9. The process of claim 8, wherein LG' is chloride and W is an aryl or
-(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3.
10. The process of claim 9, wherein the Group is derived from an amino- acid derivative or acid-addition salt (HX) thereof having the following structure:
Figure imgf000133_0001
wherein R is a substituent found in a naturally occurring amino acid and R' is a C1-6alkyl or C3-7cycloalkyl.
1 1. The process of claim 10, wherein R is methyl or isopropyl.
12. A process for preparing a composition comprising an enantiomerically or a diastereomerically enriched phosphorus-containing active, salt, or
pharmaceutically acceptable salt thereof, of formula 1-1:
0 R
II * H I *
Active p N— C— COOR'
1 H
ow
I- 1
which comprises
a) reacting a protected or unprotected Active with a base to form a salt of said active and then reacting said salt with a compound of formula II-l
Figure imgf000133_0002
II- l
wherein
the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside compound; W is an aryl or -(CH2)nSC(0)C(CH3)m(CH2OH)3-m, where n is 2 or 3 and m is 0, 1, 2, or 3; LG is a leaving group; R is a radical observed in any one of the naturally occurring amino acids, or R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkoxide, a substituted or unsubstituted aryl; and R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkaryl, or a substituted or unsubstituted aryl;
b) optionally deprotecting the compound obtained in step a) and
c) optionally subjecting the compound obtained in step a) or the compound obtained in step b) to chromatography, extraction, or crystallization to obtain compound II- 1.
13. The process of claim 12, wherein the base is a basic reagent.
14. The process of claim 12, wherein the Active is a nucleoside, a nucleoside-analog, or a non-nucleoside compound.
15. The process of claim 14, wherein the nucleoside is selected from among compounds 1-8, 10-13, 15-20, 22, 24-26, 28-32, 39, and 41-43.
16. The process of claim 15, wherein R is a radical observed in any one of the naturally occurring amino acids and R' is a Ci_6alkyl or C3-7cycloalkyl.
17. The process of claim 15, wherein R is methyl or isopropyl and R' is a C1-6alkyl or C3-7cycloalkyl.
18. The process of claim 17, wherein the LG is an aryloxide substituted with at least one electron withdrawing group.
19. The process of claim 17, wherein the LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
20. The process of claim 14, wherein the nucleoside-analog is selected from among compounds 33-38 and 40.
21. The process of claim 14, wherein the non-nucleoside compound is selected from among compounds 44-90.
22. A process for preparing a compound having the structure:
Figure imgf000135_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000135_0002
with a basic reagent to form a salt of the first compound, where Z' is hydrogen or a protecting group and Y is =0 or -OC1-6alkyl, with proviso that is a single bond and n is 1 when Y is =0, and is a double bond and n = 0 when Y is -OCi-6alkyl;
b) reacting the salt of the first compound with a second compound having the structure, Bn .
Figure imgf000136_0001
where LG is a leaving group, Z is hydrogen or a protecting group, and Bn is -CH2Ph; and
c) optionally deprotecti-ng.
23. The process of claim 22, wherein Z is hydrogen and Z' is hydrogen.
24. The process of claim 23, wherein LG is an aryloxide having at least one electron withdrawing group.
25. The process of claim 23, wherein LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
26. The process of claim 25, wherein the basic reagent is a Grignard reagent.
27. The process of claim 26, wherein the basic reagent is a t- butylmagnesium halide.
28. The process of claim 26, wherein the basic reagent is t-butylmagnesium bromide or t-butylmagnesium chloride.
29. A process for preparing a compound having the structure
Figure imgf000137_0001
which comprises:
a) reacting a first compound having the structure
Figure imgf000137_0002
with a basic reagent to form a salt of the first compound, where Z' is hydrogen or a protecting group;
b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000137_0003
where LG is a leaving group and Np is naphthalen-l-yl; and
c) optionally deprotecting.
30. The process of claim 29, wherein Z' is hydrogen.
31. The process of claim 30, wherein LG is an aryloxide having at least one electron withdrawing group.
32. The process of claim 30, wherein LG is selected from among 2- nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2- chloro-4-nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
33. The process of claim 32, wherein the basic reagent is a Grignard reagent.
34. The process of claim 32, wherein the basic reagent is a t- butylmagnesium halide.
35. The process of claim 32, wherein the basic reagent is t-butylmagnesium bromide or t-butylmagnesium chloride.
A process process for preparing a compound having the structure
Figure imgf000138_0001
which comprises:
a reacting a first compound having the structure
Figure imgf000138_0002
with a basic reagent to form a salt of the first compound, b) reacting the salt of the first compound with a second compound having the structure
Figure imgf000139_0001
where LG is a leaving group and R is a Ci-6alkyl or a C3-7 cycloalkyl.
37. The process of claim 36, wherein LG is an aryloxide having at least one electron withdrawing group.
38. The process of claim 36, LG is selected from among 2-nitrophenoxide, 4-nitrophenoxide, 2,4-dinitrophenoxide, pentafluorophenoxide, 2-chloro-4- nitrophenoxide, 2,4-dichlorophenoxide, and 2,4,6-trichlorophenoxide.
39. The process of claim 38, wherein the basic reagent is a t- butylmagnesium halide.
40. The process of claim 38, wherein the basic reagent is t-butylmagnesium bromide or t-butylmagnesium chloride.
41. A compound having the following structure:
Figure imgf000139_0002
wherein R is a Ci-6alkyl or a C3-7 cycloalkyl and the Active is comprised of any one of the following chemical structures less at least one hydrogen on a primary or secondary hydroxyl group
Figure imgf000139_0003
Figure imgf000140_0001
Figure imgf000141_0001
42. A process for preparing the compound of claim 41 , which comprises a) reacting any one of the so-noted compounds with basic reagent to obtain ι of any one of the compounds; and
b) reacting the salt of any one of the compounds with
Figure imgf000141_0002
43. The process of claim 42, wherein LG is an aryloxide having at least one electron withdrawing group.
44. The process of claim 43, wherein the basic reagent is a Grignard reagent.
45. The process of claim 44, wherein the Grignard reagent is a t- butylmagnesium halide.
46. The process of claim 45, wherein the t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 2.5 relative to any one of the compounds.
47. The process of claim 46, wherein the t-butylmagnesium halide is present in a mole equivalent amount of about 1 , about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0 about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5 relative to any one of the compounds.
48. The process of claim 46, wherein the t-butylmagnesium halide is present in a mole equivalent amount of about 1 to about 1.1 relative to any one of the compounds.
49. The process of claim 46, wherein the t-butylmagnesium halide is present in a mole equivalent amount of about 2 to about 2.1 relative to any one of the compounds.
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