WO2010141494A2 - Synthèse d'ézétimibe - Google Patents

Synthèse d'ézétimibe Download PDF

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WO2010141494A2
WO2010141494A2 PCT/US2010/036938 US2010036938W WO2010141494A2 WO 2010141494 A2 WO2010141494 A2 WO 2010141494A2 US 2010036938 W US2010036938 W US 2010036938W WO 2010141494 A2 WO2010141494 A2 WO 2010141494A2
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formula
compound
alkyl
substituted
imine
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WO2010141494A3 (fr
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Steven J. Collier
Jack Liang
Jasyln Fu Fan
Robert John Wilson
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Codexis Inc
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Codexis Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present disclosure relates to an improved process for the preparation of Ezetimibe (l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone) and Ezetimibe derivatives.
  • Ezetimibe l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone
  • Such compounds are useful as hypocholesterolemic agents in the prevention and treatment of atherosclerosis.
  • Ezetimibe is the active ingredient in ZETIA ® , manufactured by Merck/Schering-Plough Pharmaceuticals, and is approved by the United States Food and Drug Administration for use in patients with high cholesterol to reduce LDL cholesterol and total cholesterol (see e.g., US 6,207,822). Ezetimibe lowers high levels of blood cholesterol by selectively inhibiting the intestinal absorption of cholesterol and related phytosterols. Ezetimibe is commercially available in combination with simvastatin in the VYTORINTM formulation from MSP Pharmaceuticals, Inc.
  • WO 2008/151324 discloses a method of using a ketoreductase enzyme to create ezetimibe from the corresponding alcohol. This "late reduction" scheme delays the reduction of the alcohol to the carbonyl to the last step of the reaction.
  • US 6,133,001 and WO 2000/060107 also disclose a microbial late reduction process done under whole cell fermentation conditions.
  • the present disclosure provides a process for preparing azetidinines and azetidinones, or pharmaceutically acceptable salts, solvates, and prodrugs thereof.
  • R 1 is H, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted heteroaryl;
  • Y is O or S;
  • X is O, S, or N(Ci- C 6 alkyl);
  • R 3 is C 3 -C 6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C 3 -C 6 alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1 -3 substituents selected from the group consisting Of Ci-C 6 alkyl, phenyl and benzyl;
  • R 4 is a hydroxyl protecting group;
  • R 5 is NH 2 , OR a
  • R 1 is a substituted or unsubstituted phenyl group. In some embodiments R 1 is para- fluorophenyl. In some embodiments, when R 5 is OR a , then at least one of R 7 and R 8 is NH 2 or Z, where Z is Cl, Br, or I. In some embodiments, Z is Cl or Br. In some embodiments, R 5 is not Z. In some embodiments, X and Y are both independently O. In some embodiments, R 3 is phenyl. In some embodiments, R f is trimethylsilyl (TMS). In some embodiments, R a is trimethylsilyl (TMS). In some embodiments, R 4 is trimethylsilyl (TMS).
  • the group B(OR b )(OR c ) is a group of Formula Bl or B2:
  • one or more of the compounds of Formulas IV and V produced in Scheme 1 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IV and V produced in Scheme 1 are chirally pure.
  • the disclosure provides the process of Scheme 2, in which the chiral alcohol of Formula Hf and an imine of Formula IHf are condensed to form a ⁇ -(substituted- amino)amide of Formula IVf.
  • the ⁇ -(substituted-amino)amide of Formula IVf is cyclized with a silylating agent and a cyclizing agent to form a compound of Formula Vf.
  • the hydroxy protecting group is then removed from the compound of Formula Vf to afford a compound of Formula Vh, which is then oxidized to the final compound of Formula If.
  • Ph is phenyl
  • R 4 is a hydroxyl protecting group.
  • R 4 is TMS.
  • one or more of the compounds of Formulas IVf, Vf, VIf, and If produced in Scheme 2 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVf, Vf, VIf, and If produced in Scheme 2 are chirally pure.
  • the disclosure provides the process of Scheme 3, in which the chiral alcohol of Formula lib and an imine of Formula IX are condensed to form a ⁇ -(substituted- amino)amide of Formula X.
  • the ⁇ -(substituted-amino)amide of Formula X is cyclized with a silylating agent and a cyclizing agent to form a compound of Formula VIII.
  • R 4 is a hydroxyl protecting group
  • R 14 and R 15 are each independently H, OR S , Z, or OCH 3 , where Z is F, Cl, Br, or I and R s is a hydroxyl protecting group
  • R 16 is H, or OR h , where R h is a hydroxyl protecting group
  • R b and R c are independently H, Ci-C 6 alkyl, or R b and R c together form a 5-6 membered ring
  • Y is O or S
  • X is O, S, or N(Ci-C 6 alkyl)
  • R 3 is C 3 -C 6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C 3 -C 6 alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1 -3 substituents selected from the group consisting Of Ci-C 6 al
  • Z is F, Cl, or Br. In some embodiments, Z is Cl or Br. In some embodiments, R 14 is F. In some embodiments, R 15 is F. In some embodiments, R h is TMS. In some embodiments, R s is TMS.
  • one or more of the compounds of Formulas X, and VIII produced in Scheme 3 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas X and VIII produced in Scheme 3 are chirally pure. [0019] In a further aspect, the disclosure provides the process of Scheme 4, in which the chiral alcohol of Formula Hc and an imine of Formula IXa are condensed to form a ⁇ -(substituted- amino)amide of Formula Xa. The ⁇ -(substituted-amino)amide of Formula Xa is cyclized with a silylating agent and a cyclizing agent to form a compound of Formula XIa.
  • R 4 is a hydroxyl protecting group
  • R 15 is H, OR S , Z, or OCH 3 , where Z is F, Cl, Br, or I, and R s is a hydroxyl protecting group
  • R 16 is H, or OR h , where R h is a hydroxyl protecting group.
  • R s is TMS. In some embodiments R h is TMS. In some embodiments, Z is F, Cl, or Br. In some embodiments, Z is F.
  • one or more of the compounds of Formulas Xa and XIa produced in Scheme 4 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas Xa, and XIa produced in Scheme 4 are chirally pure. [0023] In addition to the novel processes described in Schemes 1-4, the disclosure also provides intermediate compounds and product compounds associated with the synthesis of ezetimibe and other azetidinones.
  • the disclosure provides imine derivatives for use in the described processes.
  • the imine has the structure of Formula VI
  • R 9 is OH, OR a , NH 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group;
  • R b and R c are independently H, Ci-Ce alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring;
  • R d is Ci-Cg alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and
  • R e is Ci-Cg alkyl, alkenyl, or aryl; or
  • R 9 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken
  • R a and R s are TMS.
  • Z is Cl or Br.
  • R 7 and R 8 are not simultaneously Z.
  • the disclosure provides imines having the structures of Formulas Via, VIb, VIc, or VId:
  • R 8 is Z, where Z is Cl, Br, or I, and R 9 and R 10 is as defined above for Formula VI. In some embodiments, Z is Cl or Br.
  • the disclosure provides imines having the specific structures of Formulas VIh and VIi:
  • the compounds of the disclosure relate to various intermediates produced using the imines described herein.
  • the compounds have the structure of Formula IV: wherein Y is O or S; X is O, S, OrN(Ci-C 6 alkyl); R 1 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 4 -C 7 cycloalkyl, or substituted or unsubstituted phenyl; R 3 is C 3 -C 6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C 3 -C 6 alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of Ci- C 6 alkyl, phenyl and benzyl; R 4 is a hydroxyl protecting group; R 5 is NH 2 , 0
  • R 5 when R 5 is OR a , then at least one of R 7 and R 8 is NH 2 , or Z, where Z is Cl, Br, or I. In some embodiments, Z is Cl or Br. In some embodiments, R 5 is not Z. In some embodiments, X and Y are both independently O. In some embodiments R 3 is phenyl. In some embodiments R 4 is trimethylsilyl. In some embodiments R a is trimethylsilyl. In some embodiments R f is trimethylsilyl.
  • the disclosure provides intermediate compounds that relate to the compounds of Formulas IVc and IVd: wherein X, Y, R a , R 1 , R 3 , R 4 , R 6 , and R 7 are as defined above for Formula IV. [0031] In some embodiments, the disclosure provides compounds of Formula IVg:
  • the compounds of Formulas IV, IVc, IVd, and IVg are substantially chirally pure compounds. In some embodiments the compounds of Formulas IV, IVc, IVd, and IVg are chirally pure compounds.
  • the disclosure provides compounds of Formula VII:
  • R 1 is H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C 4 -C7 cycloalkyl, or substituted or unsubstituted phenyl;
  • R 7 and R 8 are independently H, NH 2 , or Z, wherein Z is Cl, Br, or I;
  • R 11 is a H or a hydroxyl protecting group;
  • R 12 is OH, 0R a , NH 2 , B(0R b ) (OR C ), B(R d ) 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group;
  • R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring;
  • R d is Ci-C 8 alkyl, cycloalkyl
  • R 7 and R 8 are Z, where Z is Cl, Br, or I. In some embodiments, Z is Br or Cl. In some embodiments R a and R 11 are trimethylsilyl.
  • the compound of Formula VII has the structure of Formula Vila or Formula VIIb
  • the compound of Formula VII has the structure of Formula VIIc or Formula VIId
  • R a , R 7 and R 11 are as defined above for Formula VII.
  • the compound of Formula VII has the structure of Formula VIIe or Formula VIIf
  • R a , R 8 , R 11 and R 13 are as defined above for Formula VII.
  • the compounds of Formulas VII, VIIc, VIId, VIIe, and VIIf are substantially chirally pure compounds. In some embodiments the compounds of Formulas VII, VIIc, VIId, VIIe, and VIIf are chirally pure compounds.
  • the disclosure provides compounds of Formula XII wherein TMS is trimethylsilane:
  • TMS refers to interchangeably to trimethylsilane and trimethylsilyl
  • TMSCl refers to Chlorotrimethylsilane.
  • DIPEA N,N'-Diisopropylethylamine
  • BSA N,O-Bis(trimethylsilyl)acetamide
  • TBAF refers to tetra-n-butylammonium fluoride.
  • IPA refers to isopropylalcohol.
  • Ph refers to a phenyl
  • API refers to Active Pharmaceutical Ingredient.
  • halo and halogen are used interchangeably herein to refer to fluorine, chlorine, bromine or iodine.
  • substituted when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s).
  • Typical substituents also referred to herein as “substituent groups,” “functional groups,” or “groups" are well known in the art and include, but are not limited to heteroatoms or halo groups (e.g., -F, -Cl, -Br, -I), straight-chain, branched, or cyclic alkyls, straight-chain, branched, or cyclic alkenyls, heteroatom substituted alkyls or alkenyls (e.g., -O- alkyl, -S-alkyl), aryl or heteroaryl, and other functional groups with or without heteroatoms (e.g., - OH, -NH 2 , -CF 3 , -CN, -OCN,
  • first substituent group When a first substituent group is "substituted with one or more" second groups, one or more hydrogen atoms of the first group are replaced with a corresponding number of second groups. When the number of second groups is two or greater, each second group can be the same or different.
  • alkyl refers to straight or branched chain hydrocarbon groups. When numbers appear in subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular group can contain. For example, "Ci-Ce alkyl” refers to straight and branched chain alkyl groups with one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and so forth. Alkyl groups may be optionally substituted with one or more substituent groups.
  • Ci-Cg alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 8 carbon atoms.
  • Representative straight chain -Ci-Cg alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • a branched alkyl means that one or more straight chain alkyl groups, such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH 2 - group of a straight chain alkyl.
  • Ci-Cg alkyls include -iso-propyl, -sec -butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3-methylbutyl, - 1 , 1 -dimethylpropyl, - 1 ,2-dimethylpropyl, - 1 -methylpentyl, -2-methylpentyl, -3-methylpentyl, - 4-methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, - 1 , 1 -dimethylbutyl, - 1 ,2-dimethylbutyl, - 1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl,
  • Ci -C ⁇ alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative straight chain -(Ci-C6)alkyls include methyl, ethyl, -n- propyl, -n-butyl, -n-pentyl, and -n-hexyl.
  • Ci-C 6 alkyls include -iso-propyl, -sec -butyl, -iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3- methylbutyl, - 1 , 1 -dimethylpropyl, - 1 ,2-dimethylpropyl, -1-methylpentyl, -2-methylpentyl, -3- methylpentyl, -4-methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, - 1 , 1 -dimethtylbutyl, - 1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylmethylbuty
  • C3-C6 alkyl refers to a straight chain or branched non-cyclic hydrocarbon having from 3 to 6 carbon atoms.
  • Representative straight chain C 3 -C 6 alkyls include -n-propyl, -n butyl, -n pentyl, and -n hexyl.
  • Representative branched C 3 -C 6 alkyls include -iso-propyl, -sec-butyl, -iso- butyl, -tert-butyl, -iso-pentyl, -neopentyl, - 1 -methylbutyl, -2-methylbutyl, -3 -methylbutyl, -1,1- dimethylpropyl, - 1 ,2-dimethylpropyl, -1-methylpentyl, -2-methylpentyl, -3-methylpentyl, A- methylpentyl, - 1 -ethylbutyl, -2-ethylbutyl, -3-ethylbutyl, -1,1 -dimethtylbutyl, -1,2-dimethylbutyl, -1,3-dimethylbutyl, -2,2-dimethylbutyl, -2,3-dimethylbutyl, and
  • cycloalkyl refers to a saturated carbon ring of at least three carbon atoms, wherein the points of attachment to other groups include all positional isomers. Alternatively, the number of carbon atoms may be specified. Thus, “C 3 -C 6 cycloalkyl” means saturated carbon rings of 3 to 6 carbon atoms. C 3 -C 6 cycloalkyl groups may be optionally substituted with one or more substituent groups.
  • silacycloalkyl refers to a saturated carbon ring of at least three atoms, in which one of the carbon atoms is replaced by Si.
  • silacycloalkyl groups include silacyclobutane (siletane), silacyclopentane (silolane), and silcyclohexane (silinane)
  • C 3 -C 7 cycloalkyl refers to a saturated monocyclic hydrocarbon having from 3 to 7 carbon atoms.
  • Representative C 3 -C 7 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • C 3 -C 7 cycloalkyl groups may be optionally substituted with one or more substituent groups.
  • C 3 -C 6 alkoxycarbonyl refers to an -C(O)-O-alkyl group, in which the alkyl group is as previously described for C 3 -C 6 alkyl groups.
  • Representative C 3 -C 6 alkoxycarbonyls include methoxycarbonyl, ethoxycarbonyl, and the like.
  • C 3 -C 6 alkoxycarbonyl groups may be optionally substituted with one or more substituent groups.
  • alkenyl refers to straight or branched chain hydrocarbon groups having at least one double bond.
  • C When numbers appear in subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular group can contain.
  • Ci-Ce alkenyl refers to straight and branched chain alkyl groups with one to six carbon atoms that include at least one double bond.
  • Typical alkenyl groups include are well known in the art, and include, but are not limited to: ethenyl, 1 -methyl- ethenyl, 1- or 2-propenyl, 1-methyl-l-propenyl, l-methyl-2- propenyl, 1 , 1 -dimethyl-2propenyl, 2-methyl-2-propenyl, 1-, 2- or 3-butenyl, 1 -methyl- 1-butenyl, 2- methyl-1-butenyl, 3 -methyl- 1-butenyl, 3,3-dimethyl-l-butenyl, 2,3-dimethyl-l-butenyl, l-methyl-2- butenyl, l,l-dimethyl-2-butenyl, 2-methyl-2butenyl, 3-methyl-2-butenyl, 1,3-butadienyl, 1,3- dimethyll,3-butadienyl, 1-, 2-, 3- or 4-pentenyl, and so forth.
  • aryl refers to a monovalent aromatic hydrocarbon radical of 6 to about 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • Aryl groups may be optionally substituted with one or more substituent groups.
  • heteroaryl refers to an aryl group in which one or more of the carbon atoms of the parent aromatic ring system are replaced by a heteroatom.
  • Typical heteroaryl groups include, but are not limited to, radicals derived from e.g., pyridyl, pyrimidinyl, thienyl, furanyl, pyrrole, and indolyl ring systems.
  • tautomer refers to isomers that change into one another with great ease so that they can exist together in equilibrium.
  • stereoisomer stereoisomer
  • stereoisomeric form and the like are used interchangeably herein to refer to all isomers of individual molecules that differ only in the orientation of their atoms in space. In includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another ("diastereomers").
  • chiral center refers to a carbon atom to which four different groups are attached.
  • enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
  • a composition that is "enriched" in a particular chiral compound, enantiomer, or diastereomer comprises greater than 50% and typically comprises at least about 60%, 70%, 80%, 90%, or even more of that particular chiral compound, enantiomer, or diastereomer.
  • the amount of enrichment can be determined using conventional analytical methods routinely used by those of ordinary skill in the art, including but not limited to, NMR spectroscopy in the presence of chiral shift reagents, gas chromatographic analysis using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • a single chiral compound, enantiomer, or diastereomer will be substantially free of other corresponding chiral compound, enantiomer, or diastereomers.
  • Chirally enantiomerically, or diastereomerically enriched compositions that contain at least about 95% of a specified chiral compound, enantiomer, or diastereomer are referred to herein as "substantially chirally pure,” “substantially enantiomerically pure” and “substantially diastereomerically pure,” respectively.
  • compositions that contain at least about 99% of a specified chiral compound, enantiomer, or diastereomer are referred to herein as “chirally pure,” “enantiomerically pure,” and “diastereomerically pure,” respectively.
  • compound refers to any compounds encompassed by the identified structural Formula and/or chemical name associated with the compound as disclosed herein.
  • Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • Each compound identified by structural formulae and/or chemical name disclosed herein may contain one or more chiral centers and/or double bonds, and therefore, may exist as more than one stereoisomer, such as double-bond isomers (i.e., geometric isomers), enantiomer, or diastereomer.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include all isotopically labeled versions of the compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes that may be incorporated into the compounds of the disclosure include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, etc.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. Further, it should be understood, when partial structures of the compounds are illustrated, that brackets indicate the point of attachment of the partial structure to the rest of the molecule.
  • suitable inert solvents or “inert solvent” refers to any organic solvent or combination of solvents that is unreactive in the reaction being conducted and is a solvent for the reactants.
  • Typical inert solvents include, but are not limited to: hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2- dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or methylene chloride; alcohols, such as methanol, ethanol, isopropanol, n-propanol n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethylene
  • Lewis acid refers to a compound capable of accepting a pair of electrons from a Lewis base, and includes but is not limited to compounds such as BF 3 -etherate, AlCl 3 , Ti(OiPr) 4 , TiCl 4 , ZrCl 4 , InCl 3 , and metal triflates (e.g., Sc, In, Zn, Y, Yb).
  • a protecting group refers to a group that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality.
  • the removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, will mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups useful with the embodiments of the present disclosure can be found in P.G.M. Wuts and T. W. Greene, “Greene's Protective Groups in Organic Synthesis - Fourth Edition," John Wiley and Sons, New York, N.Y., 2007, Chapter 7 (“Greene”).
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (e.g., methyl and ethyl esters, acetate or propionate groups or glycol esters) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
  • Silyl groups can be used to "mask" the para position of a phenyl ring so as to allow a selective reaction under mild conditions to afford the "unmasked" para phenol.
  • siletanyl, siloxane, and silatrane protecting groups include siletanyl ligands such as 1 -methylsiletan- 1 -yl; siloxane groups such as Si(OR 21 )(R 22 ) 2 , where R 21 is alkyl or aryl and R 22 is alkyl, aryl, or allyl; and silatrane groups such as 2,8,9-trioxa-5-aza-l-silabicyclo[3.3.3]undecan-l-yl. Examples of these groups attached to a phenyl ring are shown below:
  • R 21 alkyl
  • aryl alkyl
  • aryl allyl
  • the present disclosure provides processes for the production of l-(4-3(R)[3(S)-(4- fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) and related azetidines.
  • This disclosure also provides reactants, intermediates, and products of the synthetic process.
  • the processes herein employ different imine derivatives, the general structure of which is further described below, that can be used to produce different intermediates, and therefore different process pathways for synthesis of the desired azetidine, such as the ezetimibe of Formula If:
  • the disclosure provides the process of Scheme 1, which uses a protected chiral alcohol of Formula II and an imine of general Formula III.
  • the chiral alcohol of Formula II and the imine of Formula III are condensed to form a ⁇ -(substituted- amino)amide of Formula IV.
  • the ⁇ -(substituted-amino)amide of Formula IV can then be cyclized to form a compound of Formula V.
  • the compound of Formula V is subject to one or more additional process step to generate the ezetimibe or azetidine derivative.
  • R 1 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 4 -C 7 cycloalkyl, or substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted heteroaryl;
  • R is H or OH; where the process can comprise at least the step of reacting a chiral alcohol of Formula II:
  • R 1 is defined as above;
  • Y is O or S
  • X is O, S, or N(Ci-C 6 alkyl);
  • R is C3-C 6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, C 3 -C 6 alkoxycarbonyl or benzyl, wherein the substitutions on phenyl and naphthyl are 1 -3 substituents selected from the group consisting Of Ci-C 6 alkyl, phenyl and benzyl; R 4 is a hydroxyl protecting group, with an imine of Formula III,
  • R 5 is NH 2 , OR a , B(OR b )(OR c ), B(R d ) 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group; R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; R d is Ci-Cg alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and R e is Ci-Cg alkyl, alkenyl, or aryl; or
  • R 5 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken together with the Si to which they are bonded, may form a silacycloalkyl ring structure having 4-8 atoms; and R n is Ci-Cg alkyl, alkenyl, aryl, or C 2 -C 4 alkyl- amines, or optionally three OR n taken together with the Si to which they are bonded, may form a tricyclic silatrane ring structure; R 6 is H or OR f , where R f is a hydroxyl protecting group;
  • R 7 and R 8 are independently H, NH 2 , or Z, where Z is Cl, Br, or I; and condensing the protected chiral alcohol of Formula II and the imine of Formula III to form a ⁇ - (substituted-amino)amide of Formula IV;
  • R 7 and R 8 are H;
  • the hydroxyl protecting group can be any suitable protecting group, such trimethylsilyl (TMS).
  • TMS trimethylsilyl
  • the condensation can be done with a Lewis acid, such as TiCU, in the presence of a tertiary amine, for example diisopropylmethylamine (DIPEA).
  • DIPEA diisopropylmethylamine
  • R 1 groups include, among others, phenyl and substituted phenyl. In some embodiments R 1 is para- fluorophenyl.
  • R 5 when R 5 is OR a , then at least one of R 7 and R 8 is NH 2 , or Z, where Z is Cl, Br, or I. In some embodiments, Z is Cl or Br.
  • X and Y are both independently O.
  • R is phenyl.
  • the process can further comprise a step of cyclizing the ⁇ - (substituted-amino)amide of Formula IV in presence of a silylating agent and a cyclizing agent to form a compound of Formula V:
  • an exemplary silylating agent is N,O-Bis-(trimethylsilyl)acetamide (BSA) while an exemplary cyclizing agent is tetra-n-butylammonium (TBAF) (which may be used in either its anhydrous or trihydrate form).
  • BSA N,O-Bis-(trimethylsilyl)acetamide
  • TBAF tetra-n-butylammonium
  • the cyclization may also be carried out using a base, including, among others, metal hydrides, such as sodium hydride, potassium hydride, and lithium hydride.
  • metal hydrides such as sodium hydride, potassium hydride, and lithium hydride.
  • the protecting groups are cleaved under appropriate conditions to generate the corresponding free hydroxyl group, e.g., free phenol or free alcohol.
  • the deprotected compound is subject to one or additional processing steps to form the compound of Formula I.
  • one or more of the compounds of Formulas IV and V produced in Scheme 1 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IV and V produced in Scheme 1 are chirally pure. [0091] As noted above, the substituents on the imine of Formula III can be varied to provide different processes for the synthesis of the compound of Formula I. In some embodiments, R 5 on the imine of Formula III is boryl group B(OR b ) (OR C ), as defined above. Exemplary boryl groups are those of Formula Bl and B2:
  • the disclosure provides a process as depicted in Scheme Ia for the preparation of the compound of Formula I.
  • the process of preparing the compound of Formula I can comprise at least the step of reacting the protected alcohol of Formula II with an imine of Formula II, where the imine has the specific structure of Formula Ha:
  • the ⁇ -(substituted-amino)amide of Formula IVa can be cyclized with a silylating agent and a cyclizing agent to form a compound of Formula Va.
  • Boryl groups can be selectively oxidized to a hydroxyl using a suitable oxidizing agent, such as H 2 O 2 , as described in more detail herein.
  • one or more of the compounds of Formulas IVa, Va, Via, and I produced in Scheme Ia are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVa, Va, Via, and I produced in Scheme Ia are chirally pure.
  • the imine of Formula III in Scheme 1 has the specific structure of Formula IHe:
  • the process of preparing the compound of Formula I can comprise at least the step of reacting the protected alcohol of Formula II with an imine of Formula IHe to form a ⁇ -(substituted-amino)amide of Formula IVe:
  • the process as illustrated in Scheme 1 e can further comprise a step of cyclizing the ⁇ - (substituted-amino)amide of Formula IVa in presence of a silylating agent and a cyclizing agent to form a compound of Formula Ve:
  • the hydroxyl protecting group R 4 on the compound of Formula Ve is removed and the resulting deprotected compound of Formula VIe is oxidized to form the compound of Formula I.
  • the oxidization step can use oxidants suitable for oxidation of the boryl group described above.
  • one or more of the compounds of Formulas IVe, Ve, VIe, and I produced in Scheme Ie are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVe, Ve, VIe, and I produced in Scheme Ie are chirally pure.
  • the imine of Formula III in Scheme 1 has the specific structure of Formula HIb: where R 8 is Z, where Z is Cl, Br, or I, and R a is a hydroxyl protecting group. In some embodiments, R 8 is Br or Cl.
  • Scheme Ib The process using the imine of Formula HIb is illustrated in Scheme Ib:
  • the process comprises at least the step of reacting the imine of Formula IHb with the protected alcohol of Formula II to form the ⁇ -(substituted-amino)amide of Formula IVb:
  • the process can further comprise a step of cyclizing the ⁇ -(substituted-amino)amide of Formula IVb in the presence of a silylating agent and a cyclizing agent to form a compound of Formula Vb:
  • the process for preparing the compound of Formula I from Formula Vb comprises removing the hydroxyl protecting group R 4 to form compound VIb, and converting the compound of Formula VIb to the compound of Formula I by removal of the halide.
  • the removal of the halide is conveniently done by hydrogenation using H 2 /Pd.
  • one or more of the compounds of Formulas IVb, Vb, VIb, and I produced in Scheme Ib are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVb, Vb, VIb, and I produced in Scheme Ib are chirally pure.
  • the process for the preparation of the compound of Formula I can comprise at least a step in which the imine of Formula IHc and the protected alcohol of Formula II are reacted and condensed to form the ⁇ -(substituted-amino)amide of Formula IVc:
  • the process can further comprise a step of cyclizing the ⁇ -(substituted-amino)amide of Formula IVc in the presence of a silylating agent and a cyclizing agent to form a compound of Formula Vc.
  • the process for preparing the compound of Formula I from Formula Vc comprises removing the hydroxyl protecting group R 4 to form the compound of Formula VIc, and converting the compound of Formula VIc to that of Formula I by removal of the halide, in the same manner as described for the imine of Formula IHb.
  • one or more of the compounds of Formulas IVc, Vc, and VIc, produced in Scheme Ic are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVc, Vc, VIc, and I produced in Scheme Ic are chirally pure.
  • the imine compound of Formula III in Scheme 1 has the specific structure of Formula IHd:
  • R 5 is NH 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group; R b and R c are independently H, Ci-Ce alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; R d is Ci-Cg alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and R e is Ci-Cg alkyl, alkenyl, or aryl; or R 5 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken together with the Si to which they are bonded, may
  • the process for the preparation of the compound of Formula I can comprise at least a step in which the imine of Formula IHd and the protected alcohol of Formula II are reacted and condensed to form the ⁇ -(substituted-amino)amide of Formula IVd:
  • the process can further comprise a step of cyclizing the ⁇ -(substituted-amino)amide of Formula IVd with a silylating agent and a cyclizing agent to form a compound of Formula Vd.
  • the compound of Formula I can be prepared from that of Formula Vd by removing the hydroxyl protecting group R 4 to form the compound of Formula VId and oxidizing the Si(R d ) 3 , Si(OR e ) 3 , Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), group R 5 to form the compound of Formula I.
  • the removal of the hydroxyl protecting group R 4 from the compound of Formula Vd to form a compound of Formula VId, and the oxidation of the compound of Formula VId to form the compound of Formula I can be combined into a single step.
  • one or more of the compounds of Formulas IVd, Vd, VId, and I produced in Scheme Id are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVd, Vd, VId, and I produced in Scheme Id are chirally pure.
  • the imine has the structure represented by Formula HIk:
  • the process of Scheme If comprises (a) reacting a protected chiral alcohol of Formula II with the imine of IHk, where Z is defined above, and condensing the protected alcohol and imine to form a ⁇ -(substituted-amino)amide of Formula IVk; (b) cyclizing ⁇ -(substituted- amino)amide of Formula IVk with a silylating agent and a cyclizing agent to form a compound of Formula Vk; (c); removing the hydroxy protecting group to afford a compound of Formula VIk; and then (d) converting the compound of Formula VIk to the final compound of Formula If.
  • step (d) can be accomplished by via a Pd catalyzed coupling with sodium or potassium hydroxides to yield the phenol.
  • Pd catalyzed coupling with sodium or potassium hydroxides to yield the phenol.
  • Ph is phenyl
  • R 4 is a hydroxyl protecting group; with an imine of Formula IHk, above; and condensing the protected chiral alcohol and imine to form a ⁇ -(substituted-amino)amide of Formula IVk:
  • one or more of the compounds of Formulas IVk, Vk, VIk, and If produced in Scheme If are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVk, Vk, VIk, and If produced in Scheme If are chirally pure.
  • the imine has the structure represented by Formula XXI:
  • the process using an imine of Formula XXI comprises (a) reacting the protected chiral alcohol of Formula Hf with an imine of Formula XXI and condensing the chiral alcohol and imine to form a ⁇ -(substituted-amino)amide of Formula XXII; (b) oxidizing the ⁇ -(substituted-amino)amide of Formula XXII to the compound of Formula XXIII; (c) cyclizing compound of Formula XXIII with a silylating agent and a cyclizing agent to form a compound of Formula XXIV; (d) removing the hydroxy protecting group to afford a compound of Formula XXV; and (e) oxidizing compound of Formula XXV to the final compound of Formula If.
  • R 4 is a hydroxyl protecting group
  • R 17 is Ci-C 6 alkyl
  • Ph is phenyl.
  • R 17 is methyl.
  • one or more of the compounds of Formulas XXII, XXIII, XXIV, and XXV produced in Scheme 4 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas XXII, XXIII, XXIV, and XXV produced in Scheme 4 are chirally pure.
  • the process for synthesis of the ezetimibe comprises: (a) reacting a chiral alcohol of Formula Hf and an imine of Formula IHf and condensing the chiral alcohol and imine to form a ⁇ -(substituted-amino)amide of Formula IVf; (b) cyclizing the ⁇ -(substituted- amino)amide of Formula IVf with a silylating agent and a cyclizing agent to form a compound of Formula Vf; (c) removing the hydroxy protecting group from the compound of Formula Vf to afford a compound of Formula VIf; and (d) oxidizing the compound of Formula VIf to the final compound of Formula If.
  • the removal of the hydroxyl protecting group R 4 from the compound of Formula Vf to form a compound of Formula VIf, and the oxidation of the compound of Formula VIf to form the compound of Formula If, can be combined into a single step.
  • Ph is phenyl; and R 4 is a hydroxyl protecting group.
  • R 4 is trimethylsilyl.
  • one or more of the compounds of Formulas IVf, Vf, VIf, and If produced in Scheme 2 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas IVf, Vf, VIf, and If produced in Scheme 2 are chirally pure.
  • the imine-based process can be used to prepare intermediates useful for synthesis of other azetidine compounds.
  • a useful intermediate is an azetidine containing a boryl group, as provided in Scheme 3 :
  • the boryl group can be used for the introduction of biphenyl groups, as described in WO2006122216. As such, a process for preparing a compound of Formula VIII: wherein
  • R 4 is a hydroxyl protecting group
  • R 14 and R 15 are each independently H, OR S , Z, or OCH 3 , where Z is F, Cl, Br, or I, and where R s is a hydroxyl protecting group;
  • R 16 is H, OR h , where R h is a hydroxyl protecting group
  • R b and R c are independently H, Ci-C 6 alkyl, or R b and R c together form a 5-6 membered ring; can comprise: (a) reacting a protected chiral alcohol of Formula lib:
  • Y is O or S
  • X is O, S, or N(Ci-C 6 alkyl);
  • R 3 is C 3 -C 6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, C 3 -C 6 alkoxycarbonyl or benzyl, wherein the substitutions on phenyl and naphthyl are 1 -3 substituents selected from the group consisting Of Ci-C 6 alkyl, phenyl and benzyl; with an imine of Formula IX,
  • R and R . 16 are as defined above; R b and R c are as defined above; and condensing the protected chiral alcohol and the imine to form a ⁇ -(substituted-amino)amide of Formula X;
  • one or more of the compounds of Formulas X, and VIII produced in Scheme 3 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas X and VIII produced in Scheme 3 are chirally pure.
  • the boryl group containing azetidine intermediate can be the compound of Formula XIa, as provided in the process of Scheme 4: Scheme 4
  • R 4 is a hydroxyl protecting group
  • R 15 is H, OR S , Z, or OCH 3 , where Z is F, Cl, Br, or I and R s is a hydroxyl protecting group
  • R 16 is H, or OR ⁇ , where R ⁇ is a hydroxyl protecting group.
  • R s is TMS.
  • R h is TMS.
  • Z is F, Cl, or Br.
  • Z is F.
  • one or more of the compounds of Formulas Xa, and XIa produced in Scheme 4 are substantially chirally pure compounds. In certain embodiments, one or more of the compounds of Formulas Xa, and XIa produced in Scheme 4 are chirally pure.
  • the compounds relate to imine derivatives for use in the described processes.
  • the imine has the structure of Formula VI
  • R 9 is OH, OR a , NH 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group; R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; R d is Ci-Cg alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and R e is Ci-Cg alkyl, alkenyl, or aryl; or R 9 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken together with the Si to which they are
  • R 7 and R 8 are independently H, NH 2 , or Z, wherein Z is Br, Cl, or I;
  • R 10 is H, OH, OR S , where R s is a hydroxyl protecting group; with the proviso that
  • R a and R s are TMS.
  • Z is Cl or Br.
  • R 7 and R 8 are not simultaneously NH 2 , or Z.
  • R 9 is OH or OR a .
  • an imine has the structure of Formula Via
  • R 8 is Z, where Z is Cl, Br, or I, and R 9 and R 10 is as defined above for Formula VI. In some embodiments, Z is Cl or Br.
  • R 9 is B(OR b )(OR c ), or B(R d ) 2 , wherein R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; and R d is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen.
  • R 9 is a group of Formula Bl or B2:
  • the disclosure provides the imines of Formula BBl and BB2
  • Z is F, Cl, Br, or I.
  • Z is F.
  • an imine has the structure of Formula VIb:
  • R 8 is Z, where Z is Cl, Br, or I, and R 9 is as defined above for Formula VI. In some embodiments, Z is Cl or Br. [0145] In some embodiments the disclosure provides an imine of Formula VIc:
  • R 7 is NH 2 , or Z, where Z is Cl, Br, or I, and R 9 and R 10 are as defined above for Formula VI. In some embodiments, Z is Cl or Br.
  • the disclosure provides an imine of Formula VId
  • R 7 is Z, where Z is Cl, Br, or I, and R 9 is as defined above for Formula VI. In some embodiments, Z is Cl or Br.
  • the imines have the specific structure of Formulas VIh and VIi:
  • the compounds of the disclosure relate to various intermediates produced using the imines described herein.
  • the compound has the structure of Formula IV:
  • Y is O or S
  • X is O, S, or N(Ci-C 6 alkyl);
  • R 1 is H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 4 -C7 cycloalkyl, or substituted or unsubstituted phenyl;
  • R is C 3 -C 6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, Cs-C 6 alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1 -3 substituents selected from the group consisting Of Ci-C 6 alkyl, phenyl and benzyl;
  • R 4 is a hydroxyl protecting group
  • R 5 is NH 2 , 0R a , B(0R b )(0R c ), B(R d ) 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group; R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; R d is Ci-Cg alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and R e is Ci-Cg alkyl, alkenyl, or aryl; or
  • R 5 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken together with the Si to which they are bonded, may form a silacycloalkyl ring structure having 4-8 atoms; and R n is Ci-Cg alkyl, alkenyl, aryl, or C 2 -C 4 alkyl- amines, or optionally three 0R n taken together with the Si to which they are bonded, may form a tricyclic silatrane ring structure;
  • R 6 is H or 0R f , where R f is a hydroxyl protecting group
  • R 7 and R 8 are independently H, NH 2 , or Z, wherein Z is Cl, Br, or I; with the proviso that
  • R 7 and R 8 are H;
  • R 5 when R 5 is OR a , then at least one of R 7 and R 8 is Z, where Z is Cl, Br, or I. In some embodiments, Z is Cl or Br. [0150] In some embodiments, R 5 is not Z. In some embodiments, X and Y are both independently O. In some embodiments R 3 is phenyl. In some embodiments R 4 is trimethylsilyl. In some embodiments R a is trimethylsilyl. In some embodiments R f is trimethylsilyl.
  • the intermediate compounds relate to the compounds of Formulas IVc and IVd:
  • R a , R 1 , R 3 , R 4 , R 6 , and R 7 are as defined above for Formula IV.
  • the compounds relate to those of Formula IVg:
  • R a , R 1 , R 3 , R 4 , R 6 , and R 7 are as defined above for Formula IV.
  • the compounds of Formulas IV, IVc, IVd, and IVg are substantially chirally pure compounds. In some embodiments the compounds of Formulas IV, IVc, IVd, and IVg are chirally pure compounds.
  • the disclosure provides compounds of Formula VII: wherein
  • R 1 is H, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C 4 -C7 cycloalkyl, or substituted or unsubstituted phenyl;
  • R 7 and R 8 are independently H, NH 2 , or Z, wherein Z is Cl, Br, or I;
  • R 11 is a H or a hydroxyl protecting group
  • R 12 is OH, NH 2 , 0R a , B(0R b ) (OR C ), B(R d ) 2 , Si(R d ) 3 , or Si(OR e ) 3 , where R a is a hydroxyl protecting group; R b and R c are independently H, Ci-C 6 alkyl, alkenyl, or aryl, or R b and R c together form a 5-6 membered ring; R d is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, and R e is Ci-C 8 alkyl, alkenyl, or aryl; or
  • R 12 is Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ), where R m is Ci-C 8 alkyl, cycloalkyl, alkenyl, aryl, or a halogen, or optionally two R m , taken together with the Si to which they are bonded, may form a silacycloalkyl ring structure having 4-8 atoms; and R n is Ci-C 8 alkyl, alkenyl, aryl, or C 2 -C 4 alkyl- amines, or optionally three OR n taken together with the Si to which they are bonded, may form a tricyclic silatrane ring structure;
  • R 13 is H, OH, or 0R a , wherein R a is a hydroxyl protecting group; with the provisos that
  • R 7 and R 8 are H;
  • R 7 and R 8 are Z, where Z is Cl, Br, or I. In some embodiments, Z is Br or Cl. In some embodiments R 9 and R 11 are trimethylsilyl.
  • the compound of Formula VII has the Formula Vila or VIIb
  • the compounds of Formula VII have the specific structures of Formula VIIc and VIId
  • the compound of Formula VII has the specific structures of Formula VIIe and VIIf
  • the compounds of Formulas VII, VIIc, VIId, VIIe, and VIIf are substantially chirally pure compounds. In some embodiments the compounds of Formulas VII, VIIc, VIId, VIIe, and VIIf are chirally pure compounds.
  • the disclosure provides compounds of Formula XII wherein TMS is trimethylsilane:
  • the protected starting compounds used in the methods of the present disclosure i.e., the protected chiral alcohols (e.g., compounds of Formula II) and the protected imines (e.g., compounds of Formula III), can be made with a suitable hydroxy-protecting group.
  • the hydroxy-protecting group is a silyl protecting group such as that derived from the silylating agents chlorotrimethylsilane (TMSCl) or t-butyldimethyl-silyl chloride (TBDMSCl), preferably TMSCl.
  • chiral alcohol and 1 -3 equivalents of imine are added to an anhydrous solvent such as CH 2 Cl 2 (DCM) at about -10° to 150 0 C, and a tertiary amine base such as DIPEA is added along with sufficient silylating agent to react with the alcohol and imine is added (e.g., 2-4 equivalents) to afford the protected products.
  • anhydrous solvent such as CH 2 Cl 2 (DCM) at about -10° to 150 0 C
  • DIPEA tertiary amine base
  • sufficient silylating agent to react with the alcohol and imine is added (e.g., 2-4 equivalents) to afford the protected products.
  • condensation of the chiral alcohol and imine to form the ⁇ -(substituted-amino)amide can be achieved by reacting at about -10° C to -50° C, preferably about -25° C to -35° C with at least 1 equivalent of a Lewis acid (e.g., TiCU), in the presence of a tertiary amine base (preferably 2-4 equivalents), preferably DIPEA for 2-4 hours.
  • a Lewis acid e.g., TiCU
  • a tertiary amine base preferably 2-4 equivalents
  • further silylation (of the substituted amino group) and cyclization to form the protected API precursor can be effected by first reacting the ⁇ - (substituted-amino)amide starting material with a silyl-enol ether silylating agent, followed by reaction with a fluoride ion generating cyclizing agent.
  • Suitable silyl-enol ether silylating agents for this reaction include bistrimethylsilyl acetamide (BSA), N-methyl-O-trimethylsilyl acetamide or iso-propenyloxy trimethylsilane, preferably BSA, provided in a suitable inert organic solvent (e.g., t-BuOMe, DMC, THF, or toluene).
  • BSA bistrimethylsilyl acetamide
  • DMC N-methyl-O-trimethylsilyl acetamide or iso-propenyloxy trimethylsilane
  • a suitable inert organic solvent e.g., t-BuOMe, DMC, THF, or toluene.
  • the silylation can be carried out, preferably in a dry, inert atmosphere, at -20 0 C to 110 0 C, preferably at about 0° to 50° C, more preferably at about 40 0 C, for about 0.5 to about 6 hours,
  • Suitable cyclizing agents generate fluoride ion to catalyze the intra-molecular cyclization reaction.
  • the fluoride ion can be in the form of a quaternary alkyl-, aryl-alkyl- or arylalkyl-alkyl- ammonium fluoride salt or a hydrate thereof, or a mixture thereof, or is an alkali metal fluoride salt or a hydrate thereof, such as cesium fluoride or potassium fluoride.
  • arylalkyl-alkyl- ammonium groups are benzyltriethyl-ammonium and benzyltrimethyl-ammonium.
  • arylalkyl- ammonium examples include phenyltriethyl-ammonium and phenyltrimethyl-ammonium.
  • Typical alkylammonium groups contain alkyl groups of 1-6 carbon atoms, e.g., tetra n-butyl-ammonium.
  • the reagent can be added in a catalytic amount, i.e., about 0.1 to about 20 mole percent, preferably about 0.5 to 5 mole percent, and when an anhydrous quaternary ammonium fluoride salt is used, it can be added in a catalytic up to a stoichiometric amount.
  • an alkali metal fluoride salt When used, it is added in catalytic amount up to a stoichiometric amount compared to the starting ⁇ -amino compound, depending on the solubility of the reagent in the solvent used (higher solubility requires less reagent).
  • a preferred fluoride ion catalyst cyclizing agent is tetrabutylammonium fluoride trihydrate (TBAF).
  • the ⁇ -(substituted-amino)amide can first be reacted with the silyl-enol ether silylating agent and then reacted with the cyclizing agent, or the ⁇ -(substituted-amino)amide can be added to a mixture of the silylating agent and the cyclizing agent.
  • the silylating agent is reacted with the starting material first and the silylation reaction is allowed to continue for up to about two hours.
  • the cyclization step also can be carried out immediately after silylation. If added to the reaction mixture after the silylation agent, the fluoride reagent is added directly to the reaction mixture resulting from silylation, and is reacted at about -20 0 C to 110 0 C, preferably at about 0° to 50° C, or more preferably at about 40 0 C, for about 0.5 to about 6 hours, preferably about 2 hours.
  • the silylating agent and the cyclizing agent can be added simultaneously.
  • the ⁇ -(substituted-amino)amides formed by condensation are then silylated by reaction with a silyl-enol ether silylating agent such as bistrimethylsilyl acetamide (BSA), N-methyl-O-trimethylsilylacetamide or iso-propenyloxy trimethylsilane, preferably BSA, in a suitable inert organic solvent, preferably toluene.
  • BSA bistrimethylsilyl acetamide
  • a suitable inert organic solvent preferably toluene
  • the silylated and cyclized compound is deprotected to afford Ezetimibe API depending on the combination of protecting groups remaining on the chiral alcohol and phenol groups.
  • a first step of deprotection can be carried using preferably, 2N H 2 SO 4 in isopropylalcohol (IPA) under N 2 , at about 25°C for 1 hour.
  • IPA isopropylalcohol
  • Oxidative deprotection of the silylated alcohol and/or phenol can also be effected using a fluoride source (e.g., KF, TBAF, CsF) and an oxidant (e.g., H 2 O 2 , metachloroperbenzoic acid (mCPBA), oxone, magnesium monoperoxyphthalate (MMPP)).
  • a fluoride source e.g., KF, TBAF, CsF
  • an oxidant e.g., H 2 O 2 , metachloroperbenzoic acid (mCPBA), oxone, magnesium monoperoxyphthalate (MMPP)
  • Silyl groups e.g., groups of the formulas Si(R d ) 3 , Si(OR e ) 3 , Si(R m ) 2 (R n ), Si(OR n ) 3 , or Si(R m ) 2 (OR n ) as described herein
  • Silyl groups are also used to mask the para position so as to allow selective reaction under mild conditions to afford the "unmasked" para phenol.
  • Exemplary siletanyl, siloxane, and silatrane protecting groups include:
  • R 21 alkyl
  • aryl alkyl
  • aryl allyl
  • boryl groups e.g., B(OR b ) (OR C ), B(R d ) 2
  • the unmasking can be effected by any suitable oxidizing agent, such as any peroxide, for example 79% H 2 O 2 .
  • suitable oxidizing agents allowing selective boryl group reaction to product the para phenol include e.g.,_mCPBA, oxone, MMPP.
  • Boryl group deprotection from the phenol position typically is carried out after the deprotection of any silyl protecting group on the chiral alcohol.
  • reaction can be accomplished via diazotization with tert-butyl nitrite and treatment with hypophosphorus acid (see e.g., Ek et al., J.Org. Chem, 2002, 67, 6376; and Giumanini et al., Tetrahedron, 1996, 52, 7137) or via reductive deamination of the aniline (see e.g., March's Advanced Organic Chemistry: Reaction, Mechanisms and Structure, 6 th Edition, by Michael B. Smith and Jerry March , Wiley, 2007 at p. 1847, section 19.69).
  • the reaction can be accomplished by hydrogenation reaction using H 2 and a palladium catalyst.
  • conditions can be 40 mg 10% Pd/C under hydrogen atmosphere (see e.g., Example 2).
  • reaction of the masking halide can be carried out via a Pd catalyzed coupling with sodium or potassium hydroxides to yield the corresponding phenol.
  • Pd 2 dba 3 Tris(dibenzylideneacetone)dipalladium(0)
  • Pd 2 dba 3 Tris(dibenzylideneacetone)dipalladium(0)
  • substituted biphenyl ligand catalyst systems for direct Pd-catalyzed synthesis of phenols from aryl halides are provided in e.g., Anderson et al., "The Selective Reaction of Aryl Halides with KOH: Synthesis of Phenols, Aromatic Ethers and Benzofurans," J. Am. Chem. Soc. 2006, 128, 10695-10695.
  • Pd catalysts with hindered biaryl monophosphines e.g., XPhos and SPhos
  • KOH can be used to effect phenol synthesis from aryl halides.
  • imines can be prepared by reaction of the reagents in IPA at 50 0 C as illustrated below:
  • reaction conditions for synthesis of the selected imines are presented in the Examples. Additional examples of reaction conditions for generating imines are described in US 6,207,822, WO2006122020, and WO2006122216.
  • Imine compound IHf 1.04 g (3.2 mmol) was weighed into a 25 mL oven dried RB Flask and dissolved in 7.5 mL anhydrous DCM prior to dropwise addition over 30 min into the preformed enolate at -30 0 C. After 4 hours, the reaction mixture was quenched by slow addition of IPA (6.4 mL) followed by DCM (15 mL) at -25 to -30 0 C and slowly warmed to 0 0 C. The reaction mixture was then poured into disodium tartrate buffer (0.2 M aq. solution, 25 mL maintained at 0 0 C) and stirred for 15-20 min while it was warmed to room temperature.
  • Imines VIh and VIi were synthesized following the procedure for imine IHf. 3-bromo-4-hydroxybenzaldehyde was used in t h e s ynthesis of imine VIh and 3-bromo-4-fluoroaniline was used for the synthesis of imine VIi.
  • the aqueous layer was extracted with ethyl acetate (10 mL x 2).
  • the combined organics were concentrated in vacuo and the oily residue was redissolved in IPA (4 mL) and 2N H 2 SO 4 (102 ⁇ L) and stirred for 30 min for deprotection of the TMS protected alcohol. Reaction completion was confirmed by TLC.
  • the reaction was quenched with 20 mL saturated NaHCO3 solution.
  • the aqueous layer was extracted with ethyl acetate (10 mL x 2).
  • the combined organics were concentrated in vacuo yielding an oily residue that was redissolved in methanol (5 mL).
  • LC/MS analysis was performed using Agilent 1200 HPLC with DAD (Diode Array Detector) in series with ABI QTrap 3200 Mass Spectrometer.
  • the mass-spectrometer is a hybrid triple quadrupole/LIT (Linear Ion Trap) system which is capable to perform LC/MS, LC/MS/MS and LC/MS 3 analysis.
  • a negative electrospray ionization mode was selected to run in Enhanced Mass Scan (EMS).
  • EMS scan utilizes the Linear Ion Trap capability that traps all the ions in the Q3 quadrupole region and scanned out to produce full spectrum data.
  • reaction mixtures used in the Pd/C hydrogenolysis reaction were only partially purified and contained amounts of the undesired diastereoisomer. After hydrogenolysis, this leads to the presence of both Ezetimibe API (If) and its diastereoisomer. The presence of this diastereomer resulted in the observation of two peaks of identical molecular weight in the LC/MS analysis. The additional peak for hydrogenolysis reaction of intermediate IVn was at 11.19 minutes, and the reaction of intermediate IVo resulted in a shouldered peak of identical molecular weight at 11.13 minutes. It is expected that optimized crystallization of the intermediates prior to Pd/C hydrogenolysis can result in diastereomerically pure Ezetimibe API via this process.
  • EMS Enhanced MS
  • the para position where the phenol resides in Ezetimibe API is "masked" during formation of intermediate XXIIb with an acetyl group and subsequently deprotected by Bayer- Villiger oxidation followed by hydrolysis to yield the desired phenol as shown in Scheme 9.
  • acetyl masked phenol can be used to make the imine compound XXI, and this compound can be used to make intermediate XXIIb.
  • This intermediate is oxidized via the Bayer-Villiger oxidation to compound XXIIIb, followed by the silylation and cyclization under the conditions described previously in Example 1 and elsewhere herein.
  • Final deprotection of the TMS protecting group and hydrolysis of the acetyl group generates the Ezetimibe API of Formula If.
  • intermediate DD The imine compound CC is used in a Ti-mediated Mannich reaction to afford intermediate DD.
  • Intermediate compound DD is silylated and cyclized under the standard conditions described above to yield intermediate EE.
  • Final removal of the aniline group from EE is achieved via diazotization with tert-butyl nitrite and hydrolysis in the presence of water to generate If. See e.g., F. Ek; O. Axelsson; L-G. Wistrand; T. Frejd, J.Org. Chem, 2002, 67, 6376; and A.G. Giumanini; G. Verardo; P. Geatti; P. Strazzolini, Tetrahedron, 1996, 52, 7137.
  • a removable aniline group attached to the aldehyde portion of the imine can be used in the Mannich reaction and subsequently be removed via the Sandmeyer type reaction with tert-butyl nitrite followed by treatment with hypophosphorus acid to yield Ezetimibe API as shown in Scheme 12 below:
  • intermediate GG is silylated and cyclized under conditions described previously to yield intermediate HH.
  • Final removal of the aniline group from HH is achieved via diazotization with tert-butyl nitrite and treatment with hypophosphorus acid to generate the Ezetimibe API (If).

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Abstract

La présente invention concerne des procédés de préparation d'ézétimibe (1-(4-fluorophényl)-3(R)-[3-(4-fluorophényl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphényl)-2-azétidinone) et de composés d'azétidine apparentés.
PCT/US2010/036938 2009-06-02 2010-06-01 Synthèse d'ézétimibe Ceased WO2010141494A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012004382A1 (fr) * 2010-07-09 2012-01-12 Moehs Iberica S.L. Nouveau procédé de préparation d'ézétimibe
CN104402790A (zh) * 2014-12-28 2015-03-11 严白双 一种制备依折麦布的改进工艺
WO2015158191A1 (fr) * 2014-04-18 2015-10-22 上海方楠生物科技有限公司 Procédé pour la synthèse stéréosélective d'ézétimibe, médicament hypolipémiant
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
CN107677753A (zh) * 2017-11-24 2018-02-09 中山奕安泰医药科技有限公司 一种依替米贝中间体的检测方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
EP1137634B1 (fr) * 1998-12-07 2005-06-15 Schering Corporation Procede relatif a la synthese d'azetidinones
EP1831162B1 (fr) * 2004-12-20 2012-10-31 Merck Sharp & Dohme Corp. Procede de synthese d'azetidinones
WO2007017705A1 (fr) * 2005-08-09 2007-02-15 Glenmark Pharmaceuticals Limited Procede de preparation d'azetidinones

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
WO2012004382A1 (fr) * 2010-07-09 2012-01-12 Moehs Iberica S.L. Nouveau procédé de préparation d'ézétimibe
WO2015158191A1 (fr) * 2014-04-18 2015-10-22 上海方楠生物科技有限公司 Procédé pour la synthèse stéréosélective d'ézétimibe, médicament hypolipémiant
CN104402790A (zh) * 2014-12-28 2015-03-11 严白双 一种制备依折麦布的改进工艺
CN104402790B (zh) * 2014-12-28 2016-09-28 严白双 一种制备依折麦布的改进工艺
CN107677753A (zh) * 2017-11-24 2018-02-09 中山奕安泰医药科技有限公司 一种依替米贝中间体的检测方法
CN107677753B (zh) * 2017-11-24 2021-03-16 中山奕安泰医药科技有限公司 一种依替米贝中间体的检测方法

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