WO2009114080A2 - Procédés de préparation de composés diol et dioxolane énantiomériquement purs - Google Patents

Procédés de préparation de composés diol et dioxolane énantiomériquement purs Download PDF

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WO2009114080A2
WO2009114080A2 PCT/US2009/001315 US2009001315W WO2009114080A2 WO 2009114080 A2 WO2009114080 A2 WO 2009114080A2 US 2009001315 W US2009001315 W US 2009001315W WO 2009114080 A2 WO2009114080 A2 WO 2009114080A2
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formula
compound
enantiomeric excess
compounds
enantiomerically pure
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WO2009114080A3 (fr
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Partha Barnerjee
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Stiefel Research Australia Pty Ltd
Stiefel Laboratories Inc
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Stiefel Research Australia Pty Ltd
Stiefel Laboratories Inc
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Priority to JP2010549642A priority Critical patent/JP2011513398A/ja
Priority to MX2010009732A priority patent/MX2010009732A/es
Priority to AU2009223833A priority patent/AU2009223833A1/en
Priority to CA2718166A priority patent/CA2718166A1/fr
Priority to CN2009801160471A priority patent/CN102015582A/zh
Priority to EP09720379A priority patent/EP2255009A4/fr
Publication of WO2009114080A2 publication Critical patent/WO2009114080A2/fr
Publication of WO2009114080A3 publication Critical patent/WO2009114080A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel processes for preparing enantiomerically pure diol and dioxolane compounds from racemic starting materials and the use of these compounds for preparing therapeutically active agents.
  • antifungal therapeutics antifungal therapeutics
  • the antimycotics currently in clinical use are limited either by their general ineffectiveness and inadequate pharmacological profile, including undesired drug-drug interactions and narrow activity spectrum, or by their high overall cytotoxicity [White et al., 1998]. Accordingly, there is a critical need for new antifungal compounds that could overcome these disadvantages.
  • Pramiconazole (l-[4-[4-[4-[4-[4-[[[(2S,4R)-4-(2,4-difluorophenyl)-4-(lH-l,2,4-triazol-l- ylmethyl)-l ,3-dioxolan-2-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-3-( 1 -methylethy!- imidazolidinone) is a potent oral broad-spectrum antifungal agent for the short course treatment
  • U.S. Patent No. 6,387,906 which is herein incorporated by reference in its entirety, describes the antifungal activity and preparation of azole compounds that include pramiconazole.
  • Phase 2A clinical trials were conducted with pramiconazole for the treatment of tinea pedis (athlete's foot), tinea corpis (ring worm), tinea cruris (jock itch), tinea versicolor and seborrheic dermatitis.
  • a phase 2A clinical trial with pramiconazole is currently underway for the treatment of toenail onychomycosis.
  • the present invention relates to the discovery of new methods for the preparation of the chiral dioxolane portion of the pramiconazole molecule in enantiomerically pure form.
  • the present invention also relates to the use of this technology for the preparation of other therapeutically active compounds that contain this particular dioxolane moiety or other chiral dioxolane moieties described herein.
  • An aspect of the invention is a process for preparing an enantiomerically pure compound of Formula (1) and Formula (2), or a salt thereof,
  • Rj is -(C] -6 alkylene); R 2 and R 3 are independently aryl or heteroaryl; and X is -OH or a leaving group.
  • Another aspect of the invention is a process for preparing an enantiomerically pure compound of Formula (1) and Formula (2), or a salt thereof, comprising treating the racemic diol of Formula (4)
  • R 2 and R 3 are independently aryl or heteroaryl, with a suitable enzyme to provide an enantiomerically pure compound of Formula (5) and Formula (6)
  • Ri is -(Ci- 6 alkylene); each R 4 is independently Ci-ealkyl or aryl; and X is -OH or a leaving group; and for Formula (8), Ri is -(Ci -6 alkylene) and X is -OH or a leaving group.
  • Another aspect of the invention is a process for preparing enantiomerically pure pramiconazole, comprising combining the dioxolane of Formula (1), wherein the dioxolane of Formula (1) is prepared by the enzyme- facilitated methods as herein described, with the piperazine derivative of Formula (9)
  • variable "X" in Formula (10) is Br or O-mesyl.
  • Another aspect of the invention is a method for preparing a therapeutically active compound, or a pharmaceutically acceptable salt thereof, comprising combining an enantiomerically pure dioxolane of Formula (1) or Formula (2) with a carbon, oxygen or nitrogen nucleophile ("Nu") under reaction conditions sufficient for the nucleophile to displace the variable X of Formula (1) or Formula (2) to provide the products of Formula (11) and Formula (12) as shown below:
  • the therapeutic compound exhibits antimicrobial or an antifungal properties.
  • the nucleophile is the compound of Formula (9) or a similar compound where the phenolic oxygen is the moiety that displaces the variable X of Formula (1) or Formula (2).
  • Another aspect of the invention is a method for preparing a therapeutically active compound, or a pharmaceutically acceptable salt thereof, comprising a step of treating the racemic diol of Formula (4)
  • R 2 and R 3 are independently aryl or heteroaryl, with a suitable enzyme to provide the enantiomerically pure diol of Formula (5) and Formula (6)
  • the compound of Formula (5) is a compound of Formula (13)
  • Formula (13) and the therapeutically active compound prepared by this method is posaconazole.
  • the therapeutically active compound prepared by this method is ZD- 0870.
  • Figure 1 shows that the production of compound 3 (as identified in Scheme 1) from treatment of the corresponding racemate with CAL-B proceeded steadily over a 10-hour period, during which the enantiomeric excess approached 100% and the percent conversion approached 60%.
  • an "effective amount” or “an amount effective to” or a “therapeutically effective amount” or any grammatically equivalent term refers to the amount that, when administered to an animal for treating a disease or condition, is sufficient to effect treatment for that disease or condition.
  • an "effective amount” may be viewed as the amount of a compound or composition that is sufficient to induce an antifungal effect.
  • enantiomerically pure refers to enantiomeric forms of the compounds as mentioned herein that are substantially free of other enantiomeric forms of the same basic molecular structure of said compounds.
  • the term “enantiomerically pure” refers to compounds having an enantiomeric excess (e.e.) of at least about 80% (i.e., a minimum of about 90% of one enantiomer and a maximum of about 10% of the other possible enantiomer) up to an enantiomeric excess of 100% (i.e., 100% of one enantiomer and none of the other enantiomer), such as, for example, compounds having an enantiomeric excess of about 90% up to 100%, such as, for example, compounds having an enantiomeric excess of about 95% up to 100%, such as, for example, compounds having an enantiomeric excess of about 97% up to 100%.
  • the enantiomeric excess of the dioxolane of Formula (1) or Formula (2) is at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or at least about 99.2% or at least about 99.4% or at least about 99.6% or at least about 99.8%.
  • variable "X” may include any conventional leaving group known to those of skill in the art.
  • the leaving group “X” includes, but is not limited to, halo (F, Cl, Br, I), mesylate (OMs), tosylate (OTs), nosylate (ONs), brosylate (OBs), triflate (OTf) or acetate (OAc).
  • nucleophile is a molecule or ion that donates a pair of electrons to form a new covalent bond.
  • Nucleophiles are typically Lewis bases and include the anion conjugate base of a protic acid.
  • Specific nucleophiles include oxygen atoms (e.g. alcohols, alkoxides or phenoxides), nitrogen atoms (e.g. amines or amides) and carbon atoms (e.g. , Grignards (i.e., compounds containing a carbon-magnesium bond) or compounds containing a carbon-lithium bond, carbon-sodium bond, and other carbon-metal bond).
  • the enzyme employed to resolve the racemic compounds represented by Formula (3) and Formula (4) may be, but is not limited to being a lipase.
  • Exemplary embodiments of the enzyme used in the present invention include, but are not limited to, Candida antarctica lipase B (CAL-B), Aspergillus niger, Pseudomonas sp., Candida rugosa, Candida cylindracea, Humicola lanuginesa, Rhizopus delemar, Penicilliium camemberti, Geotrichum candidum, Hog pancrease, Candida lipolytica, Mucor javanicus, Rhizopus niveus, Pig liver esterase, Porcine pancrease lipase, Pseudomonas cepacia (formerly called Pseudomonas fluorescens) and Penicillium roqueforti.
  • CAL-B Candida antarctica lipase B
  • Aspergillus niger Pseudomonas
  • enantiomeric forms of the compounds of this invention may be purified by the application of procedures that are well-known to those of skill in the art. For example, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or by chromatographic techniques using chiral stationary phases.
  • an "antimicrobial” is an agent that inhibits the growth of fungal and/or bacterial microorganisms or kills them outright. More specifically, an “antifungal” is an agent that inhibits the growth of fungi (i.e., a fungistat) or kills them outright (i.e., a fungicide) and an “antibacterial” or “antibiotic” is a substance that kills or slows the growth of bacteria.
  • alkyl refers to an optionally substituted straight chain, branched chain or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. means one to six carbons).
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t- butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclop ropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • Substituents for the alkyl radical are generally selected from the group of substituents described below.
  • alkylene refers to, unless otherwise stated, divalent carbon radicals.
  • an alkylene group is an eight carbon chain (i.e., Ci -8 ) or a six carbon chain (i.e., Ci -6 ) or a three carbon chain (i.e., Ci -3 ).
  • the alkylene chains may be further substituted. Specific embodiments include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(OCH 3 )-, -CH 2 CH(CH 2 OCH 3 )CH 2 CH 2 - and -CH 2 CH(Ph)CH 2 -.
  • halo refers to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • aryl refers to, unless otherwise stated, an optionally substituted polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquino
  • alkylaryl refers to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxym ethyl, 3-(l-naphthyloxy)propyl, and the like).
  • alkyl and heteroalkyl radicals are generically referred to as "alkyl group substituents" and they can be one or more of a variety of groups selected from, but not limited to: -Ci-
  • R', R", R" 1 and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R 1 , R", R"' and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1 -pyrrolidinyl and 4-morpholinyl.
  • substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.”
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from O to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -Y-(CH 2 ) r -Z-, wherein Y and Z are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR' ) S -X- (CR"R'") d -, where s and d are independently integers of from O to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituents R, R", R" and R'" are independently selected from hydrogen or substituted and unsubstituted (Ci- 6 )alkyl.
  • the present invention provides for a facile synthesis of the enantiomerically pure compound of Formula (13), which in turn may be used, in an exemplary embodiment, to provide a novel synthesis of the antifungal posaconazole.
  • Formula ( 13) The present invention provides for a facile synthesis of the enantiomerically pure compound of Formula (13), which in turn may be used, in an exemplary embodiment, to provide a novel synthesis of the antifungal D-0870.
  • the present invention provides for a facile synthesis of the enantiomerically pure compound of Formula (13), which in turn may be used, in an exemplary embodiment, to provide a novel synthesis of the antifungal SCH-51048.
  • antifungal compounds that may possibly be prepared by the methodology of the present invention for preparing enantiomerically pure compounds of, for example, Formulae (1), (2), (5) and (6) include, but are not limited to, ketoconazole, itraconazole, isoconazole, miconazole, econazole, sulconazole, fluconazole, fenticonazole, sertaconazole, tioconazole, fluconazole, voriconazole and ravuconazole.
  • the enantiomerically pure compounds of Formula (1) and Formula (2) may exist as pharmaceutically acceptable salts, either alone or as part of a larger molecule.
  • Suitable pharmaceutical acceptable salts are those of organic or inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, phosphoric acid, acetic acid, succinic acid, oxalic acid, malic acid, fumaric acid and the like.
  • Pramiconazole exhibits antifungal properties against, for example, Candida spp., Pityrosporum spp., Malassezia spp. and Trichophyton spp.
  • Candida spp. are ubiquitous fungi found throughout the world as normal body flora.
  • Candidiasis is a common mycotic infection, especially in immunocompromised hosts, that contributes to a variety of diseases, such as, but not limited to, vaginal candidiasis ⁇ e.g.
  • Candida include, but are not limited to, Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsiliosis, Candida guilliermondi, Candida lusitaniae and Candida krusei.
  • Trichophyton include, but are not limited to, Trichophyton mentagrophytes and Trichophyton rubrum.
  • Exemplary embodiments of Pityrosporum include, but are not limited to, Pityrosporum orbiculare, Pityrosporum ovale, Pityrosporum canis and Pityrosporum pachydermatis.
  • Exemplary embodiments of Malassezia include, but are not limited to, Malassezia sympodialis, Malassezia globosa, Malassezia restricta, Malassezia sloojjiae, Malassezia furfur, Malassezia obtusa and Malassezia pachydermatis.
  • pramiconazole Specific disorders that may be treated by administration of pramiconazole include, but are not limited to, tinea capitis ⁇ e.g., seborrheic dermatitis, psoriasis, folliculitis and impetigo), tinea corporis (ring worm), tinea cruris (jock itch), tinea versicolor, tinea pedis (athlete's foot) and onychomycosis (nail fungus, such as toenail onychomycosis).
  • compositions containing therapeutically active compounds that structurally incorporate the enantiomerically pure moieties of Formula (1) or Formula (2) may also optionally include other carriers, stabilizers, preservatives or adjuvants.
  • other carriers stabilizers, preservatives or adjuvants.
  • Additional therapeutic agents that may be used in combination with the compounds of the invention include, but are not limited to, antimicrobial agents ⁇ e.g., amphotericin B, clotrimazole, econazole nitrate, fluconazole, flucytosine, haloprogin, itraconazole, ketoconazole, miconazole, AN- 1677, AN2690, bifonazole, Miconazole, neticonazole, sertaconazole, tioconazole, voraconazole, posaconazole and nystatin), anti-allergic agents (e.g., astemizole, betamethasone, carbinoxamine maleate, chlorpheniramine maleate, clemastine fumarate, dexbrompheniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride and trimeprazine tartrate), anti-inflammatory agents
  • ibuprofen fenoprofen, ketoprofen, naproxen, diclofenac, etddolac, meclofenamate sodium phenylbutazone, indomethacin, piroxicam, sulindac and tolmetin
  • anti-proliferating agents e.g., mycophenolate mofetil and evodiamine
  • anti-acne agents ⁇ e.g., tretinoin, isotretinoin, salicylic acid, benzoyl peroxide and azelaic acid
  • anti-pruritic agents ⁇ e.g., azelastine, cetirizine permethrin and lindane
  • Scheme 1 shows an exemplary embodiment of the invention in which enantiomerically pure pramiconazole is ultimately prepared.
  • a commercially available racemic epoxide is converted to the corresponding diol (1), which is then transformed to the corresponding hydroxy-ketal (2).
  • Hydroxy-ketal (2) is then resolved into its 2S,4R and 2R,4S enantiomeric components, with the component that is compound (3) (i.e., 2S,4R) being treated with mesyl chloride to provide compound (4), which is a representative compound of Formula (1) (i.e., Ri is -CH 2 -, X is mesylate, R 2 is 2, 4-di fluorophenyl and R 3 is a 1,2,4-triazole).
  • Scheme 2 shows an exemplary embodiment of the invention in which enantiomerically pure compound (4) is combined with the known hydroxyphenyl piperazine compound (6) (derived from the methoxyphenyl piperazine compound (5)) to provide enantiomerically pure pramiconazole.
  • Scheme 3 below shows an exemplary embodiment of an alternative method of preparing enantiomerically pure compounds like compound (4).
  • compound (9) which differs from compound 4 in the identity of the "X" variable (i.e., Br versus OMs), is prepared through lipase resolution of racemic compound 7.
  • compound (9) can be combined with the hydroxyphenyl piperazine compound (6) to provide enantiomerically pure pramiconazole.
  • the enzyme was filtered from the reaction mixture and the vinyl acetate was evaporated at a temperature below 45°C until approximately 500 mL of the reaction mixture remained. Approximately 1,500 mL of demineralized water was added and the remaining vinyl acetate was removed under vacuum at 50 to 55°C. The resulting solids were cooled to 5 to 10 0 C and then stirred for 1 hour before being filtered and washed with approximately 300 mL of water chilled to 5 to 10 0 C. The solid filter cake was set aside.
  • the pooled mother liquor was mixed with approximately 1 ,000 mL of methyl isobutyl ketone (MIBK) and stirred for 15 to 30 minutes at 30 to 35°C before the layers were separated.
  • MIBK methyl isobutyl ketone
  • the aqueous layer was washed with successive portions of MIBK and the combined organic layers were evaporated under vacuum at 50 to 55°C until the volume was less than 200 mL.
  • Approximately 1 ,000 mL of hexane were added and the mixture was stirred for 10 to 15 minutes before being cooled to 0 to 5°C and stirred for 1 to 2 hours.
  • the resulting solid was filtered and washed with hexane.
  • the solid filter cake that was set aside in an earlier step was combined with this most recently collected solid and then mixed with 180 mL of MIBK in a round-bottomed flask and stirred for 30 to 60 minutes at 30 to 35°C. Approximately 1,000 mL of hexane were added over 30 minutes at 30 to 35°C and the mixture was stirred an additional 30 to 60 minutes at 30 to 35°C before being cooled to 0 to 5 0 C and stirred for 1 hour. The mixture was then filtered and washed with chilled (0 to 5°C) hexane before being dried under vacuum.
  • Table 1 confirms the reproducibility of the enzymatic resolution step involving treatment of compound 2 with CAL-B (as depicted in Scheme 1) by showing that for three separate 100-g samples, the enantiomeric purity of compound 3 was between 99.1 to 99.6, while the chemical purity ranged from 98.25 to 98.94.
  • “% of conversion” refers to the percent of the racemic mixture that is represented by compound 2 that is converted to the individual enantiomers
  • yield (%) refers to the isolated yield of the enantiomerically pure compound 3.
  • Figure 1 shows that the resolution of compound 2 into its enantiomeric components (as shown in Scheme 1) proceeded steadily over a 10-hour period, during which the enantiomeric excess approached 100% and the percent conversion approached 60%.
  • the reaction mixture is then filtered through Hyflo super-eel and the residual cake is washed with approximately 150 kg of EtOAc.
  • the combined filtrate is concentrated under vacuum to remove the solvent.
  • Approximately 225 kg of acetonitrile was added and the reaction mixture was concentrated under vacuum at a temperature of no higher than 50 0 C.
  • Approximately 225 kg of acetonitrile was added and the reaction mixture was cooled to 20 ⁇ 5°C and stirred for not less than two hours.
  • the reaction mixture was then cooled to -5 ⁇ 5°C and stirred for not less than two hours.
  • the resulting crystals were filtered and washed with 165 kg of acetonitrile at a temperature of-5 ⁇ 5°C before being dried under vacuum at a temperature of no higher than 50°C. Yield: 30-45%.
  • the pH value of the aqueous layer is ascertained - if the pH is less than 6, an aqueous solution of sodium hydrogen carbonate is added. After separation, the organic layer is concentrated under vacuum and purified by silica gel column (mobile phase: MTBE-EtOAc). The fractions corresponding to compound 9 were collected and concentrated under vacuum. Methyl tert-butyl ether (MTBE) was added to the concentrated material, followed by dropwise addition of methanesulphonic acid. (Note: the methansulfonic acid may be diluted by MTBE or EtOAc before the dropwise addition). The amount of methanesulfonic acid was based on the recovered amount of compound 9. The resulting crystals were filtered, rinsed and dried under vacuum. Yield: 30-75%.

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Abstract

La présente invention concerne de nouveaux procédés de préparation composés diol et dioxolane énantiomériquement purs à partir de matières premières racémiques et l’utilisation de ces composés dans la préparation d’agents thérapeutiquement actifs.
PCT/US2009/001315 2008-03-03 2009-03-02 Procédés de préparation de composés diol et dioxolane énantiomériquement purs Ceased WO2009114080A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2010549642A JP2011513398A (ja) 2008-03-03 2009-03-02 鏡像異性的に純粋なジオールおよびジオキソラン化合物の製造方法
MX2010009732A MX2010009732A (es) 2008-03-03 2009-03-02 Procedimientos para preparar compuestos de diol y dioxolano enantiomericamente puros.
AU2009223833A AU2009223833A1 (en) 2008-03-03 2009-03-02 Processes for preparing enantiomerically pure diol and dioxolane compounds
CA2718166A CA2718166A1 (fr) 2008-03-03 2009-03-02 Procedes de preparation de composes diol et dioxolane enantiomeriquement purs
CN2009801160471A CN102015582A (zh) 2008-03-03 2009-03-02 光学纯二元醇和二氧戊环化合物的制备方法
EP09720379A EP2255009A4 (fr) 2008-03-03 2009-03-02 Procédés de préparation de composés diol et dioxolane énantiomériquement purs

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US3326608P 2008-03-03 2008-03-03
US61/033,266 2008-03-03

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WO2009114080A2 true WO2009114080A2 (fr) 2009-09-17
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CN102234267A (zh) * 2010-04-21 2011-11-09 中国科学院上海药物研究所 新型三氮唑类抗真菌化合物、其药物组合物及其制备方法和用途

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US5661151A (en) * 1993-12-21 1997-08-26 Schering Corporation Tetrahydrofuran antifungals
TW593312B (en) * 1997-07-11 2004-06-21 Janssen Pharmaceutica Nv 2,4,4-trisubstituted-1,3-dioxolane antifungals
MXPA05001451A (es) * 2002-08-06 2005-09-30 Pharmasset Ltd Procesos para preparar nucleosidos de 1,3-dioxolano.
US7585881B2 (en) * 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102234267A (zh) * 2010-04-21 2011-11-09 中国科学院上海药物研究所 新型三氮唑类抗真菌化合物、其药物组合物及其制备方法和用途

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EP2255009A4 (fr) 2011-08-10
AU2009223833A1 (en) 2009-09-17
EP2255009A2 (fr) 2010-12-01
MX2010009732A (es) 2010-09-30
CA2718166A1 (fr) 2009-09-17
WO2009114080A3 (fr) 2010-03-04
CN102015582A (zh) 2011-04-13
JP2011513398A (ja) 2011-04-28

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