WO2006008612A2 - Preparation of beta-amino acids having affinity for the alpha-2-delta protein - Google Patents

Preparation of beta-amino acids having affinity for the alpha-2-delta protein Download PDF

Info

Publication number
WO2006008612A2
WO2006008612A2 PCT/IB2005/001966 IB2005001966W WO2006008612A2 WO 2006008612 A2 WO2006008612 A2 WO 2006008612A2 IB 2005001966 W IB2005001966 W IB 2005001966W WO 2006008612 A2 WO2006008612 A2 WO 2006008612A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
methyl
alkyl
aryl
ethyl ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2005/001966
Other languages
French (fr)
Other versions
WO2006008612A3 (en
Inventor
Brian Galvin Conway
Thomas Norman Nanninga
Haifeng Wu
Garrett Hoge
Bruce Allen Pearlman
Derick Dale Winkle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA002573128A priority Critical patent/CA2573128A1/en
Priority to MXPA06014662A priority patent/MXPA06014662A/en
Priority to BRPI0513028-0A priority patent/BRPI0513028A/en
Priority to EP05754890A priority patent/EP1768952A2/en
Priority to RU2007100355/04A priority patent/RU2007100355A/en
Priority to JP2007519908A priority patent/JP2008505879A/en
Priority to US11/909,318 priority patent/US20090247743A1/en
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of WO2006008612A2 publication Critical patent/WO2006008612A2/en
Publication of WO2006008612A3 publication Critical patent/WO2006008612A3/en
Priority to IL179851A priority patent/IL179851A0/en
Priority to NO20065643A priority patent/NO20065643L/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/32—Decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This invention relates to materials and methods for preparing optically- active ⁇ -amino acids that bind to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of a calcium channel.
  • These compounds including their pharmaceutically acceptable complexes, salts, solvates and hydrates, are useful for treating pain, fibromyalgia, and a variety of psychiatric and sleep disorders.
  • sleep disorders such as insomnia; fibromyalgia; epilepsy; neuropathic pain, including acute and chronic pain; migraine; hot flashes; pain associated with irritable bowel syndrome; restless leg syndrome; anorexia; panic disorder; depression; seasonal affective disorders; and anxiety, including general anxiety disorder, obsessive compulsive behavior, and attention deficit hyperactivity disorder, among others.
  • the present invention provides comparatively efficient and cost-effective methods for preparing compounds of Formula 1,
  • R 1 and R 2 are independently hydrogen atoms or C 1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom; and
  • R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl, aryl- C 1-3 alkyl, or arylamino, wherein each alkyl of R 3 is optionally substituted with one to five fluorine atoms, and each aryl of R 3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C 1-3 alkylamino, C 1-3 alkyl optionally substituted with one to three fluorine atoms, and C 1-3 alkoxy optionally substituted with from one to three fluorine atoms.
  • One aspect of the present invention includes reacting a compound of Formula 2,
  • R 1 , R 2 , and R 3 in Formula 2, Formula 3, and Formula 4 are as defined in Formula 1;
  • R 4 in Formula 2, Formula 3, and Formula 4 is a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, halo-C 1-7 alkyl, halo- C 2-7 alkenyl, halo-C 2-7 alkynyl, aryl-C 1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C 2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and
  • R 5 in Formula 2 and R 19 in Formula 3 are independently hydrogen atom, carboxy, C 1-7 alkanoyl, C 2-7 alkenoyl, C 2-7 alkynoyl, C 3-7 cycloalkanoyl, C 3-7 cycloalkenoyl, halo-C 1-7 alkanoyl, halo-C 2-7 alkenoyl, halo-C 2-7 alkynoyl, C 1-6 alkoxycarbonyl, halo-C 1-6 alkoxycarbonyl, C 3-7 cycloalkoxycarbonyl, aryl- C 1-7 alkanoyl, aryl-C 2-7 alkenoyl, aryl-C 2-7 alkynoyl, aryloxycarbonyl, or aryl- C 1-6 alkoxycarbonyl, provided that R 5 is not a hydrogen atom; and optionally converting the compound of Formula 3 or its diastereomer to the compound of Formula 1 or its diastereomer
  • a useful chiral catalyst for asymmetric hydrogenation of the compounds of Formula 2 or Formula 4 includes a chiral ligand bound to a transition metal through one or more phosphorus atoms.
  • Such catalysts include (R ⁇ S ⁇ -TANGPhos, (R)- BESTAPINE, (R)-eTCFP, or (R)-mTCFP, or stereoisomers thereof, which are bound to rhodium.
  • the asymmetric hydrogenation is typically carried out using a single chiral catalyst.
  • the method may also employ multiple chiral catalysts in which the prochiral substrate (Formula 2 or Formula 4) is reacted successively with first and second chiral catalysts (e.g., (R)-BINAPINE and (R)-mTCFP, respectively, or opposite enantiomers thereof).
  • first and second chiral catalysts e.g., (R)-BINAPINE and (R)-mTCFP, respectively, or opposite enantiomers thereof.
  • the first chiral catalyst has greater stereoselectivity than the second chiral catalyst under the same conditions
  • the second chiral catalyst has a faster rate of reaction than the first chiral catalyst under the same conditions.
  • the compound of Formula 2 may be prepared by reacting the compound of Formula 4,
  • R 5 in Formula 5 is as defined in Formula 2 and X in Formula 5 is a hydroxy or a leaving group, such as halogeno, aryloxy or heteroaryloxy, or -OC(O)R 15 , in which R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, halo-C 1-6 alkyl, halo-C 2-6 alkenyl, halo-C 2-6 alkynyl, aryl, aryl-C 1-6 alkyl, heterocyclyl, heteroaryl, or heteroaryl-C 1-6 alkyl.
  • R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, halo-C 1-6 alkyl, halo-C 2-6 alkenyl, halo-C 2-6 alkynyl, aryl, aryl-C 1-6 al
  • the compound of Formula 4 may be prepared by reacting a compound of Formula 6,
  • ammonia source e.g., ammonia or a mixture of ammonium acetate and acetic acid
  • R 1 , R 2 , and R 3 in Formula 6 are as defined in Formula 1 and R 4 is as defined in Formula 2.
  • Another aspect of the present invention includes reducing an amino moiety of a compound of Formula 7,
  • R 1 , R 2 , and R 3 in Formula 7 are as defined in Formula 1 and R 6 is C 1-6 alkyl (e.g., methyl), C 2-6 alkenyl (e.g., allyl) or aryl-C 1-3 alkyl (e.g., benzyl); and optionally converting the compound of Formula 1 or its diastereomer to a pharmaceutically acceptable complex, salt, solvate or hydrate.
  • the amino moiety may be reduced by reacting the compound of Formula 7 with H 2 in the presence of a catalyst.
  • a catalyst include transition metal catalysts, such as Pd/C and Raney nickel.
  • the compound of Formula 7 may be prepared by reacting a compound of Formula 8,
  • R , R , and R in Formula 8 are as defined in Formula 1 and R 6 is as defined in Formula 7.
  • the compound of Formula 8 may be prepared by cyclizing a compound of Formula 9,
  • R , R , and R in Formula 9 are as defined in Formula 1 and R 6 is as defined in Formula 7.
  • the hydroxy moiety in Formula 9 may be activated (e.g., by conversion to a sulfonate ester) to give an activated alcohol, which is subsequently cyclized by treatment with a base (e.g., a carbonate).
  • the compound of Formula 9 may be prepared by reacting a compound of Formula 10,
  • R , R , and R in Formula 10 are as defined in Formula 1 and R in Formula 11 is as defined in Formula 7.
  • the carboxylic acid moiety of the compound of Formula 10 may be activated using a coupling agent, such as DMT-MM.
  • the compound of Formula 10 may be prepared by reacting the above compound of Formula 6 with H 2 in the presence of a chiral catalyst to give a compound of Formula 12,
  • R 1 , R 2 , R 3 , and R 4 in Formula 12 are as defined in Formula 1 and Formula 2; and optionally converting the compound of Formula 12, or its diastereomer, to the compound of Formula 10.
  • An additional aspect of the present invention includes reducing an amine moiety of a compound of Formula 13,
  • R 1 , R 2 , R 3 , and R 4 in Formula 37 and Formula 13 are as defined in Formula 1 and Formula 2, respectively, and R 7 in Formula 13 is Ci -6 alkyl, C 2-6 alkenyl (e.g., allyl) or aryl-C 1-3 alkyl (e.g., benzyl); and optionally converting the compound of Formula 37 or its diastereomer to the compound of Formula 1 or its diastereomer or to a pharmaceutically acceptable complex, salt, solvate or hydrate of the compound of Formula 1 or its diastereomer.
  • the amine moiety of the compound of Formula 13 may be reduced by reacting the compound of Formula 13 with H 2 in the presence of a catalyst.
  • a catalyst include transition metal catalysts, such as Pd/C and Raney nickel.
  • the compound of Formula 13 may be prepared by treating a compound of Formula 14,
  • R , 1 , R TJ 2 , and R > 3 i •n Formula 15 are as defined in Formula 1, R in Formula 15 is as defined in Formula 2, and R 7 in Formula 14 is as defined in Formula 13.
  • the compound of Formula 15 may be prepared by reacting a compound of Formula 16,
  • R 1 , R 2 , and R 3 in Formula 16 are as defined in Formula 1
  • R 4 in Formula 16 is as defined in Formula 2
  • R 8 is a leaving group.
  • the compound of Formula 16 may be prepared by reacting a compound of Formula 17,
  • R 8 is R 9 O-
  • R 1 , R 2 , and R 3 in Formula 17 are as defined in Formula 1
  • R 4 in Formula 17 is as defined in Formula 2
  • R 9 is tosyl, mesyl, brosyl, closyl, nosyl, or triflyl
  • X 2 is halogen or R 9 O-.
  • the compound of Formula 17 may be prepared by reducing a ⁇ -carbonyl moiety of the above compound of Formula 6.
  • the compound of Formula 6 may be reacted with H 2 in the presence of a catalyst to give the compound of Formula 17.
  • Useful catalysts include transition metal catalysts, such as platinum and ruthenium-based catalysts.
  • the compound of Formula 15 may be prepared by reacting a compound of Formula 39,
  • R , R , and R in Formula 39 are as defined in Formula 1 and R in Formula 39 is as defined in Formula 2.
  • the compound of Formula 39 may be prepared by reacting a compound of Formula 38,
  • the present invention also provides methods of making compounds of Formula 6, above.
  • another aspect of the present invention includes treating a compound of Formula 19,
  • R 1 , R 2 , R 3 , and R 4 in Formula 19 are as defined in Formula 1 and Formula 2.
  • the compound of Formula 19 may be prepared by reacting a compound of Formula 20,
  • R 1 , R 2 , and R 3 in Formula 20 and R in Formula 21 are as defined in Formula 1 and Formula 2, and R 10 in Formula 20 is a leaving group, such as a chiral oxazolidin-2- one-3-yl or an imidazol-1-yl.
  • Useful chiral oxazolidin-2-one-3-yls include (5)-4- isopropyloxazolidin-2-one-3-yl, (i?)-4-isopropyloxazolidin-2-one-3-yl, (S)-4- benzyloxazolidin-2-one-3-yl, (/?)-4-benzyloxazolidin ⁇ 2-one-3-yl, (5)-4- phenyloxazolidin-2-one-3-yl, (7?) ⁇ 4-phenyloxazolidin-2-one-3-yl, (45',5i?)-4-methyl-5- phenyloxazolidin-2-one-3-yl, or (4i?,55)-4-methyl-5-phenyloxazolidin-2-one-3-yl or stereoisomers thereof.
  • the compound of Formula 20 may be prepared by reacting a compound of Formula 22,
  • coupling agent examples include CDI, DCC, DMT-MM, FDPP, TATU, BOP, PyBOP, EDCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, iV,2V-bis-(2-oxo-3-oxazolidmyl)- phosphinic chloride, diphenylphosphoryl azide, diphenylphosphinic chloride, or diphenylphosphoryl cyanide.
  • the compound of Formula 22 may be prepared by hydrolyzing a compound of Formula 23,
  • R , R , and R in Formula 23 are as defined in Formula 1.
  • the compound of Formula 23 may be prepared by reacting a compound of Formula 24,
  • the compound of Formula 24 may be prepared by reacting a compound of Formula 25,
  • Formula 25 are as defined in Formula 1, R in Formula 26 is a tosyl, mesyl, brosyl, closyl, nosyl, or triflyl, and X is halogen.
  • the compound of Formula 22 may be prepared by hydrolyzing a compound of Formula 27,
  • R 1 , R 2 , and R 3 in Formula 27 are as defined in Formula 1, and R 13 , R 14 , R 15 , and R 16 are independently hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl- C 1-6 alkyl, aryl, or aryl-Ci- 3 alkyl, provided that R 15 and R 16 are different and are not both hydrogen atoms.
  • An additional aspect of the present invention includes treating a compound of Formula 33,
  • Formula 1 and Formula 2, and R in Formula 32 is a leaving group.
  • the compound of Formula 32 may be prepared by reacting a compound of Formula 34,
  • the present invention also provides compounds represented by Formula 2 to 4, 6 to 10, 12, 13, 15 to 17, 19, 20, 22, and 39, which are given above, and includes their complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures.
  • R , R , and R in Formula 40 are as defined above in Formula 1;
  • R 20 is a hydrogen atom, hydroxy, R 6 -O-NH-, R 9 O- or R 19 -NH-, or
  • R 21 is a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • R 6 , R 7 , R 9 , and R 19 are as defined in Formula 7, Formula 13, Formula 18, and Formula 3, respectively.
  • a further aspect of the present invention provides compounds of Formula 39,
  • R 1 , R 2 , and R 3 in Formula 39 are as defined in Formula 1, and R 4 is as defined above in Formula 2.
  • R , R , and R in Formula 41 are as defined in Formula 1, R is as defined in Formula 2, and R is a hydrogen atom or carboxy.
  • R 1 , R 2 , and R 3 in Formula 42 are as defined in Formula 1, and R is a hydrogen atom or a chiral oxazolidin-2-one-3-yl.
  • the present invention also includes the following compounds, as well as their pharmaceutically acceptable complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures:
  • the present invention includes all complexes and salts, whether pharmaceutically acceptable or not, solvates, hydrates, and polymorphic forms of the disclosed compounds.
  • Certain compounds may contain an alkenyl or cyclic group, so that cisltrans (or ZIE) stereoisomers are possible, or may contain a keto or oxime group, so that tautomerism may occur.
  • the present invention generally includes all ZIE isomers and tautomeric forms, whether they are pure, substantially pure, or mixtures.
  • wavy bonds When attached to a stereogenic center, the wavy bonds refer to both stereoisomers, either individually or as mixtures. Likewise, when attached to a double bond, the wavy bonds indicate a Z-isomer, an E-isomer, or a mixture of Z and
  • Substituted groups are those in which one or more hydrogen atoms have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
  • Alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (i.e., C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms).
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, /-propyl, ⁇ -butyl, s-butyl, /-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2,2-trimethyleth-l-yl, n-hexyl, and the like.
  • Alkenyl refers to straight chain and branched hydrocarbon groups having one or more unsaturated carbon-carbon bonds, and generally having a specified number of carbon atoms.
  • alkenyl groups include, without limitation, ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, 1- buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl- 1-propen- l-yl, 2-methyl-2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
  • Alkynyl refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms.
  • alkynyl groups include, without limitation, ethynyl, 1- propyn-1-yl, 2-propyn-l-yl, 1-butyn-l-yl, 3-butyn-l-yl, 3-butyn-2-yl, 2-butyn-l-yl, and the like.
  • alkanoyl refers to alkyl-C(O)-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon.
  • alkanoyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
  • alkenoyl and alkynoyl refer, respectively, to alkenyl-C(O)- and alkynyl-C(O)-, where alkenyl and alkynyl are defined above. References to alkenoyl and alkynoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon.
  • alkenoyl groups include, without limitation, propenoyl, 2-methylpropenoyl, 2-butenoyl, 3-butenoyl, 2-methyl-2-butenoyl, 2-methyl-3- butenoyl, 3-methyl-3-butenoyl, 2-pentenoyl, 3-pentenoyl, 4-pentenoyl, and the like.
  • alkynoyl groups include, without limitation, propynoyl, 2-butynoyl, 3- butynoyl, 2-pentynoyl, 3-pentynoyl, 4-pentynoyl, and the like.
  • alkoxy and “alkoxycarbonyl” refer, respectively, to alkyl-O-, alkenyl-O, and alkynyl-O, and to alkyl-O-C(O)-, alkenyl-O-C(O)-, alkynyl-O-C(O)-, where alkyl, alkenyl, and alkynyl are defined above.
  • alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, /-propoxy, n-butoxy, s-butoxy, t- butoxy, n-pentoxy, s-pentoxy, and the like.
  • alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i- propoxycarbonyl, n-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, n- pentoxycarbonyl, s-pentoxycarbonyl, and the like.
  • Halo “Halo,” “halogen” and “halogeno” may be used interchangeably, and refer to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers, respectively, to alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl are defined above.
  • haloalkyl groups include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.
  • Cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring (i.e., C 3-7 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members).
  • the cycloalkyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements.
  • the cycloalkyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
  • Examples of monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Examples of bicyclic cycloalkyl groups include, without limitation, bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[3.3.1]n
  • Cycloalkenyl refers monocyclic and bicyclic hydrocarbon rings having one or more unsaturated carbon-carbon bonds and generally having a specified number of carbon atoms that comprise the ring (i.e., C 3-7 cycloalkenyl refers to a cycloalkenyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members).
  • the cycloalkenyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements.
  • the cycloalkenyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
  • Cycloalkanoyl and “cycloalkenoyl” refer to cycloalkyl-C(O)- and cycloalkenyl-C(O)-, respectively, where cycloalkyl and cycloalkenyl are defined above.
  • References to cycloalkanoyl and cycloalkenoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon.
  • cycloalkanoyl groups include, without limitation, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, 1-cyclobutenoyl, 2-cyclobutenoyl, 1-cyclopentenoyl, 2-cyclopentenoyl, 3-cyclopentenoyl, 1-cyclohexenoyl, 2-cyclohexenoyl, 3- cyclohexenoyl, and the like.
  • Cycloalkoxy and “cycloalkoxycarbonyl” refer, respectively, to cycloalkyl-O- and cycloalkenyl-0 and to cycloalkyl-O-C(O)- and cycloalkenyl-O- C(O)-, where cycloalkyl and cycloalkenyl are defined above.
  • References to cycloalkoxy and cycloalkoxycarbonyl generally include a specified number of carbon atoms, excluding the carbonyl carbon.
  • cycloalkoxy groups include, without limitation, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, 1- cyclobutenoxy, 2-cyclobutenoxy, 1-cyclopentenoxy, 2-cyclopentenoxy, 3- cyclopentenoxy, 1-cyclohexenoxy, 2-cyclohexenoxy, 3-cyclohexenoxy, and the like.
  • cycloalkoxycarbonyl groups include, without limitation, 99 cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, l-cyclobutenoxycarbonyl, 2-cyclobutenoxycarbonyl, 1- cyclopentenoxycarbonyl, l-cyclopentenoxycarbonyl, S-cyclopentenoxycarbonyl, 1- cyclohexenoxycarbonyl, l-cyclohexenoxycarbonyl, 3-cyclohexenoxycarbonyl, and the like.
  • Aryl and “arylene” refer to monovalent and divalent aromatic groups, respectively, including 5- and 6-membered monocyclic aromatic groups that contain 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, furanyl, thiopheneyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and the like.
  • Aryl and arylene groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings described above.
  • multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiopheneyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, indolizinyl, and the like.
  • aryl and arylene groups may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements.
  • aryl and arylene groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.
  • Heterocycle and “heterocyclyl” refer to saturated, partially unsaturated, or unsaturated monocyclic or bicyclic rings having from 5 to 7 or from 7 to 11 ring members, respectively. These groups have ring members made up of carbon atoms and from 1 to 4 heteroatoms that are independently nitrogen, oxygen or sulfur, and may include any bicyclic group in which any of the above-defined monocyclic heterocycles are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to a parent group or to O -2 a substrate at any heteroatom or carbon atom unless such attachment would violate valence requirements.
  • any of the carbon or nitrogen ring members may include a non-hydrogen substituent unless such substitution would violate valence requirements.
  • Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.
  • heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH- indazolyl, indolenyl, indolin
  • ⁇ eteroaryl and “heteroarylene” refer, respectively, to monovalent and divalent heterocycles or heterocyclyl groups, as defined above, which are aromatic. ⁇ eteroaryl and heteroarylene groups represent a subset of aryl and arylene groups, respectively.
  • Arylalkyl and “heteroarylalkyl” refer, respectively, to aryl-alkyl and heteroaryl-alkyl, where aryl, heteroaryl, and alkyl are defined above. Examples include, without limitation, benzyl, fluorenylmethyl, imidazol-2-yl-methyl, and the like.
  • Arylalkanoyl refers, respectively, to aryl-alkanoyl, heteroaryl-alkanoyl, aryl-alkenoyl, heteroaryl-alkenoyl, aryl-alkynoyl, and heteroaryl-alkynoyl, where aryl, heteroaryl, alkanoyl, alkenoyl, and alkynoyl are defined above.
  • Examples include, without limitation, benzoyl, benzylcarbonyl, fluorenoyl, fluorenylmethylcarbonyl, imidazol-2-oyl, imidazol-2-yl-methylcarbonyl, phenylethenecarbonyl, 1-phenylethenecarbonyl, 1-phenyl-propenecarbonyl, 2-phenyl- propenecarbonyl, 3-phenyl-propenecarbonyl, imidazol-2-yl-ethenecarbonyl, 1- (imidazol-2-yl)-ethenecarbonyl, l-(imidazol-2-yl)-propenecarbonyl, 2-(imidazol ⁇ 2- yl)-propenecarbonyl, 3 -(imidazol-2-yl)-propenecarbonyl, phenylethynecarbonyl, phenylpropynecarbonyl, (imidazol-2-yl)-ethyn
  • Arylalkoxy and “heteroarylalkoxy” refer, respectively, to aryl-alkoxy and heteroaryl-alkoxy, where aryl, heteroaryl, and alkoxy are defined above. Examples include, without limitation, benzyloxy, fluorenylmethyloxy, imidazol-2-yl- methyloxy, and the like.
  • Aryloxy and “heteroaryloxy” refer, respectively, to aryl-O- and heteroaryl-O-, where aryl and heteroaryl are defined above. Examples include, without limitation, phenoxy, imidazol-2-yloxy, and the like.
  • Aryloxycarbonyl refers, respectively, to aryloxy-C(O)-, heteroaryloxy- C(O)-, arylalkoxy-C(O)-, and heteroarylalkoxy-C(O)-, where aryloxy, heteroaryloxy, arylalkoxy, and heteroarylalkoxy are defined above.
  • Leaving group refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group .and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons.
  • nucleofugal leaving group The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups.
  • Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate).
  • Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides.
  • Some stronger bases, such as NH 2 and OH " can be made better leaving groups by treatment with an acid.
  • Common electrofugal leaving groups include the proton, CO 2 , and metals.
  • Enantiomeric excess or "ee” is a measure, for a given sample, of the excess of one enantiomer over a racemic sample of a chiral compound and is expressed as a percentage. Enantiomeric excess is defined as 100 x (er - 1) / (er + 1), where "er” is the ratio of the more abundant enantiomer to the less abundant enantiomer.
  • Diastereomeric excess or "de” is a measure, for a given sample, of the excess of one diastereomer over a sample having equal amounts of diastereomers and is expressed as a percentage. Diastereomeric excess is defined as 100 x (dr - 1) / (dr + 1), where "dr” is the ratio of a more abundant diastereomer to a less abundant diastereomer.
  • Stepselective refer to a given process (e.g., hydrogenation) that yields more of one stereoisomer, enantiomer, or diastereoisomer than of another, respectively.
  • High level of stereoselectivity refers to a given process that yields products having an excess of one stereoisomer, enantiomer, or diastereoisomer, which comprises at least about 90% of the products.
  • a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.
  • Steps of the invention refer, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another.
  • the degree of enrichment may be measured by % of total product, or for a pair of enantiomers or diastereomers, by ee or de.
  • substantially pure stereoisomer refers, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 95% of the sample.
  • a substantially pure enantiomer or diastereomer would correspond to samples having an ee or de of about 90% or greater.
  • a "pure stereoisomer,” “pure enantiomer,” “pure diastereomer,” and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 99.5% of the sample.
  • a pure enantiomer or pure diastereomer would correspond to samples having an ee or de of about 99% or greater.
  • Optesite enantiomer refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.
  • Stepoisomers of a specified compound refer to the opposite enantiomer of the compound and to any diastereoisomers or geometric isomers (Z/E) of the compound.
  • Z/E geometric isomers
  • the specified compound has S,R,Z stereochemical configuration
  • its stereoisomers would include its opposite enantiomer having R,S,Z configuration, its diastereomers having S,S,Z configuration and R,R,Z configuration
  • its geometric isomers having S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration.
  • Solvate refers to a molecular complex comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., EtOH).
  • solvent molecules e.g., EtOH
  • Hydrate refers to a solvate comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.
  • “Pharmaceutically acceptable complexes, salts, solvates, or hydrates” refers to complexes, acid or base addition salts, solvates or hydrates of claimed and disclosed compounds, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Pre-catalyst or “catalyst precursor” refers to a compound or set of compounds that are converted into a catalyst prior to use.
  • Treating refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition to which such term applies, or to preventing one or more symptoms of such disorder or condition.
  • Treatment refers to the act of "treating,” as defined immediately above.
  • certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites.
  • Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound.
  • protecting group strategies a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and the like, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000), which are herein incorporated by reference in their entirety for all purposes.
  • the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about RT, but particular reactions may require the use of higher temperatures (e.g., reflux conditions) or lower temperatures, depending on reaction kinetics, yields, and the like. Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be ' polar protic solvents, polar aprotic solvents, non-polar solvents, or some combination. Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., includes the indicated endpoints.
  • This disclosure concerns materials and methods for preparing optically active ⁇ -amino acids represented by Formula 1, above, including diastereomers thereof and pharmaceutically acceptable complexes, salts, solvates and hydrates thereof.
  • the claimed and disclosed methods provide compounds of Formula 1 that are stereoisomerically enriched, and which in many cases, are pure or substantially pure stereoisomers.
  • the compounds of Formula 1 have at least two stereogenic centers and include substituents R 1 , R 2 , and R 3 .
  • Substituents R 1 and R 2 are independently hydrogen atoms or C 1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R 1 is a hydrogen atom, R 2 is not a hydrogen atom.
  • Substituent R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl, aryl-C 1-3 alkyl, or arylamino, wherein each alkyl of R is optionally substituted with one to five fluorine atoms, and each aryl of R is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C 1-3 alkylamino, C 1-3 alkyl optionally substituted with one to three fluorine atoms, and C 1-3 alkoxy optionally substituted with from one to three fluorine atoms.
  • R 1 independently hydrogen or C 1-3 alkyl, provided that R and R are not both hydrogen, and those in which R 3 is C 1-6 alkyl.
  • Representative compounds of Formula 1 also include those in which R 1 is hydrogen, R 2 is methyl, and R 3 is methyl, ethyl or n- propyl, i.e., (3 1 S,5i?)-3-amino-5-methyl-heptanoic acid, (35,5/?)-3-amino-5-methyl- octanoic acid, and (35,5i?)-3-amino-5-methyl-nonanoic acid.
  • Scheme I illustrates a method of preparing a desired stereoisomer of the compound of Formula 1.
  • the stereoselective synthesis includes reacting an optically active ⁇ -dicarbonyl (Formula 6) with a source of ammonia to give an optically active enamine (Formula 4) that is optionally reacted with an acylating agent (Formula 5) to give an optically active enamide (Formula 2).
  • the enamine (Formula 4) or the enamide (Formula 2) is reacted with hydrogen in the presence of a chiral catalyst to yield the compound of Formula 3, which is optionally hydrolyzed to the compound of Formula 1 by treatment with an acid or base.
  • Substituents R 1 , R 2 , and R 3 in Formula 2, 3, 4 and 6 are as defined in Formula 1; substituent R 4 in Formula 2, 3, 4, and 6 is a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, halo-C 1-7 alkyl, halo-C 2-7 alkenyl, halo-C 2-7 alkynyl, aryl-C 1-6 alkyl, aryl-C 2-6 alkenyl, or aryl-C 2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and substituents R 5 in Formula 2 and Formula 5 and R in Formula 3 are independently hydrogen atom, carboxy, C 1-7 alkanoyl, C 2-7 alkenoy
  • R 1 , R 2 , R 3 , etc. when used in a subsequent formula, will have the same definition as in the earlier formula.
  • R in a first formula is hydrogen atom, halogeno, or C 1-6 alkyl
  • R in a second formula is also hydrogen, halogeno, or C 1-6 alkyl.
  • the ⁇ -dicarbonyl (Formula 6) may be prepared using methods illustrated in Scheme IV and Scheme V, below, and is converted to the enamine (Formula 4) through treatment with an ammonia source.
  • Representative ⁇ -dicarbonyl compounds (Formula 6) include various C 1-6 alkyl esters of (2?)-5-methyl-3-oxo-heptanoic acid, (/?)-5-methyl-3-oxo-octanoic acid, and (i?)-5-methyl-3-oxo-nonanoic acid.
  • Examples of ⁇ -dicarbonyls thus include (/?)-5-methyl-3-oxo-heptanoic acid ethyl ester, (R)S- methyl-3-oxo-octanoic acid ethyl ester, and (Z?)-5-methyl-3-oxo-nonanoic acid ethyl ester.
  • Useful sources of ammonia include ammonia and ammonium acetate, among others. See, e.g., P. G. Baraldi et al., Synthesis (ll):902-903 (1983). The reaction is typically carried out with excess ammonium acetate (e.g., 1.2 eq. or greater) in a protic solvent, such as EtOH or HOAc, and at RT or above (up to reflux temperature).
  • a protic solvent such as EtOH or HOAc
  • the enamine (Formula 4) is optionally converted to the enamide (Formula 2) via contact with an acylating agent (Formula 5).
  • Representative enamines include C 1-6 alkyl esters of the Z- and E-isomers of (R)-3- amino-5-methyl-hept-2-enoic acid, (i?)-3-amino-5-methyl-oct-2-enoic acid, and (R)-3- amino-5-methyl-non-2-enoic acid.
  • Examples of enamines thus include the Z- and E- isomers of (/?)-3-amino-5-methyl-hept-2-enoic acid ethyl ester, (/?)-3-amino-5- methyl-oct-2-eiioic acid ethyl ester, and (/?)-3-amino-5-methyl-non-2-enoic acid ethyl ester.
  • Useful acylating agents include carboxylic acids, which have been activated either prior to contacting the enamine (Formula 4) or in-situ (i.e., in the presence of the enamine using an appropriate coupling agent).
  • Representative activated carboxylic acids include acid halides, anhydrides, mixed carbonates, and the like, in which X 1 is a leaving group, such as halogeno, aryloxy (e.g. phenoxy, 3,5- dimethoxyphenoxy, etc.) and heteroaryloxy (e.g., imidazolyloxy), or -OC(O)R 15 , in which R 15 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, halo-C 1-6 alkyl, halo-C 2-6 alkenyl, halo-C 2-6 alkynyl, aryl, aryl-C 1-6 alkyl, heterocyclyl, heteroaryl, or heteroaryl-Ci. 6 alkyl.
  • X 1 is a leaving group, such as halogeno, aryloxy (e.g. phenoxy, 3,5- dimethoxyphenoxy, etc.) and hetero
  • Suitable acylating agents include carboxylic acids, which are activated in-situ using a coupling agent.
  • the reaction is carried out in an aprotic solvent, such as ACN, DMF, DMSO, toluene, MeCl 2 , NMP, THF, etc., and may also employ a catalyst.
  • Coupling agents include, but are not limited to DCC, DMT-MM, FDPP, TATU, BOP, PyBOP, EDCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, iV,iV-bis-(2-oxo-3-oxazolidinyl) ⁇ phosphinic chloride, diphenylphosphoryl azide, diphenylphosphinic chloride, and diphenylphosphoryl cyanide.
  • Useful catalysts for the coupling reaction include DMAP, HODhbt, HOBt, and HOAt.
  • optically active enamine (Formula 4) or enamide (Formula 2) undergoes asymmetric hydrogenation in the presence of a chiral catalyst to give the compound of Formula 3.
  • useful enamide hydrogenation substrates (Formula 2) include individual Z- or E-isomers or a mixture of Z- and E- isomers, and include C 1-6 alkyl esters of the Z- and E- isomers of (/?)-3-acetylamino-5- methyl-hept-2-enoic acid, (i?)-3-acetylamino-5-methyl-oct-2-enoic acid, and (R)-3- acetylamino-5-methyl-non-2-enoic acid.
  • Examples of useful enamides thus include the Z- and E- isomers of (i?) ⁇ 3-acetylamino-5-methyl-hept-2-enoic acid ethyl ester, (i?)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester, and (i?)-3-acetylamino-5- methyl-non-2-enoic acid ethyl ester.
  • the method may optionally include converting the carboxylic acid to a Group 1, Group 2, or ammonium salt prior to asymmetric hydrogenation through contact with a suitable base, such as a primary amine (e.g., t-BuNH 2 ), a secondary amine (DIPEA), and the like.
  • a suitable base such as a primary amine (e.g., t-BuNH 2 ), a secondary amine (DIPEA), and the like.
  • a salt of the enamide (Formula 2) or enamine (Formula 4) may increase conversion, improve stereoselectivity, or provide other advantages.
  • the method may employ an inorganic salt of the carboxylic acid obtained through contact with a suitable base such as NaOH, Na 2 CO 2 , LiOH, Ca(OH) 2 , and the like.
  • the asymmetric hydrogenation generates an excess (de) of a diastereoisomer of Formula 3.
  • a de of the desired diastereoisomer of about 50 % or greater is desirable; a de of about 70 % or greater is more desirable; and a de of about 85 % is still more desirable.
  • Particularly useful asymmetric hydrogenations are those in which the de of the desired diastereoisomer is about 90 % or greater.
  • a desired diastereoisomer or enantiomer is considered to be substantially pure if it has a de or ee of 95 % or greater.
  • the asymmetric hydrogenation of the enamide (Formula 2) or enamine (Formula 4) employs a chiral catalyst having the requisite stereochemistry.
  • Useful chiral catalysts include, without limitation, cyclic or acyclic, chiral phosphine ligands (e.g., monophosphines, bisphosphines, bisphospholanes, etc.) or phosphinite ligands bound to transition metals, such as ruthenium, rhodium, iridium or palladium.
  • Ru-, Rh-, Ir- or Pd-phosphine, phosphinite or phosphino oxazoline complexes are optically active because they possess a chiral phosphorus atom or a chiral group connected to a phosphorus atom, or because in the case of BINAP and similar atropisomeric ligands, they possess axial chirality.
  • Useful chiral ligands include, without limitation, BisP*; (R)-BINAPINE; (S)-Me-ferrocene- Ketalphos, (R 5 R)-DIOP; (R 5 R)-DIPAMP; (R)-(S)-BPPFA; (S,S)-BPPM; (+)-CAMP; (S 5 S)-CHIRAPHOS; (R)-PROPHOS; (R 5 R)-NORPHOS; (R)-BINAP; (R)-CYCPHOS; (R 5 R)-BDPP; (R 5 R)-DEGUPHOS; (R 5 R)-Me-DUPHOS; (R 5 R)-Et-DUPHOS; (R 5 R)-/- Pr-DUPHOS; (R 5 R)-Me-BPE; (R 5 R)-Et-BPE (R)-PNNP; (R)-BICHEP; (R,S,R,S)-Me- PENNPHOS;
  • Other useful chiral ligands include, without limitation, (R) ⁇ (-)-l-[(S)-2- (di(3,5-bistrifluoromethylphenyl)phosphino)ferrocenyl]ethyldicyclohexyl-phosphine; (R)-(-)-l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocen-yl]ethyldi(3,5- dimethylphenyl)phosphine; (R)-(-)-l-[(S)-2-(di-t-butylphosphino)ferro- cenyl]ethyldi(3,5-dimethylphenyl)phosphine; (R)-(-)-l-[(S)-2-(dicyclohexylphosphi- no)ferrocenyl]ethyldi-t-butyl
  • Useful ligands may also include stereoisomers (enantiomers and diastereoisomers) of the chiral ligands described in the preceding paragraphs, which may be obtained by inverting all or some of the stereogenic centers of a given ligand or by inverting the stereogenic axis of an atropoisomeric ligand.
  • useful chiral ligands may also include (,S)-Cl-MeO-BIPHEP; (S)-PHA ⁇ EPHOS; (5,S)-Me-DUPHOS; (5,S)-Et-DUPHOS; (S)-BINAP; (S)-ToI-BINAP; (R)-(R)- JOSIPHOS; (S)-(S)-JOSIPHOS; (S)-eTCFP; (S)-mTCFP and so on.
  • a catalyst precursor or pre-catalyst is a compound or set of compounds, which are converted into the chiral catalyst prior to use.
  • Catalyst precursors typically comprise Ru, Rh, Ir or Pd complexed with the phosphine ligand and either a diene (e.g., norboradiene, COD, (2-methylallyl) 2 , etc.) or a halide (Cl or Br) or a diene and a halide, in the presence of a counterion, X “ , such as OTf " , PF 6 “ , BF 4 “ , SbF 6 “ , ClO 4 " , etc.
  • a diene e.g., norboradiene, COD, (2-methylallyl) 2 , etc.
  • a halide Cl or Br
  • a catalyst precursor comprised of the complex, [(bisphosphine ligand)Rh(COD)] + X ⁇ may be converted to a chiral catalyst by hydrogenating the diene (COD) in MeOH to yield [(bisphosphine ligand)Rh(MeOH) 2 ] + X ⁇ MeOH is subsequently displaced by the enamide (Formula 2) or enamine (Formula 4), which undergoes enantioselective hydrogenation to the desired chiral compound (Formula 3).
  • Examples of chiral catalysts or catalyst precursors include (+)-TMBTP- ruthenium(II) chloride acetone complex; (S)-Cl-MeO-B EPHEP-ruthenium(II) chloride Et 3 N complex; (S)-BINAP-rathenium(II) Br 2 complex; (S)-tol-BINAP-ruthenium(II) Br 2 complex; [((3i?,4i?)-3,4-bis(diphenylphosphino)-l-methylpyrrolidine)-rhodium- (l,5-cyclooctadiene)]-tetrafluoroborate complex; [((R,R,S,S)-TANGPhos)-rhodium(I)- bis(l,5-cyclooctadiene)]-trifluoromethane sulfonate complex; [(R)-BINAPINE- rhodium-(l,5-cyclooctaidene
  • the molar ratio of the substrate and catalyst may depend on, among other things, H 2 pressure, reaction temperature, and solvent (if any).
  • the substrate-to- catalyst ratio exceeds about 100:1 or 200:1, and substrate-to-catalyst ratios of about 1000: 1 or 2000: 1 are common.
  • the chiral catalyst may be recycled, higher substrate-to-catalyst ratios are more useful.
  • the asymmetric hydrogenation is typically carried out at about RT or above, and under about 10 kPa (0.1 atm) or more of H 2 .
  • the temperature of the reaction mixture may range from about 20°C to about 80°C, and the H 2 pressure may range from about 10 kPa to about 5000 kPa or higher, but more typically, ranges from about 10 kPa to about 100 kPa.
  • the combination of temperature, H 2 pressure, and substrate-to-catalyst ratio is generally selected to provide substantially complete conversion (i.e., about 95 wt %) of the substrate (Formula 2 or 4) within about 24 h. With many of the chiral catalysts, decreasing the H 2 pressure increases the enantioselectivity.
  • a variety of solvents may be used in the asymmetric hydrogenation, including protic solvents, such as water, MeOH, EtOH, and z ' -PrOH.
  • Other useful solvents include aprotic polar solvents, such as THF, ethyl acetate, and acetone.
  • the stereoselective hydrogenation may employ a single solvent or may employ a mixture of solvents, such as THF and MeOH, THF and water, EtOH and water, MeOH and water, and the like.
  • the method may provide for reacting the enamide or enamine successively with first and second chiral catalysts to exploit the comparatively greater stereoselectivity, but lower reaction rate of the first (or second) chiral catalyst.
  • the method provides for reacting the substrate with hydrogen in the presence of a chiral catalyst comprised of (R)-BINAPINE or its opposite enantiomer, followed by reaction in the presence of a chiral catalyst comprised of (R)-mTCFP or its opposite enantiomer.
  • the method optionally provides for conversion of the hydrogenation product (Formula 3) into the optically active ⁇ -amino acid (Formula 1).
  • the ester and amide moieties may be hydrolyzed by treatment with an acid or a base or by treatment with a base (or acid) followed by treatment with an acid (or base).
  • treating the compound of Formula 3 with HCl, H 2 SO 4 , and the like, with excess H 2 O generates the ⁇ -amino acid (Formula 1) or an acid addition salt.
  • Treating the compound of Formula 3 with an aqueous inorganic base such as LiOH, KOH, NaOH, CsOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , and the like, in an optional polar solvent (e.g., THF, MeOH, EtOH, acetone, ACN, etc.) gives a base addition salt of a ⁇ -amido acid, which may be treated with an acid to generate the ⁇ -amino acid (Formula 1) or an acid addition salt.
  • R 19 in Formula 3 is hydrogen, the ester moiety may be hydrolyzed by treatment with an acid or base to give the ⁇ -amino acid (Formula 1) or an acid or base addition salt.
  • ester and amide hydrolysis may be carried out at RT or at temperatures up to reflux temperature, and if desired, treatment of the acid or base addition salts with a suitable base (e.g., NaOH) or acid (e.g., HCl) gives the free amino acid (zwitterion).
  • a suitable base e.g., NaOH
  • acid e.g., HCl
  • Useful compounds represented by Formula 3 include ⁇ -amino and ⁇ - amido C 1-6 alkyl esters in which R 1 and R 2 are independently hydrogen or C 1-3 alkyl, provided that R 1 and R 2 are not both hydrogen, and those in which R 3 is C 1-6 alkyl.
  • Useful compounds of Formula 3 also include those in which R is hydrogen, R is methyl, and R is methyl, ethyl or n-propyl, i.e., C 1-6 alkyl esters of (3,S',5/?)-3-amino- 5-methyl-heptanoic acid, (35,5/?)-3-amino-5-methyl-octanoic acid, (3S,5R)-3-amhio- 5-methyl-nonanoic acid, (35,5/?)-3-acetylamino-5-methyl-heptanoic acid, (3S,5R)-3- acetylamino-5-methyl-octanoic acid, and (3S,5R)-3-acetylamino-5-methyl-nonanoic acid.
  • Examples of useful ⁇ -amino C 1-6 alkyl esters thus include (3S,5/?)-3-amino-5- methyl-heptanoic acid ethyl ester, (35',5i?)-3-amino-5-methyl-octanoic acid ethyl ester, and (35 r ,5i?)-3-amino-5-methyl-nonanoic acid ethyl ester.
  • useful ⁇ - amido C 1-6 alkyl esters include (3S,5R)-3-acetylamino-5-methyl-heptanoic acid ethyl ester, (3S,5R)-3-acetylamino ⁇ 5-methyl-octanoic acid ethyl ester, and (3S,5R)-3- acetylamino-5-methyl-nonanoic acid ethyl ester.
  • Compounds of Formula 3 also include ⁇ -amido acids in which R 1 and R 2 are independently hydrogen or C 1-3 alkyl, provided that R 1 and R 2 are not both hydrogen, and those in which R 3 is C 1-6 alkyl.
  • Useful ⁇ -amido acids of Formula 3 also include those in which R is hydrogen, R is methyl, and R is methyl, ethyl or n- propyl, i.e., (3S,5i?)-3-acetylamino ⁇ 5-methyl-heptanoic acid, (35',5/?)-3-acetylamino- 5-methyl-octanoic acid, and (3S,5R)-3-acetylamino-5-methyl-nonanoic acid.
  • the compound of Formula 1, or its diastereoisomer may be further enriched through, e.g., fractional recrystallization or chromatography or by recrystallization in a suitable solvent.
  • compounds of Formula 1 or 3 may be enriched through treatment with an enzyme such as a lipase or amidase.
  • Scheme II illustrates another method for preparing the desired stereoisomer of the compound of Formula 1.
  • the stereoselective synthesis includes reacting an optically active ⁇ -dicarbonyl (Formula 6) with hydrogen in the presence of a chiral catalyst to yield an optically active ⁇ -hydroxy carboxylic acid derivative (Formula 12) that is subsequently hydrolyzed to give the corresponding ⁇ -hydroxy acid (Formula 10).
  • the activated acid is reacted with an amine (Formula 11) to give an optically active amide (Formula 9), which is cyclized under Mitsunobu conditions (e.g., Ph 3 P, DEAD, dry THF) to give a chiral lactam (Formula 8) with inversion of the stereocenter.
  • Mitsunobu conditions e.g., Ph 3 P, DEAD, dry THF
  • a chiral lactam (Formula 8) with inversion of the stereocenter.
  • other useful azodicarboxylates include DBAD, DIAD, and l,l'-(azodicarbonyl)dipiperidine.
  • the alcohol (Formula 9) may be activated by conversion to a sulfonate ester (e.g., reaction with MsCl and pyridine), which is subsequently cyclized by treatment with a base (e.g., a carbonate).
  • a base e.g., a carbonate.
  • Treatment of the lactam (Formula 8) with an acid or base gives a secondary amine (Formula 7), which is subsequently reduced via, e.g., catalytic hydrogenolysis to give the compound of Formula 1.
  • Substituents R 1 , R 2 , and R 3 in Formula 7 to 10 and Formula 12 are as defined in Formula 1; substituent R 4 in Formula 12 is as defined in Formula 6; and substituent R 6 in Formula 7 to 9 and Formula 11 is aryl-C 1-3 alkyl (e.g., benzyl, 3,5-dimethoxybenzyl, etc.), C 1-6 alkyl (e.g., methyl) or C 2-6 alkenyl (e.g., allyl).
  • aryl-C 1-3 alkyl e.g., benzyl, 3,5-dimethoxybenzyl, etc.
  • C 1-6 alkyl e.g., methyl
  • C 2-6 alkenyl e.g., allyl
  • the chiral catalyst should promote the formation of a hydroxy-substituted stereocenter (Formula 12) having the opposite stereochemical configuration as that of the ⁇ -carbon of the final product (Formula 1).
  • reagents and conditions for coupling the ⁇ -hydroxy carboxylic acid (Formula 10) and the primary amine (Formula 11) to give the chiral amide (Formula 9) include reagents and conditions described in Scheme I for acylation of the enamine (Formula 4).
  • the ⁇ -hydroxy carboxylic acid (Formula 10) may be activated in-situ with a coupling agent (e.g., DMT-MM) and reacted with a primary amine (e.g., BnONH 2 or BnONH 3 + Cl " ) to give the chiral amide (Formula 9 in which R 6 is Bn).
  • Useful ⁇ -hydroxy carboxylic acids include (3R,5R)-3- hydroxy-5-methyl-heptanoic acid, (3/?,5i?)-3-hydroxy-5-methyl-octanoic acid, and (3/?,5i?)-3-hydroxy-5-methyl-nonanoic acid.
  • Representative ⁇ -hydroxy amides include aryl-C 1-3 alkyl amides derived from the aforementioned carboxylic acids, including (3i?,5/?)-3-hydroxy-5-methyl-heptanoic acid benzyloxy- amide, (3/?,5/?)-3-hydroxy-5-methyl-octanoic acid benzyloxy-amide, and (3R,5R)-3- hydroxy-5-methyl-nonanoic acid benzyloxy-amide.
  • reagents and conditions for hydrolyzing the ⁇ -hydroxy carboxylic acid derivative (Formula 12) or the lactam (Formula 8) include reagents and conditions described in Scheme I for hydrolysis of the amino acid ester (Formula 3).
  • Useful, ⁇ -hydroxy carboxylic acid derivatives (Formula 12) include C 1-6 alkyl esters of (3/?,5/?)-3-hydroxy-5-methyl-heptanoic acid, (3R,5i?)-3-hydroxy- 5-methyl-octanoic acid, and (3R,5i?)-3-hydroxy-5-methyl-nonanoic acid.
  • Examples of useful ⁇ -hydroxy C 1-6 alkyl esters include (3/?,5/?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester, (3i?,5i?)-3-hydroxy-5-methyl-octanoic acid ethyl ester, and (3R,5K)- 3-hydroxy-5-methyl-nonanoic acid ethyl ester.
  • Representative lactams include (2/?,45>l-(aryl-C 1-3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-one, (2R,45)-1- (aryl-Ci- 3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-one, and (2 ⁇ ,45)-l-(aryl- C 1-3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-ones.
  • Hydrogenolysis is carried out in the presence of a catalyst and one or more polar solvents, including without limitation, alcohols, ethers, esters and acids, such as MeOH, EtOH, IPA, THF, EtOAc, and HOAc.
  • the reaction may be carried out at temperatures ranging from about 5°C to about 100 0 C, though reactions at RT are common.
  • the substrate-to-catalyst ratio may range from about 1:1 to about 1000: 1, based on weight, and H 2 pressure may range from about atmospheric pressure, 0 psig, to about 1500 psig. More typically, the substrate-to-catalyst ratios range from about 4:1 to about 20:1, and H 2 pressures range from about 25 psig to about 150 psig.
  • Useful substrates include those in which R 1 and R 2 are independently hydrogen or C 1-3 alkyl, provided that R and R are not both hydrogen, and those in which R 3 is C 1-6 alkyl.
  • Representative compounds of Formula 7 include those in which R 1 is hydrogen, R 2 is methyl, R 3 is methyl, ethyl or n-propyl, and R 6 is benzyl, i.e., (3S,5R)-3-benzyloxyamino-5-methyl-heptanoic acid, (3,S,5i?)-3- benzyloxyamino-5-methyl-octanoic acid, and (3S,5i?)-3-benzyloxyamino-5-methyl- nonanoic acid.
  • Useful catalysts include, without limitation, heterogeneous catalysts containing from about 0.1% to about 20%, and more typically, from about 1% to about 5%, by weight, of transition metals such as Ni, Pd, Pt, Rh, Re, Ru, and Ir, including oxides and combinations thereof, which are typically supported on various materials, including Al 2 O 3 , C, CaCO 3 , SrCO 3 , BaSO 4 , MgO, SiO 2 , TiO 2 , ZrO 2 , and the like. Many of these metals, including Pd, may be doped with an amine, sulfide, or a second metal, such as Pb, Cu, or Zn.
  • transition metals such as Ni, Pd, Pt, Rh, Re, Ru, and Ir, including oxides and combinations thereof, which are typically supported on various materials, including Al 2 O 3 , C, CaCO 3 , SrCO 3 , BaSO 4 , MgO, SiO 2 , TiO 2 , ZrO 2
  • Useful catalysts thus include palladium catalysts such as Pd/C, Pd/SrCO 3 , PdZAl 2 O 3 , Pd/MgO, PdZCaCO 3 , PdZBaSO 4 , PdO, Pd black, PdCl 2 , and the like, containing from about 1% to about 5% Pd, based on weight.
  • Other useful catalysts include Raney nickel, RhZC, RuZC, ReZC, PtO 2 , RhZC, RuO 2 , and the like.
  • Scheme III illustrates an additional method for preparing the desired stereoisomer of the compound of Formula 1.
  • the stereoselective synthesis includes reducing an optically active ⁇ -dicarbonyl (Formula 6) by, e.g., reacting it with hydrogen in the presence of a metal catalyst, to give an optically active ⁇ -hydroxy carboxylic acid derivative (Formula 17).
  • Substituents R 1 , R 2 , and R 3 and substituent R in Formula 13, 15 to 17, and 37 are as defined in Formula 1 and Formula 6, respectively;
  • substituent R 7 in Formula 13 and 14 is C 1-6 alkyl, C 2-6 alkenyl, or aryl-C 1-3 alkyl;
  • substituent R 8 in Formula 16 is a leaving group (e.g., R 9 O-);
  • substituent R 9 in Formula 18 is tosyl, mesyl, brosyl, closyl (p-chloro- benzenesulfonyl), nosyl, or triflyl;
  • substituent X 2 in Formula 18 is halogeno or R 9 O-.
  • Representative optically active secondary or tertiary amines include ⁇ -amino C 1-6 alkyl esters of (lS,3S,5R)-3-[benzyl-(l-phenyl- ethyl)-amino]-5-methyl-heptanoic acid, (15',35',5/?)-3-[benzyl-(l-phenyl-ethyl)- amino]-5-methyl-octanoic acid, and (15 r ,35,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5- methyl-nonanoic acid.
  • Examples of useful ⁇ -amino C 1-6 alkyl esters thus include (15,3 1 S r ,5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-heptanoic acid ethyl ester, (15,3iS',5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester, and (15',35,5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester.
  • ⁇ -hydroxy moiety of the compound of Formula 17 is activated via reaction with the compound of Formula 18.
  • Useful ⁇ - hydroxy carboxylic acid derivatives include C 1-6 alkyl esters of (5i?)-3- hydroxy-5-methyl-heptanoic acid, (5i?)-3-hydroxy-5-methyl-octanoic acid, and (5R)- 3-hydroxy-5-methyl-nonanoic acid.
  • Representative ⁇ -hydroxy C 1-6 alkyl esters thus include (52?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester, (5/?)-3-hydroxy-5- methyl-octanoic acid ethyl ester, and (5i?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester.
  • Useful compounds of Formula 18 include sulfonylating agents, such as TsCl, MsCl, BsCl, NsCl, TfCl, and the like, and their corresponding anhydrides (e.g., /7-toluenesulfonic acid anhydride).
  • compounds of Formula 17 may be reacted with TsCl in the presence of pyridine and an aprotic solvent, such as ethyl acetate, MeCl 2 , ACN, THF, and the like, to give C 1-6 alkyl esters of (5R)-5-methyl-3- (toluene-4-sulfonyloxy)-heptanoic acid, (5/?)-5-methyl-3-(toluene-4-sulfonyloxy)- octanoic acid, and (5i?)-5-methyl-3-(toluene-4-sulfonyloxy)-nonanoic acid.
  • an aprotic solvent such as ethyl acetate, MeCl 2 , ACN, THF, and the like
  • compounds of Formula 17 may be reacted with MsCl in the presence of a an aprotic solvent and a strong or hindered base, such as Et 3 N, to give C 1-6 alkyl esters of (5R)-3- methanesulfonyloxy-5-methyl-heptanoic acid, (5/?)-3-methanesulfonyloxy-5-methyl- octanoic acid, and (5/?)-3-methanesulfonyloxy-5-methyl-nonanoic acid.
  • a strong or hindered base such as Et 3 N
  • the resulting intermediate (Formula 16) is reacted with a base to give an unsaturated carboxylic acid derivative (Formula 15).
  • the reaction is typically carried out at RT or above and in the presence of an aprotic solvent, such as ethyl acetate, THF, MeCl 2 , ACN, and the like.
  • Useful bases include strong or hindered bases (i.e., non-nucleophilic bases) such as Et 3 N, t- BuOK, DBN, DBU, and the like.
  • Useful substrates for the conjugate addition include Z- or E-isomers or a mixture of Z- and E- isomers of the unsaturated carboxylic acid derivative (Formula 15) and include C 1-6 alkyl esters of the Z- and E-isomers of (R)-5- methyl-hept-2-enoic acid, (/?)-5-methyl-oct-2-enoic acid, and (i?)-5-methyl-non ⁇ 2- enoic acid.
  • Examples include the Z- and E-isomers of (/?)-5-methyl-hept-2 ⁇ enoic acid ethyl ester, (/?)-5-methyl-oct ⁇ 2 ⁇ enoic acid ethyl ester, and (i?)-5-methyl-non-2-enoic acid ethyl ester.
  • Useful chiral amines include (i?)-(+)-N-benzyl- ⁇ - methylbenzylamine, (5>(-)-N-benzyl- ⁇ -methylbenzylamine, and the like. See S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry 2(3): 183-186 (1991); and /. Chem. Soc, Perkins Trans. 1 2931-2938 (2001).
  • the chiral amine (Formula 14) is typically treated with a strong base, such as n-BuLi and the like, in an ethereal solvent, such as Et 2 O, THF, etc., and at a temperature of about -78°C to RT.
  • a strong base such as n-BuLi and the like
  • Et 2 O, THF, etc. ethereal solvent
  • the resulting deprotonated amine is subsequently reacted with the unsaturated carboxylic acid derivative (Formula 15) to give the optically active secondary or tertiary amine (Formula 13) having the desired stereochemical configuration.
  • Scheme III shows an ⁇ alternative method for preparing the compound of Formula 15.
  • the method includes reacting a sorbate ester (Formula 38) or amide with a Grignard reagent (Formula 29) and a catalytic amount of another metal (e.g., copper salt) and an optional chiral catalyst.
  • the resulting enantiomerically enriched compound (Formula 39) is subsequently isomerized by treatment with a base (e.g., triethylamine) in a polar solvent (e.g., THF) to give the compound of Formula 15.
  • a base e.g., triethylamine
  • a polar solvent e.g., THF
  • the compound of Formula 39 may be isomerized by treatment with a metal catalyst, including Ru, Rh or Pd salts complexed with a counterion, such as a halogen anion, COD, and the like.
  • a metal catalyst including Ru, Rh or Pd salts complexed with a counterion, such as a halogen anion, COD, and the like.
  • Compounds of Formula 15 and 39 may also be enantiomerically enriched by treatment with a lipase under standard conditions.
  • the optional chiral catalysts may include those described above in connection with the asymmetric hydrogenation of the enamide (Formula 2) and enamine (Formula 4) in Scheme I.
  • Substituents R 1 , R 2 , and R 3 and substituent R 4 in Formula 29, 38 and 39 are as defined in Formula 1 and Formula 6, respectively, and substituent X 4 in Formula 29 is halogeno.
  • Useful compounds of Formula 39 thus include, without limitation, C 1-6 alkyl esters of the Z- and E-isomers of (i?)-5-methyl-hept-3-enoic acid, (/?)-5-methyl-oct-3-enoic acid, and (i?)-5-methyl-non-3-enoic acid.
  • Examples include the Z- and E-isomers of (/?)-5-methyl-hept-3-enoic acid ethyl ester, (/?)-5-methyl-oct- 3-enoic acid ethyl ester, and (i?)-5-methyl-non-3-enoic acid ethyl ester.
  • the compound of Formula 37 may be prepared from the compound of Formula 15 by catalytic asymmetric conjugate addition of an amine. See, e.g., Hamashima et al., Organic Letters 6:1861-1864 (2004), the complete disclosure of which is herein incorporated by reference.
  • Scheme IV illustrates a method for preparing ⁇ -dicarbonyls (Formula 6) used in Scheme I, II, and III.
  • the method includes activating a chiral alcohol (Formula 25) via, e.g., reaction with a sulfonylating agent (Formula 26), to give an intermediate (Formula 24), which is subsequently treated with a source of cyanide ion to yield an optically active nitrile (Formula 23). Hydrolyzing the nitrile (Formula 23) through contact with an acid gives a chiral carboxylic acid (Formula 22 or salt), which is subsequently activated through, e.g., reaction with a coupling agent such as CDI.
  • a coupling agent such as CDI.
  • the activated carboxylic acid derivative (Formula 20) is reacted with a malonic acid salt or ester (Formula 21) in the presence of a base to give an ⁇ - substituted malonic acid intermediate (Formula 19), which is decarboxylated by treatment with an acid to provide the desired ⁇ -dicarbonyl (Formula 6).
  • Useful sulfonylating agents include those described in connection with Formula 18; useful sources of cyanide ion include, without limitation, sodium cyanide, potassium cyanide, zinc cyanide, hydrogen cyanide, acetone cyariohydrin, and the like, either alone or in combination.
  • the method may employ an activated prochiral enoate (Formula 30), which is reacted with a deprotonated chiral oxazolidinone to give an TV-acylated oxazolidinone (Formula 28).
  • the deprotonated oxazolidinone may be prepared from a chiral oxazolidinone (Formula 31) by separate treatment with a strong base (e.g., /i-BuLi) or by in-situ treatment with a hindered base (e.g., Et 3 N).
  • the JV-acylated oxazolidinone (Formula 28) is subsequently reacted with a Grignard reagent (Formula 29) in the presence of a copper salt (e.g., CuBrDMS) to give a conjugate addition product (Formula 27).
  • a copper salt e.g., CuBrDMS
  • the conjugate addition product (Formula 27 or Formula 20 in which R 10 is a chiral oxazolidin-2-one-3-yl) may be reacted with the malonic acid derivative (Formula 21) to give the ⁇ -substituted malonic acid intermediate (Formula 19).
  • the chiral side chain may be cleaved following asymmetric synthesis via, e.g., acid or base hydrolysis, using for instance, an alkali metal hydroxide or peroxide such as LiOOH in aq. THF followed by reduction, to give the carboxylic acid of Formula 22 or a salt thereof and to regenerate the chiral auxiliary
  • R 1 , R 2 , and R 3 in Formula 19, 20, 22 to 25, and 27, 28 and 30 are as defined above in Formula 1;
  • R 4 in Formula 19 and 21 is as defined in Formula 2;
  • R 10 , R 11 , and R 17 in Formula 20, 24, and 30 are leaving groups, which may be the same or different;
  • R 12 in Formula 26 is a tosyl, mesyl, brosyl, closyl, nosyl, or triflyl;
  • X 3 in Formula 26 is halogeno;
  • R 13 , R 14 , R 15 , and R 16 in Formula 27, 28, and 31 are independently hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl, or aryl-C 1-3 alkyl, provided that R 15 and R 16 are not both hydrogen atoms.
  • representative chiral alcohols (Formula 25) and corresponding activated forms (Formula 24) include, without limitation, (2?)-2-methyl-butanol, (/?)-2-methyl ⁇ pentanol, (/?)-2-methyl-hexanol, (R)-2- methyl- 1 -(toluene-4-sulf onyloxy)-butane, (/?)-2-methyl- 1 -(toluene-4-sulf onyloxy)- pentane, (R)-2-methyl- 1 -(toluene-4-sulfonyloxy)-hexane, (R)- 1 -methanesulf onyloxy- 2-methyl-butane, (R)-I -methanesulf onyloxy-2-methyl-pentane, and (R)-I- methanesulfonyloxy-2-methyl-hexane.
  • nitriles (Formula 23), chiral carboxylic acids (Formula 22) and corresponding activated forms (Formula 20) include, without limitation, (/?)-3-methyl-pentanenitrile, (i?)-3-methyl-hexanenitrile, (R)-3 -methyl-heptanenitrile, (R)- 1 -imidazol- 1 -yl-3 -methyl-pentan- 1 -one, (R)- 1 - imidazol- 1 -yl-3 -methyl-hexan- 1 -one, and (R)- 1 -imidazol- 1 -yl-3 -methyl-heptan- 1 -one.
  • representative activated prochiral enoates include, without limitation, acid halides of the Z- and E- isomers of but-2-enoic acid, such as but-2-enoyl chloride.
  • Representative chiral oxazolidinones include, without limitation, (7?)-4-isopropyl-oxazolidin-2-one, (/?)-4-phenyl- oxazolidin-2-one, (R)-4-benzyl-oxazolidin-2-one, and (4/?,5S)-4-methyl-5-phenyl- oxazolidin-2-one.
  • representative N-acylated oxazolidinones include, without limitation, the Z- and E-isomers of (i?)-3-(but-2-enoyl)-4-isopropyl- oxazolidin-2-one, (i?) ⁇ 3-(but-2-enoyl)-4-phenyl-oxazolidin-2-one, (i?)-4-benzyl-3- (but-2-enoyl)-oxazolidin-2-one, and (4/?,55')-3-(but-2-enoyl)-4-methyl-5-phenyl- oxazolidin-2-one.
  • representative Michael adducts include, without limitation, (i?,/?)-4-isopropyl-3-(3-methyl-pentanoyl)- oxazolidin-2-one, (/?,/?)-4-isopropyl-3-(3-methyl-hexanoyl)-oxazolidin-2-one, (R,R)- 4-isopropyl-3-(3-methyl-heptanoyl)-oxazolidin-2-one, (7?,/?)-3-(3-methyl-pentanoyl)- 4-phenyl-oxazolidin-2-one, (R,i?)-3-(3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one, (i?,/?)-3-(3-methyl-heptanoyl)-4-phenyl-oxazolidin-2-one, (i?,i?)-4-benzyl-3-(3-(3-(3-)
  • Scheme V illustrates another method for preparing the ⁇ -dicarbonyl (Formula 6) used in Scheme I, II, and III.
  • the method includes activating a chiral alcohol (Formula 34) via, e.g., reaction with a sulfonylating agent (Formula 26), to give an intermediate (Formula 32), which is subsequently reacted with a deprotonated acetoacetate derivative (Formula 36).
  • the resulting chiral anion (Formula 35) or a corresponding salt is treated with an acid to yield, via tautomerization, the desired ⁇ - dicarbonyl (Formula 6).
  • the displacement of substituent R 18 results in inversion of the stereogenic center and occurs via attack by a dianion intermediate (Formula 36 or corresponding salt).
  • the dianion (Formula 36) may be prepared by treating an acetoacetate derivative (Formula 33) successively with one or more equivalents of a first base (e.g., LiH, NaH, etc.) and a second base (e.g., BuLi) that are strong enough to deprotonate, respectively, the central methylene and terminal methyl groups.
  • the acetoacetate derivative may be treated with two or more equivalents of a single base that can deprotonate the terminal methyl group.
  • substituents R , R , and R in Formula 32 and 34 are as defined above in Formula 1; R 4 in Formula 33 and 36 is as defined above in Formula 2; and R 18 is a leaving group.
  • representative chiral alcohols (Formula 34) and corresponding activated forms (Formula 32) include, without limitation, (S)-butan-2-ol, (5)-pentan-2-ol, (S)-hex-2-ol, (5)-2-(toluene-4- sulfonyloxy)-butane, ( ⁇ S)-2-(toluene-4-sulfonyloxy)-pentane, ( ⁇ S)-2-(toluene-4- sulfonyloxy)-hexane, (S)-2-(chlorobenzene ⁇ 4 ⁇ sulfonyloxy) ⁇ butane, (S)-2- (chlorobenzene-4-sulfonyloxy)-pentane, (>S')-2-(chlorobenzene-4-sulfonyloxy)-hexane, (5)-2-methanesulfony
  • Representative acetoacetate derivatives include, without limitation, C 1-6 alkyl esters of acetoacetate, including acetoacetate ethyl ester.
  • Representative dianions include, without limitation, Z- and E-isomers of 1-C 1-6 alkoxy-buta-l,3-diene-l,3-diol dianions, such as (Z)- and (E)-I- ethoxy-buta-l,3-diene-l,3-diol dianion.
  • representative chiral anions include, without limitation, Z- and E-isomers of (R)-I-C 1-6 alkoxy-4- methyl-hex-l-en-2-ol anion, (R)-I-C 1-6 alkoxy-4-methyl-hept-l-en-2-ol anion, and (R)-I-C 1-6 alkoxy-4-methyl-oct-l-en-2-ol anion, which include Z- and E-isomers of (R)- 1 -ethoxycarbonyl-4-methyl-hex- 1 -en-2-ol anion, (R)- 1 -ethoxycarbonyl-4-methyl- hept-l-en-2-ol anion, and (R)- l-ethoxycarbonyl-4-methyl-oct-l -en-2-ol anion.
  • the activation of the chiral alcohol (Formula 34), subsequent displacement of R 18 (Formula 32), and treatment of the chiral anion (Formula 35) with acid may be carried out at about -5O 0 C to reflux, while the preparation of the dianion (Formula 36) generally occurs at temperatures less than about 0 0 C, and more typically, at temperatures less than about -3O 0 C but greater than about -80 0 C.
  • salts include, without limitation, acid addition salts (including di-acids) and base salts.
  • Pharmaceutically acceptable acid addition salts include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
  • Pharmaceutically acceptable base salts include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include, without limitation, sodium cations (Na + ), potassium cations (K + ), magnesium cations (Mg 2+ ), calcium cations (Ca 2+ ), and the like.
  • suitable amines include, without limitation, iV,iV'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
  • Disclosed and claimed compounds may exist in both unsolvated and solvated forms and as other types of complexes besides salts.
  • Useful complexes include clathrates or compound-host inclusion complexes where the compound and host are present in stoichiometric or non-stoichiometric amounts.
  • Useful complexes may also contain two or more organic, inorganic, or organic and inorganic components in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • solvates also include hydrates and solvates in which the crystallization solvent may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 - DMSO, etc.
  • references to an unsolvated form of a compound also include the corresponding solvated or hydrated form of the compound.
  • the disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as H and H; isotopes of carbon, such as 13 C and 14 C; isotopes of nitrogen, such as 15 N; isotopes of oxygen, such as 17 O and 18 O; isotopes of phosphorus, such as 31 P and 32 P; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as F; and isotopes of chlorine, such as 36 Cl.
  • Use of isotopic variations e.g., deuterium, H
  • certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 1 C), which may be useful in drug and/or substrate tissue distribution studies.
  • the hexane layer is concentrated by vacuum distillation giving (i?)-3-methyl-hexanenitrile as an oil.
  • the oil is reacted by adding aq HCl and heating the mixture to 5O 0 C to 60 0 C for 6 hours.
  • the reaction mixture is extracted with diethyl ether and the organic layer is concentrated by vacuum distillation, which provides the titled compound as an oil.
  • the oil was diluted with ethyl acetate (60 L), concentrated by vacuum distillation, again diluted with EtOAc (60 L), cooled to -10 0 C to -20 C and further diluted with methanesulfonyl chloride (12.1 kg).
  • the resulting solution was cooled to -10°C to -20 C and Et 3 N (26 kg) was slowly added while maintaining the temperature below 20°C.
  • the solution was warmed to 40°C to 6O 0 C for at least 12 hours, then cooled to O 0 C to 10 0 C, and quenched by the addition of aq HCl.
  • the organic solution was washed with water and concentrated by vacuum distillation resulting in an oil.
  • the resulting solution was heated to 80°C to 100°C for a minimum of 12 hours and admixed with toluene.
  • the solution was partitioned into upper and lower layers. The lower layer was separated and concentrated by vacuum distillation to a volume of about 50 L.
  • the solution was cooled and the resulting precipitate was collected by filtration, washed with toluene, then dried under vacuum to provide an off-white solid (7 kg).
  • the solid was recrystallized from isopropanol and toluene to give the titled compound as a white product (5 kg, 30% yield).
  • the oil was diluted with ethyl acetate (60 L), concentrated by vacuum distillation, diluted again with EtOAc (60 L), cooled to -10 to -20 C, and further diluted with methanesulfonyl chloride (12.1 kg).
  • the solution was cooled to -10°C to -20 0 C and Et 3 N (23 kg) was slowly added while maintaining the temperature below 2O 0 C.
  • the solution was warmed to about 5O 0 C for at least 12 hours, cooled to 0°C to 1O 0 C, and quenched with aq HCl.
  • the organic solution was washed with water and concentrated by vacuum distillation resulting in an oil.
  • the solution was heated to 80°C to 100°C for a minimum of 12 hours and then admixed with toluene.
  • the solution was partitioned into upper and lower layers. The lower layer was separated and concentrated by vacuum distillation to a volume of about 100 L.
  • the solution was diluted with concentrated aq. HCl (12 kg) and cooled. The resulting precipitate was collected by filtration, washed with toluene, then dried under vacuum to give an off-white solid (21 kg).
  • the solid was recrystallized twice from aq HCl to provide the titled compound as a white solid (11 kg, 40% yield).
  • EXAMPLE 17 Preparation of (35',5/?)-3-acetylamino-5-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (i?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (i?,i?,5',5')-TangPhos-Rh catalyst
  • the flask was then placed in a nitrogen-filled glove bag along with a vial containing bis(l,5-cyclooctadiene)Rh(I)trifluoromethane sulfonate (0.123 g, 0.263 mmol, 1.00 mol%) and a vial containing (R,R,S,S)- TangPhos (0.070 g, 0.245 mmol, 0.93 mol%).
  • the vials were opened and their contents were charged to the flask.
  • the flask, which contained the catalyst precursors, was sealed, moved to a hood, purged again with vacuum and nitrogen, and held under a positive nitrogen pressure.
  • reaction flask was again inerted (with agitation) using several vacuum/nitrogen purges. Hydrogen was then introduced as a rapid stream that was vented through a bubbler. After about 10 minutes the hydrogen flow rate was reduced so that it maintained a small positive pressure, estimated at about 5 psig to about 10 psig, as indicated by the bubbler. The reaction was run at ambient temperature, without heating or cooling to give the titled compound. Samples were taken via syringe for TLC and chiral GC analysis, and the reaction was found to be complete after about 4 hours (97.1% de via chiral GC).
  • EXAMPLE 18 Preparation of (S ⁇ SR ⁇ -acetylamino-S-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (R)-BINAPINE-Rh catalyst
  • EXAMPLE 19 Preparation of (3 l S',5R)-3-acetylamino-5-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (R)-mTCFP-Rh catalyst
  • a portion of the enamine (25 g) was dissolved in toluene (150 mL), and reacted further by adding acetic anhydride (24 g) and pyridine (24 mL) and heating the mixture at 100°C to 110°C for 16 hours.
  • the reaction mixture was cooled to 10°C to 2O 0 C and quenched by the addition of water.
  • the reaction mixture was partitioned into upper and lower layers and the upper layer was washed with dilute aqueous NaHSO 4 , water, and was concentrated to give the titled compound as an oil (26 g).
  • a pressure vessel was charged with (/?)-5-Methyl-3-oxo-nonanoic acid ethyl ester (50 g), EtOH (250 mL), and ammonia (about 8 g). The resulting mixture was allowed to react at 50°C for about 20 hours. The mixture was subsequently cooled to RT and concentrated by vacuum distillation. The resulting concentrate was dissolved in octane and concentrated by vacuum distillation to give the titled compound as an oil (50 g).
  • EXAMPLE 24 Preparation of (3S,5R)-3-acetylamino-5-methyl-nonanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester using (R)-BINAPINE-Rh catalyst and (R)-mTCFP-Rh catalyst
  • a pressure vessel was charged with (R,Z)-3-acetylamino-5-methyl-non-2- enoic acid ethyl ester (100 kg) and MeOH (320 kg) and was purged with nitrogen.
  • (R)-BINAPINE-Rh(COD)BF 4 500 g was added and rinsed into the vessel using nitrogen-purged MeOH (20 L).
  • the reaction vessel was purged with hydrogen and the contents allowed to react at 35 0 C under 25 psig H 2 for 2 to 5 days.
  • (R)-mTCFP- Rh(COD)BF 4 (about 60 g) was added and rinsed into the vessel using nitrogen-purged MeOH (20 L).
  • the solution was cooled to 35°C to 50°C, washed with toluene (300 L), and concentrated slightly by vacuum distillation.
  • the resulting concentrate was diluted with toluene (300 L).
  • Adding 35% aq HCl (150 L) and slowly cooling the solution to about 10°C resulted in a solid precipitate, which was collected by filtration and washed with hexane and dried.
  • the solids were dissolved in /-PrOH and were recrystallized by adding hexanes and slowly cooling the solution. The solids were collected by filtration, washed with hexanes, and then dried to give the titled compound as a solid (51 kg, 39% yield).
  • a pressure vessel is charged with (i?,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester (10 g) and 2,2,2-trifluoroethanol (32 g) and the contents are purged with nitrogen.
  • To the vessel is added (R)-(S)- JOSIPHOS-Rh(COD)BF 4 (50 mg).
  • the vessel contents are purged with hydrogen and are reacted at 50°C under 100 psig H 2 for 1 to 2 days or until the reaction is complete.
  • the mixture is concentrated by vacuum distillation to give the above titled compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Nutrition Science (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Disclosed are materials and methods for preparing optically active ß-amino acids of Formula (1), which bind to the alpha-2-delta (α2δ) subunit of a calcium channel.

Description

PREPARATION OF BETA-AMINO ACIDS HAVING AFFINITY FOR THE
ALPHA-2-DELTA PROTEIN
BACKGROUND OF THE INVENTION
FIELD OF INVENTION
[0001] This invention relates to materials and methods for preparing optically- active β-amino acids that bind to the alpha-2-delta (α2δ) subunit of a calcium channel. These compounds, including their pharmaceutically acceptable complexes, salts, solvates and hydrates, are useful for treating pain, fibromyalgia, and a variety of psychiatric and sleep disorders.
DISCUSSION
[0002] U.S. Patent Application No. 2003/0195251 Al to Barta et al. (the '251 application) describes β-amino acids that bind to the α2δ subunit of a calcium channel. These compounds, including their pharmaceutically acceptable complexes, salts, solvates, and hydrates, may be used to treat a number of disorders, conditions, and diseases. These include, without limitation, sleep disorders, such as insomnia; fibromyalgia; epilepsy; neuropathic pain, including acute and chronic pain; migraine; hot flashes; pain associated with irritable bowel syndrome; restless leg syndrome; anorexia; panic disorder; depression; seasonal affective disorders; and anxiety, including general anxiety disorder, obsessive compulsive behavior, and attention deficit hyperactivity disorder, among others.
[0003] Many of the β-amino acids described in the '251 application are optically active. Some of the compounds, like those represented by Formula 1 below, possess two or more stereogenic (chiral) centers, which make their preparation challenging. Although the '251 application describes useful methods for preparing optically- active β-amino acids at laboratory bench scale, many of the methods may be problematic for pilot- or full-scale production because of efficiency or cost concerns. Thus, improved methods for preparing optically-active β-amino acids, such as those given by Formula 1, would be desirable. SUMMARY OF THE INVENTION
[0004] The present invention provides comparatively efficient and cost-effective methods for preparing compounds of Formula 1,
Figure imgf000003_0001
or a diastereomer thereof or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, wherein:
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl- C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms.
[0005] One aspect of the present invention includes reacting a compound of Formula 2,
Figure imgf000003_0002
or Formula 4,
Figure imgf000004_0001
with H2 in the presence of a chiral catalyst to give a compound of Formula 3,
Figure imgf000004_0002
or a diastereomer thereof, wherein
R1, R2, and R3 in Formula 2, Formula 3, and Formula 4 are as defined in Formula 1;
R4 in Formula 2, Formula 3, and Formula 4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo- C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and
R5 in Formula 2 and R19 in Formula 3 are independently hydrogen atom, carboxy, C1-7 alkanoyl, C2-7 alkenoyl, C2-7 alkynoyl, C3-7 cycloalkanoyl, C3-7 cycloalkenoyl, halo-C1-7 alkanoyl, halo-C2-7 alkenoyl, halo-C2-7 alkynoyl, C1-6 alkoxycarbonyl, halo-C1-6 alkoxycarbonyl, C3-7 cycloalkoxycarbonyl, aryl- C1-7 alkanoyl, aryl-C2-7 alkenoyl, aryl-C2-7 alkynoyl, aryloxycarbonyl, or aryl- C1-6 alkoxycarbonyl, provided that R5 is not a hydrogen atom; and optionally converting the compound of Formula 3 or its diastereomer to the compound of Formula 1 or its diastereomer or to a pharmaceutically acceptable complex, salt, solvate or hydrate of the compound of Formula 1 or its diastereomer.
[0006] A useful chiral catalyst for asymmetric hydrogenation of the compounds of Formula 2 or Formula 4 includes a chiral ligand bound to a transition metal through one or more phosphorus atoms. Such catalysts include (R^S^-TANGPhos, (R)- BESTAPINE, (R)-eTCFP, or (R)-mTCFP, or stereoisomers thereof, which are bound to rhodium. The asymmetric hydrogenation is typically carried out using a single chiral catalyst. However, the method may also employ multiple chiral catalysts in which the prochiral substrate (Formula 2 or Formula 4) is reacted successively with first and second chiral catalysts (e.g., (R)-BINAPINE and (R)-mTCFP, respectively, or opposite enantiomers thereof). In such cases, the first chiral catalyst has greater stereoselectivity than the second chiral catalyst under the same conditions, and the second chiral catalyst has a faster rate of reaction than the first chiral catalyst under the same conditions.
[0007] The compound of Formula 2 may be prepared by reacting the compound of Formula 4,
Figure imgf000005_0001
or a salt thereof with a compound of Formula 5,
Figure imgf000005_0002
5
wherein R5 in Formula 5 is as defined in Formula 2 and X in Formula 5 is a hydroxy or a leaving group, such as halogeno, aryloxy or heteroaryloxy, or -OC(O)R15, in which R15 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, halo-C1-6 alkyl, halo-C2-6 alkenyl, halo-C2-6 alkynyl, aryl, aryl-C1-6 alkyl, heterocyclyl, heteroaryl, or heteroaryl-C1-6 alkyl.
[0008] The compound of Formula 4 may be prepared by reacting a compound of Formula 6,
Figure imgf000006_0001
with an ammonia source (e.g., ammonia or a mixture of ammonium acetate and acetic acid), wherein R1, R2, and R3 in Formula 6 are as defined in Formula 1 and R4 is as defined in Formula 2.
[0009] Another aspect of the present invention includes reducing an amino moiety of a compound of Formula 7,
Figure imgf000006_0002
7 or a diastereomer thereof or a salt thereof to give the compound of Formula 1, wherein R1, R2, and R3 in Formula 7 are as defined in Formula 1 and R6 is C1-6 alkyl (e.g., methyl), C2-6 alkenyl (e.g., allyl) or aryl-C1-3 alkyl (e.g., benzyl); and optionally converting the compound of Formula 1 or its diastereomer to a pharmaceutically acceptable complex, salt, solvate or hydrate.
[0010] The amino moiety may be reduced by reacting the compound of Formula 7 with H2 in the presence of a catalyst. Useful catalysts include transition metal catalysts, such as Pd/C and Raney nickel.
[0011] The compound of Formula 7 may be prepared by reacting a compound of Formula 8,
Figure imgf000007_0001
or a diastereomer thereof, with an acid or base, wherein R , R , and R in Formula 8 are as defined in Formula 1 and R6 is as defined in Formula 7.
[0012] The compound of Formula 8 may be prepared by cyclizing a compound of Formula 9,
Figure imgf000007_0002
or a diastereomer thereof, wherein R , R , and R in Formula 9 are as defined in Formula 1 and R6 is as defined in Formula 7. For instance, the hydroxy moiety in Formula 9 may be activated (e.g., by conversion to a sulfonate ester) to give an activated alcohol, which is subsequently cyclized by treatment with a base (e.g., a carbonate).
[0013] The compound of Formula 9 may be prepared by reacting a compound of Formula 10,
Figure imgf000007_0003
or a diastereomer thereof with a compound of Formula 11, NH2 R6-0
11
wherein R , R , and R in Formula 10 are as defined in Formula 1 and R in Formula 11 is as defined in Formula 7. To facilitate reaction, the carboxylic acid moiety of the compound of Formula 10 may be activated using a coupling agent, such as DMT-MM.
[0014] The compound of Formula 10 may be prepared by reacting the above compound of Formula 6 with H2 in the presence of a chiral catalyst to give a compound of Formula 12,
Figure imgf000008_0001
or a diastereomer thereof, wherein R1, R2, R3, and R4 in Formula 12 are as defined in Formula 1 and Formula 2; and optionally converting the compound of Formula 12, or its diastereomer, to the compound of Formula 10.
[0015] An additional aspect of the present invention includes reducing an amine moiety of a compound of Formula 13,
Figure imgf000008_0002
or a diastereomer thereof, to give a compound of Formula 37,
Figure imgf000009_0001
or a diastereomer thereof, wherein R1, R2, R3, and R4 in Formula 37 and Formula 13 are as defined in Formula 1 and Formula 2, respectively, and R7 in Formula 13 is Ci-6 alkyl, C2-6 alkenyl (e.g., allyl) or aryl-C1-3 alkyl (e.g., benzyl); and optionally converting the compound of Formula 37 or its diastereomer to the compound of Formula 1 or its diastereomer or to a pharmaceutically acceptable complex, salt, solvate or hydrate of the compound of Formula 1 or its diastereomer.
[0016] The amine moiety of the compound of Formula 13 may be reduced by reacting the compound of Formula 13 with H2 in the presence of a catalyst. Useful catalysts include transition metal catalysts, such as Pd/C and Raney nickel.
[0017] The compound of Formula 13 may be prepared by treating a compound of Formula 14,
Figure imgf000009_0002
14
or its opposite enantiomer with a base to give a deprotonated chiral amine and reacting the deprotonated chiral amine with a compound of Formula 15,
Figure imgf000009_0003
wherein R , 1 , R TJ2 , and R > 3 i •n Formula 15 are as defined in Formula 1, R in Formula 15 is as defined in Formula 2, and R7 in Formula 14 is as defined in Formula 13.
[0018] The compound of Formula 15 may be prepared by reacting a compound of Formula 16,
Figure imgf000010_0001
with a base, wherein R1, R2, and R3 in Formula 16 are as defined in Formula 1, R4 in Formula 16 is as defined in Formula 2, and R8 is a leaving group.
[0019] The compound of Formula 16 may be prepared by reacting a compound of Formula 17,
Figure imgf000010_0002
with a compound of Formula 18,
R9-X2 18
to give the compound of Formula 16 in which R8 is R9O-, wherein R1, R2, and R3 in Formula 17 are as defined in Formula 1, R4 in Formula 17 is as defined in Formula 2, R9 is tosyl, mesyl, brosyl, closyl, nosyl, or triflyl, and X2 is halogen or R9O-.
[0020] The compound of Formula 17 may be prepared by reducing a β-carbonyl moiety of the above compound of Formula 6. For example, the compound of Formula 6 may be reacted with H2 in the presence of a catalyst to give the compound of Formula 17. Useful catalysts include transition metal catalysts, such as platinum and ruthenium-based catalysts.
[0021] Alternatively, the compound of Formula 15 may be prepared by reacting a compound of Formula 39,
Figure imgf000011_0001
with a base, wherein R , R , and R in Formula 39 are as defined in Formula 1 and R in Formula 39 is as defined in Formula 2.
[0022] The compound of Formula 39 may be prepared by reacting a compound of Formula 38,
Figure imgf000011_0002
with a compound of Formula 29,
R3-CH2MgX4 29
in the presence of copper and a chiral catalyst, wherein R1, R2, and R3 in Formula 29 a anndd 3388 a arree a ass d deeffiinneedd i inn F Foorrmmυula 1, R4 in Formula 38 is as defined in Formula 2, and X4 in Formula 29 is halogeno.
[0023] The present invention also provides methods of making compounds of Formula 6, above. Thus, another aspect of the present invention includes treating a compound of Formula 19,
Figure imgf000012_0001
or a salt thereof with an acid, wherein R1, R2, R3, and R4 in Formula 19 are as defined in Formula 1 and Formula 2.
[0024] The compound of Formula 19 may be prepared by reacting a compound of Formula 20,
Figure imgf000012_0002
20
with a compound of Formula 21,
Figure imgf000012_0003
21
or a salt thereof, in the presence of a base and, optionally, a metal ion, wherein R1, R2, and R3 in Formula 20 and R in Formula 21 are as defined in Formula 1 and Formula 2, and R10 in Formula 20 is a leaving group, such as a chiral oxazolidin-2- one-3-yl or an imidazol-1-yl. Useful chiral oxazolidin-2-one-3-yls include (5)-4- isopropyloxazolidin-2-one-3-yl, (i?)-4-isopropyloxazolidin-2-one-3-yl, (S)-4- benzyloxazolidin-2-one-3-yl, (/?)-4-benzyloxazolidin~2-one-3-yl, (5)-4- phenyloxazolidin-2-one-3-yl, (7?)~4-phenyloxazolidin-2-one-3-yl, (45',5i?)-4-methyl-5- phenyloxazolidin-2-one-3-yl, or (4i?,55)-4-methyl-5-phenyloxazolidin-2-one-3-yl or stereoisomers thereof. [0025] The compound of Formula 20 may be prepared by reacting a compound of Formula 22,
Figure imgf000013_0001
22
or a salt thereof, with coupling agent. Useful coupling agents include CDI, DCC, DMT-MM, FDPP, TATU, BOP, PyBOP, EDCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, iV,2V-bis-(2-oxo-3-oxazolidmyl)- phosphinic chloride, diphenylphosphoryl azide, diphenylphosphinic chloride, or diphenylphosphoryl cyanide.
[0026] The compound of Formula 22 may be prepared by hydrolyzing a compound of Formula 23,
Figure imgf000013_0002
in the presence of an acid, wherein R , R , and R in Formula 23 are as defined in Formula 1.
[0027] The compound of Formula 23 may be prepared by reacting a compound of Formula 24,
Figure imgf000013_0003
1 0 1^ with a source of cyanide ion, wherein R , R , and R in Formula 24 are as defined in Formula 1 and R11 is a leaving group. Useful sources of cyanide ion include sodium cyanide, potassium cyanide, zinc cyanide, hydrogen cyanide or acetone cyanohydrin, alone or in combination. [0028] The compound of Formula 24 may be prepared by reacting a compound of Formula 25,
Figure imgf000014_0001
with a compound of Formula 26,
R12_χ3
26
to give the compound of Formula 24 in which R11 is R12O-, wherein R1, R2, and R3 in
10
Formula 25 are as defined in Formula 1, R in Formula 26 is a tosyl, mesyl, brosyl, closyl, nosyl, or triflyl, and X is halogen.
[0029] Alternatively, the compound of Formula 22 may be prepared by hydrolyzing a compound of Formula 27,
Figure imgf000014_0002
27
wherein R1, R2, and R3 in Formula 27 are as defined in Formula 1, and R13, R14, R15, and R16 are independently hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-6 alkyl, aryl, or aryl-Ci-3 alkyl, provided that R15 and R16 are different and are not both hydrogen atoms.
[0030] An additional aspect of the present invention includes treating a compound of Formula 33,
Figure imgf000015_0001
33
with a base to generate a dianion; reacting the dianion with a compound of Formula 32,
Figure imgf000015_0002
32
to give an intermediate; and treating the intermediate with an acid to give the compound of Formula 6, wherein R1, R2, and R3 in Formula 32 and R4 in Formula 33 are as defined in
Formula 1 and Formula 2, and R in Formula 32 is a leaving group.
[0031] The compound of Formula 32 may be prepared by reacting a compound of Formula 34,
H0>^R3
R1 V
34
with the compound of Formula 26, above, to give the compound of Formula 32 in which R18 is R12O-, wherein R1, R2, and R3 in Formula 34 are as defined in Formula 1.
[0032] The present invention also provides compounds represented by Formula 2 to 4, 6 to 10, 12, 13, 15 to 17, 19, 20, 22, and 39, which are given above, and includes their complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures.
[0033] Thus, another aspect of the present invention provides compounds of Formula 40,
Figure imgf000016_0001
40 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which:
R , R , and R in Formula 40 are as defined above in Formula 1;
R20 is a hydrogen atom, hydroxy, R6-O-NH-, R9O- or R19-NH-, or
Figure imgf000016_0002
R21 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo-C2-7 alkenyl, halo- C2-7 alkynyl, aryl-Ci-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion, a secondary ammonium ion or R6-O-NH-; and
R6, R7, R9, and R19 are as defined in Formula 7, Formula 13, Formula 18, and Formula 3, respectively.
[0034] A further aspect of the present invention provides compounds of Formula 39,
Figure imgf000016_0003
including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which R1, R2, and R3 in Formula 39 are as defined in Formula 1, and R4 is as defined above in Formula 2. [0035] An additional aspect of the present invention provides compounds of Formula 41,
Figure imgf000017_0001
41 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, λ O T geometric isomers, and mixtures thereof, in which R , R , and R in Formula 41 are as defined in Formula 1, R is as defined in Formula 2, and R is a hydrogen atom or carboxy.
[0036] Yet another aspect of the present invention provides compounds of Formula 42,
Figure imgf000017_0002
42 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which R1, R2, and R3 in Formula 42 are as defined in Formula 1, and R is a hydrogen atom or a chiral oxazolidin-2-one-3-yl.
[0037] The present invention also includes the following compounds, as well as their pharmaceutically acceptable complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures:
(Z?)-5-methyl-3~oxo~heptanoic acid ethyl ester;
(i?)-5-methyl-3-oxo-octanoic acid ethyl ester;
(i?)-5-methyl-3-oxo-nonanoic acid ethyl ester;
(/?,Z)-3-amino-5-methyl-hept-2-enoic acid ethyl ester;
(i?,Z)-3-amino-5-methyl-oct-2-enoic acid ethyl ester;
(i?,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester;
(i?,Z)-3-acetylamino-5-methyl-hept-2-enoic acid ethyl ester; (/?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester; (R,Z)-3-acetylamino-5-methyl~non-2-enoic acid ethyl ester; (3£,5R)-3-ammo-5-methyl-heptanoic acid ethyl ester; (35,5i?)-3-amino-5-methyl-octanoic acid ethyl ester; (35,5/?)-3-amino-5-methyl-nonanoic acid ethyl ester; (3S,5R)-3-acetylamino-5-methyl-heptanoic acid ethyl ester; (35',5/?)-3-acetylamino-5-methyl-octanoic acid ethyl ester; (3S,5R)-3-acetylamino-5-methyl-nonanoic acid ethyl ester; (3S,5i?)-3-acetylamino-5-methyl-heptanoic acid; (3lS,5/?)-3-acetylamino-5-methyl-octanoic acid; (3>S,5i?)-3-acetylamino-5-methyl-nonanoic acid; (3/?,5/?)-3-hydroxy-5-methyl-heptanoic acid; (3i?,5/?)-3-hydroxy-5-methyl-octanoic acid; (3/?,5i?)-3-hydroxy-5-methyl-nonanoic acid; (3i?,5i?)-3-hydroxy-5-methyl-heptanoic acid benzyloxy- amide; (3i?,5/?)-3-hydroxy-5-methyl-octanoic acid benzyloxy-amide; (3i?,5/?)-3~hydroxy-5-methyl-nonanoic acid benzyloxy-amide; (3/?,5R)-3-hydroxy-5-methyl-heptanoic acid ethyl ester; (3/?,5i?)-3-hydroxy-5-methyl-octanoic acid ethyl ester; (3i?,5i?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester; (2R,4S)- 1 -benzyloxy-4-(2-methyl-butyl)-azetidin-2-one; (2R,4S)- 1 -benzyloxy-4-(2-methyl-pentyl)-azetidin-2-one; (2R,4S)- 1 -benzyloxy-4-(2-methyl-hexyl)-azetidin-2-one; (SS'jS^-S-benzyloxyamino-S-methyl-heptanoic acid; (35',5i?)-3-benzyloxyamino-5-methyl-octanoic acid; (3S,5R)-3 -benzyloxyamino-5-methyl-nonanoic acid; (l.S',35f,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-heptanoic acid ethyl ester;
(15,35,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester;
(15,35',5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester; (5i?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester; (5/?)-3-hydroxy-5-methyl-octanoic acid ethyl ester; (5/?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester; (/?,E)-5-methyl-hept-2-enoic acid ethyl ester; (R,E)-5-methyl-oct-2-enoic acid ethyl ester; (7?,E)~5-methyl-non-2-enoic acid ethyl ester; (i?,E)-5-methyl-hept-3-enoic acid ethyl ester; (i?,E)-5-methyl-oct-3-enoic acid ethyl ester; (7?,E)-5-methyl-non-3~enoic acid ethyl ester; (5/?)-5-methyl-3-(toluene-4-sulfonyloxy)-heptanoic acid ethyl ester; (5/?)-5-methyl-3-(toluene-4-sulfonyloxy)-octanoic acid ethyl ester; (5/?)-5-methyl-3-(toluene-4-sulfonyloxy)-nonanoic acid ethyl ester; (5i?)-3-methanesulfonyloxy-5-methyl-heptanoic acid ethyl ester; (5i?)-3-methanesulfonyloxy-5-methyl-octanoic acid ethyl ester; (5i?)-3-methanesulfonyloxy-5-methyl-nonanoic acid ethyl ester; (i?)-l-imidazol-l-yl-3-methyl-pentan-l-one; (i?)-l-imidazol-l-yl-3-methyl-hexan-l-one; and (R)- 1-imidazol- l-yl-3-methyl-heptan- 1-one.
[0038] The present invention includes all complexes and salts, whether pharmaceutically acceptable or not, solvates, hydrates, and polymorphic forms of the disclosed compounds. Certain compounds may contain an alkenyl or cyclic group, so that cisltrans (or ZIE) stereoisomers are possible, or may contain a keto or oxime group, so that tautomerism may occur. In such cases, the present invention generally includes all ZIE isomers and tautomeric forms, whether they are pure, substantially pure, or mixtures.
DETAILED DESCRIPTION
DEFINITIONS AND ABBREVIATIONS
[0039] Unless otherwise indicated, this disclosure uses definitions provided below. Some of the definitions and formulae may include a dash ("-") to indicate a bond between atoms or a point of attachment to a named or unnamed atom or group of atoms. Other definitions and formulae may include an equal sign ("=") or an identity symbol ("≡") to indicate a double bond or a triple bond, respectively. Certain formulae may also include one or more asterisks ("*") to indicate stereogenic (asymmetric or chiral) centers, although the absence of an asterisk does not indicate that the compound lacks a stereocenter. Such formulae may refer to the racemate or to individual enantiomers or to individual diastereomers, which may or may not be pure or substantially pure. Other formulae may include one or more wavy bonds ("ΛΛΛΛΛ,"). When attached to a stereogenic center, the wavy bonds refer to both stereoisomers, either individually or as mixtures. Likewise, when attached to a double bond, the wavy bonds indicate a Z-isomer, an E-isomer, or a mixture of Z and
E isomers. Some formulae may include a dashed bond " " to indicate a single or a double bond.
[0040] "Substituted" groups are those in which one or more hydrogen atoms have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution. '
[0041] "About" or "approximately," when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within ±10 percent of the indicated value, whichever is greater.
[0042] "Alkyl" refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (i.e., C1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, /-propyl, π-butyl, s-butyl, /-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2,2-trimethyleth-l-yl, n-hexyl, and the like. [0043] "Alkenyl" refers to straight chain and branched hydrocarbon groups having one or more unsaturated carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, 1- buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl- 1-propen- l-yl, 2-methyl-2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
[0044] "Alkynyl" refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkynyl groups include, without limitation, ethynyl, 1- propyn-1-yl, 2-propyn-l-yl, 1-butyn-l-yl, 3-butyn-l-yl, 3-butyn-2-yl, 2-butyn-l-yl, and the like.
[0045] "Alkanoyl" refers to alkyl-C(O)-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon. Examples of alkanoyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.
[0046] "Alkenoyl" and "alkynoyl" refer, respectively, to alkenyl-C(O)- and alkynyl-C(O)-, where alkenyl and alkynyl are defined above. References to alkenoyl and alkynoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of alkenoyl groups include, without limitation, propenoyl, 2-methylpropenoyl, 2-butenoyl, 3-butenoyl, 2-methyl-2-butenoyl, 2-methyl-3- butenoyl, 3-methyl-3-butenoyl, 2-pentenoyl, 3-pentenoyl, 4-pentenoyl, and the like. Examples of alkynoyl groups include, without limitation, propynoyl, 2-butynoyl, 3- butynoyl, 2-pentynoyl, 3-pentynoyl, 4-pentynoyl, and the like.
[0047] "Alkoxy" and "alkoxycarbonyl" refer, respectively, to alkyl-O-, alkenyl-O, and alkynyl-O, and to alkyl-O-C(O)-, alkenyl-O-C(O)-, alkynyl-O-C(O)-, where alkyl, alkenyl, and alkynyl are defined above. Examples of alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, /-propoxy, n-butoxy, s-butoxy, t- butoxy, n-pentoxy, s-pentoxy, and the like. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i- propoxycarbonyl, n-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, n- pentoxycarbonyl, s-pentoxycarbonyl, and the like.
[0048] "Halo," "halogen" and "halogeno" may be used interchangeably, and refer to fluoro, chloro, bromo, and iodo.
[0049] "Haloalkyl," "haloalkenyl," "haloalkynyl," "haloalkanoyl," "haloalkenoyl," "haloalkynoyl," "haloalkoxy," and "haloalkoxycarbonyl" refer, respectively, to alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, alkoxy, and alkoxycarbonyl are defined above. Examples of haloalkyl groups include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.
[0050] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring (i.e., C3-7 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, the cycloalkyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
[0051] Examples of monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include, without limitation, bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.0]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.2.2]decyl, bicyclo[4.3.1]decyl, bicyclo[4.4.0]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.3.2]undecyl, bicyclo[4.3.3]dodecyl, and the like.
[0052] "Cycloalkenyl" refers monocyclic and bicyclic hydrocarbon rings having one or more unsaturated carbon-carbon bonds and generally having a specified number of carbon atoms that comprise the ring (i.e., C3-7 cycloalkenyl refers to a cycloalkenyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkenyl may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, the cycloalkenyl groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
[0053] "Cycloalkanoyl" and "cycloalkenoyl" refer to cycloalkyl-C(O)- and cycloalkenyl-C(O)-, respectively, where cycloalkyl and cycloalkenyl are defined above. References to cycloalkanoyl and cycloalkenoyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of cycloalkanoyl groups include, without limitation, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, 1-cyclobutenoyl, 2-cyclobutenoyl, 1-cyclopentenoyl, 2-cyclopentenoyl, 3-cyclopentenoyl, 1-cyclohexenoyl, 2-cyclohexenoyl, 3- cyclohexenoyl, and the like.
[0054] "Cycloalkoxy" and "cycloalkoxycarbonyl" refer, respectively, to cycloalkyl-O- and cycloalkenyl-0 and to cycloalkyl-O-C(O)- and cycloalkenyl-O- C(O)-, where cycloalkyl and cycloalkenyl are defined above. References to cycloalkoxy and cycloalkoxycarbonyl generally include a specified number of carbon atoms, excluding the carbonyl carbon. Examples of cycloalkoxy groups include, without limitation, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, 1- cyclobutenoxy, 2-cyclobutenoxy, 1-cyclopentenoxy, 2-cyclopentenoxy, 3- cyclopentenoxy, 1-cyclohexenoxy, 2-cyclohexenoxy, 3-cyclohexenoxy, and the like. Examples of cycloalkoxycarbonyl groups include, without limitation, 99 cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, l-cyclobutenoxycarbonyl, 2-cyclobutenoxycarbonyl, 1- cyclopentenoxycarbonyl, l-cyclopentenoxycarbonyl, S-cyclopentenoxycarbonyl, 1- cyclohexenoxycarbonyl, l-cyclohexenoxycarbonyl, 3-cyclohexenoxycarbonyl, and the like.
[0055] "Aryl" and "arylene" refer to monovalent and divalent aromatic groups, respectively, including 5- and 6-membered monocyclic aromatic groups that contain 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, furanyl, thiopheneyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and the like. Aryl and arylene groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiopheneyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, indolizinyl, and the like. They aryl and arylene groups may be attached to a parent group or to a substrate at any ring atom, unless such attachment would violate valence requirements. Likewise, aryl and arylene groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.
[0056] "Heterocycle" and "heterocyclyl" refer to saturated, partially unsaturated, or unsaturated monocyclic or bicyclic rings having from 5 to 7 or from 7 to 11 ring members, respectively. These groups have ring members made up of carbon atoms and from 1 to 4 heteroatoms that are independently nitrogen, oxygen or sulfur, and may include any bicyclic group in which any of the above-defined monocyclic heterocycles are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to a parent group or to O -2 a substrate at any heteroatom or carbon atom unless such attachment would violate valence requirements. Likewise, any of the carbon or nitrogen ring members may include a non-hydrogen substituent unless such substitution would violate valence requirements. Useful substituents include, without limitation, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.
[0057] Examples of heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
[0058] "Ηeteroaryl" and "heteroarylene" refer, respectively, to monovalent and divalent heterocycles or heterocyclyl groups, as defined above, which are aromatic. Ηeteroaryl and heteroarylene groups represent a subset of aryl and arylene groups, respectively. [0059] "Arylalkyl" and "heteroarylalkyl" refer, respectively, to aryl-alkyl and heteroaryl-alkyl, where aryl, heteroaryl, and alkyl are defined above. Examples include, without limitation, benzyl, fluorenylmethyl, imidazol-2-yl-methyl, and the like.
[0060] "Arylalkanoyl," "heteroarylalkanoyl," "arylalkenoyl," "heteroarylalkenoyl," "arylalkynoyl," and "heteroarylalkynoyl" refer, respectively, to aryl-alkanoyl, heteroaryl-alkanoyl, aryl-alkenoyl, heteroaryl-alkenoyl, aryl-alkynoyl, and heteroaryl-alkynoyl, where aryl, heteroaryl, alkanoyl, alkenoyl, and alkynoyl are defined above. Examples include, without limitation, benzoyl, benzylcarbonyl, fluorenoyl, fluorenylmethylcarbonyl, imidazol-2-oyl, imidazol-2-yl-methylcarbonyl, phenylethenecarbonyl, 1-phenylethenecarbonyl, 1-phenyl-propenecarbonyl, 2-phenyl- propenecarbonyl, 3-phenyl-propenecarbonyl, imidazol-2-yl-ethenecarbonyl, 1- (imidazol-2-yl)-ethenecarbonyl, l-(imidazol-2-yl)-propenecarbonyl, 2-(imidazol~2- yl)-propenecarbonyl, 3 -(imidazol-2-yl)-propenecarbonyl, phenylethynecarbonyl, phenylpropynecarbonyl, (imidazol-2-yl)-ethynecarbonyl, (imidazol-2-yl)- propynecarbonyl, and the like.
[0061] "Arylalkoxy" and "heteroarylalkoxy" refer, respectively, to aryl-alkoxy and heteroaryl-alkoxy, where aryl, heteroaryl, and alkoxy are defined above. Examples include, without limitation, benzyloxy, fluorenylmethyloxy, imidazol-2-yl- methyloxy, and the like.
[0062] "Aryloxy" and "heteroaryloxy" refer, respectively, to aryl-O- and heteroaryl-O-, where aryl and heteroaryl are defined above. Examples include, without limitation, phenoxy, imidazol-2-yloxy, and the like.
[0063] "Aryloxycarbonyl," "heteroaryloxycarbonyl," "arylalkoxycarbonyl," and "heteroarylalkoxycarbonyl" refer, respectively, to aryloxy-C(O)-, heteroaryloxy- C(O)-, arylalkoxy-C(O)-, and heteroarylalkoxy-C(O)-, where aryloxy, heteroaryloxy, arylalkoxy, and heteroarylalkoxy are defined above. Examples include, without limitation, phenoxycarbonyl, imidazol-2-yloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, imidazol-2-yl-metliyloxycarbonyl, and the like. [0064] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group .and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH2 and OH" can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO2, and metals.
[0065] "Enantiomeric excess" or "ee" is a measure, for a given sample, of the excess of one enantiomer over a racemic sample of a chiral compound and is expressed as a percentage. Enantiomeric excess is defined as 100 x (er - 1) / (er + 1), where "er" is the ratio of the more abundant enantiomer to the less abundant enantiomer.
[0066] "Diastereomeric excess" or "de" is a measure, for a given sample, of the excess of one diastereomer over a sample having equal amounts of diastereomers and is expressed as a percentage. Diastereomeric excess is defined as 100 x (dr - 1) / (dr + 1), where "dr" is the ratio of a more abundant diastereomer to a less abundant diastereomer.
[0067] "Stereoselective," "enantioselective," "diastereoselective," and variants thereof, refer to a given process (e.g., hydrogenation) that yields more of one stereoisomer, enantiomer, or diastereoisomer than of another, respectively.
[0068] "High level of stereoselectivity," "high level of enantioselectivity," "high level of diastereoselectivity," and variants thereof, refer to a given process that yields products having an excess of one stereoisomer, enantiomer, or diastereoisomer, which comprises at least about 90% of the products. For a pair of enantiomers or diastereomers, a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.
[0069] "Stereoisomerically enriched," "enantiomerically enriched," "diastereomerically enriched," and variants thereof, refer, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another. The degree of enrichment may be measured by % of total product, or for a pair of enantiomers or diastereomers, by ee or de.
[0070] "Substantially pure stereoisomer," "substantially pure enantiomer," "substantially pure diastereomer," and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 95% of the sample. For pairs of enantiomers and diastereomers, a substantially pure enantiomer or diastereomer would correspond to samples having an ee or de of about 90% or greater.
[0071] A "pure stereoisomer," "pure enantiomer," "pure diastereomer," and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 99.5% of the sample. For pairs of enantiomers and diastereomers, a pure enantiomer or pure diastereomer" would correspond to samples having an ee or de of about 99% or greater.
[0072] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.
[0073] "Stereoisomers" of a specified compound refer to the opposite enantiomer of the compound and to any diastereoisomers or geometric isomers (Z/E) of the compound. For example, if the specified compound has S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, its diastereomers having S,S,Z configuration and R,R,Z configuration, and its geometric isomers having S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration.
[0074] "Solvate" refers to a molecular complex comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., EtOH).
[0075] "Hydrate" refers to a solvate comprising a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.
[0076] "Pharmaceutically acceptable complexes, salts, solvates, or hydrates" refers to complexes, acid or base addition salts, solvates or hydrates of claimed and disclosed compounds, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
[0077] "Pre-catalyst" or "catalyst precursor" refers to a compound or set of compounds that are converted into a catalyst prior to use.
[0078] "Treating" refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition to which such term applies, or to preventing one or more symptoms of such disorder or condition.
[0079] "Treatment" refers to the act of "treating," as defined immediately above.
[0080] Table 1 lists abbreviations used throughout the specification.
TABLE l. List of Abbreviations
Abbreviation Description
Ac acetyl
ACN acetonitrile Abbreviation Description
Ac2O acetic anhydride aq aqueous
(R,R)-BDPP (2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane
(R)-BICHEP (R)-(-)-2,2'-bis(dicyclohexylphosphino)-6,6' -dimethyl-1 , 1 ' - biphenyl
(5,S)-BICP (2S,2 ' S)-bis (diphenylphosphino)-( 1 S, 1 ' S)-bicyclopentane BIFUP 2,2'-bis(diphenylphosphino)-4,4',6,6'- tetrakis(trifluoromethyl)- 1,1' -biphenyl
(R)-ToI-BINAP (R)-(+)-2,2 ' -bis(di-p-tolylphosphino)- 1,1' -binaphthyl
(S)-ToI-BINAP (S)-(+)-2,2 ' -bis(di-p-tolylphosphino)- 1,1' -binaphthyl
(R)-BINAP (R)-2,2'-bis(diphenylphosphino)-l'l-binaphthyl
(S)-BINAP (S)-2,2'-bis(diphenylphosphino)-l'l-binaphthyl
BIPHEP 2,2 ' -bis(diphenylphosphino)- 1,1' -biphenyl
(R)-MeO-BIPHEP (R)-(6,6 ' -dimethoxybiphenyl-2,2' -diyl)- bis(diphenylphosphine)
(R)-Cl-MeO-BPHEP (R)-(+)-5,5 ' -dichloro-6,6 ' -dimethoxy-2,2' - bis(diphenylphosphino)- 1,1' -biphenyl (S)-Cl-MeO-BIPHEP (S)-(+)-5,5'-dichloro-6,6'-dimethoxy-2,2'- bis(diphenylphosphino)- 1,1' -biphenyl
BisP* (S, S)- 1 ,2-bis(t-butylmethylphosphino)ethane (+)-tetraMeBITIANP (S)-(+)-2,2 ' -bis(diphenylphosphino)-4,4' ,6,6 ' -tetramethyl-
3 ,3 ' -bibenzo[Z?]thiophene
Bn benzyl
BnBr, BnCl benzylbromide, benzylchloride B oc t-butoxycarbonyl BOP benzotriazol- 1 -yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
(R)-(S)-BPPFA (-)-(R)~N,iV-dimethyl-l-((S)-l',2- bis(diphenylphosphino)ferrocenyl)ethylamine
(R5R)-Et-BPE (+)- 1 ,2-bis((2R,5i)-2,5-diethylphospholano)ethane Abbreviation Description
(R5R)-Me-BPE (+)-1,2-bis((2R,5R)-2,5-dimethylρhosρholano)ethane OS5S)-BPPM (-)~(2S,4S)-2-diphenylphosphinomethyl-4- diphenylphosphino-1-t-butoxycarbonylpyrrolidine
Bs brosyl or p-bromo-benzenesulfonyl
Bu butyl ft-BuLi rø-butyl lithium t-Bu tertiary butyl t-BuOK potassium tertiary-butoxide t-BuOLi lithium tertiary-butoxide
(+)-CAMP (R)-(+)-cyclohexyl(2-anisyl)methylphosphine; a monophosphine
CARBOPHOS methyl-α-D-glucopyranoside-2,6-dibenzoate-3,4-di(bis(3,5- dimethylphenyl)phosphinite)
Cbz benzyloxycarbonyl
CDI N,yV-carbonyldiimidazole
(5,S)-CHIRAPHOS (2S,3S)-(-)-bis(diphenylphosphino)butane
CnTunaPHOS 2,2'-bis-diphenylphosphanyl-biphenyl having an -O-
(CH2)n-O- group linking the 6,6' carbon atoms of the biphenyl (e.g., (R)-1, 14-bis-diphenylphosphanyl-6,7, 8,9- tetrahydro-5,10-dioxa-dibenzo[a,c]cyclodecene for n=4).
(R)-CYCPHOS (R)- 1 ,2-bis(diphenylphosphino)- 1-cyclohexylethane
DBAD di-t-butyl azodicarboxylate
DBN l,5-diazabicyclo[4.3.0]non-5-ene
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCC dicycohexylcarbodiimide de diastereomeric excess
DEAD diethyl azodicarboxylate
(R,R)-DEGUPHOS N-benzyl-(3R,4R)-3,4-bis(diphenylphosphino)pyrrolidine
DIAD diisopropyl azodicarboxylate
(R,R)-Diop (4R,5R)-(-)-O-isoρropylidene-2,3-dihydroxy- 1 ,4- Abbreviation Description bis(diphenylphosphino)butane
(R5R)-DiPAMP (R,R)-(-)-i,2-bis[(o- methoxyphenyl)(ρhenyl)ρhosphino]ethane
DMAP 4-(dimethylamino) pyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
DMT-MM 4-(4,6-dimethoxy- 1 ,3 ,5-triazin-2-yl)-4-methylmorpholinium chloride
(R,R)-Et-DUPHθs (-)- 1 ,2-bis((2R,5R)-2,5-diethylphospholano)benzene
(5,S)-Et-DUPHOS (-)- 152-bis((2S,5S>255-dietfiylphospholano)benzene
(R5R)-Z-Pr-DUPHOS (+)- 1 ,2-bis((2R,5R)-2,5-di-/-propylphospholano)benzene
(R,R)-Me-DUPHOS (-)- 1 ,2-bis((2R,5R)-2,5-dimethylphospholano)benzene
0S,S)-Me-DUPHOS (-)- 1 ,2-bis((26',55)-2,5-dimethylphospholano)benzene
EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide ee enantiomeric excess
Et ethyl
Et3N triethyl-amine
EtOAc ethyl acetate
Et2O diethyl ether
EtOH ethyl alcohol
FDPP pentafluorophenyl diphenylphosphinate
(R,R)-Et-FerroTANE 1,1' -bis((2R,4R)-2,4-diethylphosphotano)ferrocene
Fmoc 9-fluoroenylmethoxycarbonyl h, min, s hour(s), minute(s), second(s)
HOAc acetic acid
HOAt l-hydroxy-7-azabenzotriazole
HOBt iV-hydroxybenzotriazole
HODhbt 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine
(R)-(R)-JOSiPHOS (R)-(-)-i-[(R)-2-
(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine Abbreviation Description
GSMS)-JOSIFHOS (S)-(-)-l-[(S)-2-
(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (R)-(S)-JOSIPHOS (R)-(-)-l-[(S)-2-
(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine
KHMDS potassium hexamethyldisilazane
LDA lithium diisopropylamide
LHMDS lithium hexamethyldisilazane
LICA lithium isopropylcyclohexylamide
LTMP 2,2,6,6-tetramethylpiperidine
Me methyl
MeCl2 methylene chloride
MEK methylethylketone or butan-2-one
MeOH methyl alcohol
(R,R)-t-butyl-miniPHOS (R,R)- 1 ,2-bis(di-^-butylmethylphosphino)methane
(S,S) MandyPhos (S,S)-(-)-2,2'-bis[(R)-(N,N-dimethylamino) (ρhenyl)methyl]-
1 , 1 ' -bis(diphenylphosphino)ferrocene
(R)-MonoPhos (R)-(-)-[4,iV,N-dimethylammo]dinaphtho[2, 1-d: 1 ' ,2' - f] [ 1 ,3 ,2]dioxaphosphepin
(R)-MOP (R)-(+)-2-(diphenylphosphino)-2' -methoxy- 1,1' -binaphthyl
MPa mega Pascals mp melting point
Ms mesyl or methanesulfonyl
MTBE methyl tertiary butyl ether
NMP N-methylpyrrolidone
Ns nosyl or nitrobenzene sulfonyl
(R5R)-NORPHOS (2R,3R)-(-)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5- ene
PdCl2(dppf)2 dichloro [ 1 , 1 ' -bis (diphenylphosphino)f errocene]palladium
(II) dichloromethane adduct (R,S,R,S)-Me- (lR,2S,4R,5S)-2,5-dimethyl-7-phosρhadicyclo[2.2.1]heρtane Abbreviation Description
PENNPHOS
Ph phenyl
Ph3P triphenylphosphine
Ph3As triphenylarsine
(R)-PHANEPHOS (R)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane
(S)-PHANEPHOS (S)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane
(R)-PNNP N,N'-bis[(R)-(+)-α-methylbenzyl]-iV,iV'- bis(diphenylphosphino)ethylene diamine
PPh2-PhOx-Ph (R)-(-)-2-[2-(diphenylphosphino)phenyl]-4-phenyl-2- oxazoline
Pr propyl
/-Pr isopropyl
(R)-PROPHOS (R)-(+)- 1 ,2-bis(diphenylphosphino)propane
PyBOP benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
(R)-QUINAP (R)-(+)- 1 -(2-diphenylphosphino- 1 -naphthyl)isoquinoline
RT room temperature (approximately 20°C to 25 °C) s/c substrate-to-catalyst molar ratio
(R)-SpirOP ( lR,5R,6R)-spiro[4.4]nonane- 1 ,6-diyl-diphenylphosphinous acid ester; a spirocyclic phosphinite ligand
(R,R,S,S) TangPhos (R,R,S,S) l,l'-di-t-butyl-[2,2']biphospholanyl TATU O-(7-azabenzotriazol- 1-yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluoroborate
(R)-eTCFP (R)-2- { [(di-t-butyl-phosphanyl)-ethyl] -methyl-phosphanyl } - 2-methyl-propane (S)-eTCFP (5)-2- { [(di-t-butyl-phosphanyl)-ethyl]-methyl-phosphanyl } - 2-methyl-propane (R)-mTCFP (R)-2- { [(di-t-butyl-phosphanyl)-methyl] -methyl- phosphanyl } -2-methyl-propane (,S)-HiTCFP (S)-2- { [(di-t-butyl-phosphanyl)-methyl] -methyl- Abbreviation Descrip phosphanyl } -2-methyl-propane
TEA triethanolamine
Tf triflyl or trifluoromethylsulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin-layer chromatography
TMS trimethylsilyl
Tr trityl or triphenylmethyl
Ts tosyl or/?-toluenesulfonyl
[0081] Some of the schemes and examples below may omit details of common reactions, including oxidations, reductions, and so on, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974-2005). Starting materials and reagents may be obtained from commercial sources or may be prepared using literature methods.
[0082] In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and the like, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000), which are herein incorporated by reference in their entirety for all purposes. [0083] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about RT, but particular reactions may require the use of higher temperatures (e.g., reflux conditions) or lower temperatures, depending on reaction kinetics, yields, and the like. Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be ' polar protic solvents, polar aprotic solvents, non-polar solvents, or some combination. Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., includes the indicated endpoints.
[0084] This disclosure concerns materials and methods for preparing optically active β-amino acids represented by Formula 1, above, including diastereomers thereof and pharmaceutically acceptable complexes, salts, solvates and hydrates thereof. The claimed and disclosed methods provide compounds of Formula 1 that are stereoisomerically enriched, and which in many cases, are pure or substantially pure stereoisomers.
[0085] The compounds of Formula 1 have at least two stereogenic centers and include substituents R1, R2, and R3. Substituents R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom. Substituent R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R is optionally substituted with one to five fluorine atoms, and each aryl of R is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms.
[0086] Compounds of Formula 1 thus include those in which R1 and R2 are
1 0 independently hydrogen or C1-3 alkyl, provided that R and R are not both hydrogen, and those in which R3 is C1-6 alkyl. Representative compounds of Formula 1 also include those in which R1 is hydrogen, R2 is methyl, and R3 is methyl, ethyl or n- propyl, i.e., (31S,5i?)-3-amino-5-methyl-heptanoic acid, (35,5/?)-3-amino-5-methyl- octanoic acid, and (35,5i?)-3-amino-5-methyl-nonanoic acid.
[0087] Scheme I illustrates a method of preparing a desired stereoisomer of the compound of Formula 1. The stereoselective synthesis includes reacting an optically active β-dicarbonyl (Formula 6) with a source of ammonia to give an optically active enamine (Formula 4) that is optionally reacted with an acylating agent (Formula 5) to give an optically active enamide (Formula 2). The enamine (Formula 4) or the enamide (Formula 2) is reacted with hydrogen in the presence of a chiral catalyst to yield the compound of Formula 3, which is optionally hydrolyzed to the compound of Formula 1 by treatment with an acid or base. Substituents R1, R2, and R3 in Formula 2, 3, 4 and 6 are as defined in Formula 1; substituent R4 in Formula 2, 3, 4, and 6 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and substituents R5 in Formula 2 and Formula 5 and R in Formula 3 are independently hydrogen atom, carboxy, C1-7 alkanoyl, C2-7 alkenoyl, C2-7 alkynoyl, C3-7 cycloalkanoyl, C3-7 cycloalkenoyl, halo-C1-7 alkanoyl, halo-C2-7 alkenoyl, halo- C2-7 alkynoyl, C1-6 alkoxycarbonyl, halo-C1-6 alkoxycarbonyl, C3-7 cycloalkoxycarbonyl, aryl-C1-7 alkanoyl, aryl-C2-7 alkenoyl, aryl-C2-7 alkynoyl, aryloxycarbonyl, or aryl-C1-6 alkoxycarbonyl, provided that R5 is not a hydrogen atom.
[0088] Generally, and unless stated otherwise, when a particular substituent identifier (R1, R2, R3, etc.) is defined for the first time in connection with a formula, the same substituent identifier, when used in a subsequent formula, will have the same definition as in the earlier formula. Thus, for example, if R in a first formula is hydrogen atom, halogeno, or C1-6 alkyl, then unless stated differently or otherwise c clleeaarr f frroomm t thhee context of the text, R in a second formula is also hydrogen, halogeno, or C1-6 alkyl. [0089] The β-dicarbonyl (Formula 6) may be prepared using methods illustrated in Scheme IV and Scheme V, below, and is converted to the enamine (Formula 4) through treatment with an ammonia source. Representative β-dicarbonyl compounds (Formula 6) include various C1-6 alkyl esters of (2?)-5-methyl-3-oxo-heptanoic acid, (/?)-5-methyl-3-oxo-octanoic acid, and (i?)-5-methyl-3-oxo-nonanoic acid. Examples of β-dicarbonyls thus include (/?)-5-methyl-3-oxo-heptanoic acid ethyl ester, (R)S- methyl-3-oxo-octanoic acid ethyl ester, and (Z?)-5-methyl-3-oxo-nonanoic acid ethyl ester. Useful sources of ammonia include ammonia and ammonium acetate, among others. See, e.g., P. G. Baraldi et al., Synthesis (ll):902-903 (1983). The reaction is typically carried out with excess ammonium acetate (e.g., 1.2 eq. or greater) in a protic solvent, such as EtOH or HOAc, and at RT or above (up to reflux temperature).
[0090] As shown in Scheme I, the enamine (Formula 4) is optionally converted to the enamide (Formula 2) via contact with an acylating agent (Formula 5). Representative enamines include C1-6 alkyl esters of the Z- and E-isomers of (R)-3- amino-5-methyl-hept-2-enoic acid, (i?)-3-amino-5-methyl-oct-2-enoic acid, and (R)-3- amino-5-methyl-non-2-enoic acid. Examples of enamines thus include the Z- and E- isomers of (/?)-3-amino-5-methyl-hept-2-enoic acid ethyl ester, (/?)-3-amino-5- methyl-oct-2-eiioic acid ethyl ester, and (/?)-3-amino-5-methyl-non-2-enoic acid ethyl ester. Useful acylating agents include carboxylic acids, which have been activated either prior to contacting the enamine (Formula 4) or in-situ (i.e., in the presence of the enamine using an appropriate coupling agent). Representative activated carboxylic acids (Formula 5) include acid halides, anhydrides, mixed carbonates, and the like, in which X1 is a leaving group, such as halogeno, aryloxy (e.g. phenoxy, 3,5- dimethoxyphenoxy, etc.) and heteroaryloxy (e.g., imidazolyloxy), or -OC(O)R15, in which R15 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, halo-C1-6 alkyl, halo-C2-6 alkenyl, halo-C2-6 alkynyl, aryl, aryl-C1-6 alkyl, heterocyclyl, heteroaryl, or heteroaryl-Ci.6 alkyl.
Figure imgf000039_0001
aly
Figure imgf000039_0002
Figure imgf000039_0003
Hydrolysis
Figure imgf000039_0004
Figure imgf000039_0005
Scheme I
[0091] Other suitable acylating agents include carboxylic acids, which are activated in-situ using a coupling agent. Typically, the reaction is carried out in an aprotic solvent, such as ACN, DMF, DMSO, toluene, MeCl2, NMP, THF, etc., and may also employ a catalyst. Coupling agents include, but are not limited to DCC, DMT-MM, FDPP, TATU, BOP, PyBOP, EDCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, iV,iV-bis-(2-oxo-3-oxazolidinyl)~ phosphinic chloride, diphenylphosphoryl azide, diphenylphosphinic chloride, and diphenylphosphoryl cyanide. Useful catalysts for the coupling reaction include DMAP, HODhbt, HOBt, and HOAt.
[0092] The optically active enamine (Formula 4) or enamide (Formula 2) undergoes asymmetric hydrogenation in the presence of a chiral catalyst to give the compound of Formula 3. As depicted in Scheme I, useful enamide hydrogenation substrates (Formula 2) include individual Z- or E-isomers or a mixture of Z- and E- isomers, and include C1-6 alkyl esters of the Z- and E- isomers of (/?)-3-acetylamino-5- methyl-hept-2-enoic acid, (i?)-3-acetylamino-5-methyl-oct-2-enoic acid, and (R)-3- acetylamino-5-methyl-non-2-enoic acid. Examples of useful enamides thus include the Z- and E- isomers of (i?)~3-acetylamino-5-methyl-hept-2-enoic acid ethyl ester, (i?)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester, and (i?)-3-acetylamino-5- methyl-non-2-enoic acid ethyl ester.
[0093] When substituent R4 in Formula 2 or 4 is a hydrogen atom, the method may optionally include converting the carboxylic acid to a Group 1, Group 2, or ammonium salt prior to asymmetric hydrogenation through contact with a suitable base, such as a primary amine (e.g., t-BuNH2), a secondary amine (DIPEA), and the like. In some instances, the use of a salt of the enamide (Formula 2) or enamine (Formula 4) may increase conversion, improve stereoselectivity, or provide other advantages. Optionally, the method may employ an inorganic salt of the carboxylic acid obtained through contact with a suitable base such as NaOH, Na2CO2, LiOH, Ca(OH)2, and the like.
[0094] Depending on which enantiomer of the chiral catalyst is used, the asymmetric hydrogenation generates an excess (de) of a diastereoisomer of Formula 3. Although the amount of the desired diastereoisomer produced will depend on, among other things, the choice of chiral catalyst, a de of the desired diastereoisomer of about 50 % or greater is desirable; a de of about 70 % or greater is more desirable; and a de of about 85 % is still more desirable. Particularly useful asymmetric hydrogenations are those in which the de of the desired diastereoisomer is about 90 % or greater. For the purposes of this disclosure, a desired diastereoisomer or enantiomer is considered to be substantially pure if it has a de or ee of 95 % or greater.
[0095] As noted above, the asymmetric hydrogenation of the enamide (Formula 2) or enamine (Formula 4) employs a chiral catalyst having the requisite stereochemistry. Useful chiral catalysts include, without limitation, cyclic or acyclic, chiral phosphine ligands (e.g., monophosphines, bisphosphines, bisphospholanes, etc.) or phosphinite ligands bound to transition metals, such as ruthenium, rhodium, iridium or palladium. Ru-, Rh-, Ir- or Pd-phosphine, phosphinite or phosphino oxazoline complexes are optically active because they possess a chiral phosphorus atom or a chiral group connected to a phosphorus atom, or because in the case of BINAP and similar atropisomeric ligands, they possess axial chirality. Useful chiral ligands include, without limitation, BisP*; (R)-BINAPINE; (S)-Me-ferrocene- Ketalphos, (R5R)-DIOP; (R5R)-DIPAMP; (R)-(S)-BPPFA; (S,S)-BPPM; (+)-CAMP; (S5S)-CHIRAPHOS; (R)-PROPHOS; (R5R)-NORPHOS; (R)-BINAP; (R)-CYCPHOS; (R5R)-BDPP; (R5R)-DEGUPHOS; (R5R)-Me-DUPHOS; (R5R)-Et-DUPHOS; (R5R)-/- Pr-DUPHOS; (R5R)-Me-BPE; (R5R)-Et-BPE (R)-PNNP; (R)-BICHEP; (R,S,R,S)-Me- PENNPHOS; (S5S)-BICP; (R,R)-Et-FerroTANE; (R,R)-t-butyl-miniPHOS; (R)-ToI- BINAP; (R)-MOP; (R)-QUINAP; CARBOPHOS; (R)-(S)-JOSIPHOS; (R)- PHANEPHOS; BIPHEP; (R)-Cl-MeO-BIPHEP; (R)-MeO-BIPHEP; (R)-MonoPhos; BIFUP; (R)-SpirOP; (+)-TMBTP; (+)-tetraMeBITIANP; (R5R5S5S) TANGPhos; (R)- PPh2-PhOx-Ph; (S,S) MandyPhos; (R)-eTCFP; (R)-mTCFP; and (R)-CnTunaPHOS, where n is an integer of 1 to 6.
[0096] Other useful chiral ligands include, without limitation, (R)~(-)-l-[(S)-2- (di(3,5-bistrifluoromethylphenyl)phosphino)ferrocenyl]ethyldicyclohexyl-phosphine; (R)-(-)-l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocen-yl]ethyldi(3,5- dimethylphenyl)phosphine; (R)-(-)-l-[(S)-2-(di-t-butylphosphino)ferro- cenyl]ethyldi(3,5-dimethylphenyl)phosphine; (R)-(-)-l-[(S)-2-(dicyclohexylphosphi- no)ferrocenyl]ethyldi-t-butylphosphine; (R)-(-)-l-[(S)-2-(dicyclohexyrphosphino)fer- rocenyl]ethyldicyclohexylphosphine; (R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferro- cenyl]ethyldiphenylphosphine; (R)-(-)-l-[(S)-2-(di(3,5-dimethyl-4-methoxyphen- yl)phosphino)ferrocenyl]ethyldicyclohexylphosphine; (R)-(-)-l-[(S)-2-(diphenylphos- phino)ferrocenyl]ethyldi-t-butylphosphine; (/?)-N-[2-(iV,N-diinethylamino)ethyl]-N- methyl-l-[(5)-l',2-bis(diphenylphosphino)ferrocenyl]ethylamine; (R)-(-i-)-2-[2- (diphenylphosphino)phenyl]-4-(l-methylethyl)-4,5-dihydrooxazole; { l-[((R,R)-2- benzyl-phospholanyl)-phen-2-yl]-(R*,R*)-phospholan~2-yl}-phenyl-methane; and { 1- [((i?,R)-2-benzyl-phospholanyl)-ethyl]-(R*,i?*)-phospholan-2-yl}-phenyl-methane.
[0097] Useful ligands may also include stereoisomers (enantiomers and diastereoisomers) of the chiral ligands described in the preceding paragraphs, which may be obtained by inverting all or some of the stereogenic centers of a given ligand or by inverting the stereogenic axis of an atropoisomeric ligand. Thus, for example, useful chiral ligands may also include (,S)-Cl-MeO-BIPHEP; (S)-PHAΝEPHOS; (5,S)-Me-DUPHOS; (5,S)-Et-DUPHOS; (S)-BINAP; (S)-ToI-BINAP; (R)-(R)- JOSIPHOS; (S)-(S)-JOSIPHOS; (S)-eTCFP; (S)-mTCFP and so on.
[0098] Many of the chiral catalysts, catalyst precursors, or chiral ligands may be obtained from commercial sources or may be prepared using known methods. A catalyst precursor or pre-catalyst is a compound or set of compounds, which are converted into the chiral catalyst prior to use. Catalyst precursors typically comprise Ru, Rh, Ir or Pd complexed with the phosphine ligand and either a diene (e.g., norboradiene, COD, (2-methylallyl)2, etc.) or a halide (Cl or Br) or a diene and a halide, in the presence of a counterion, X",such as OTf ", PF6 ", BF4 ", SbF6 ", ClO4 ", etc. Thus, for example, a catalyst precursor comprised of the complex, [(bisphosphine ligand)Rh(COD)]+X~ may be converted to a chiral catalyst by hydrogenating the diene (COD) in MeOH to yield [(bisphosphine ligand)Rh(MeOH)2]+X~ MeOH is subsequently displaced by the enamide (Formula 2) or enamine (Formula 4), which undergoes enantioselective hydrogenation to the desired chiral compound (Formula 3). Examples of chiral catalysts or catalyst precursors include (+)-TMBTP- ruthenium(II) chloride acetone complex; (S)-Cl-MeO-B EPHEP-ruthenium(II) chloride Et3N complex; (S)-BINAP-rathenium(II) Br2 complex; (S)-tol-BINAP-ruthenium(II) Br2 complex; [((3i?,4i?)-3,4-bis(diphenylphosphino)-l-methylpyrrolidine)-rhodium- (l,5-cyclooctadiene)]-tetrafluoroborate complex; [((R,R,S,S)-TANGPhos)-rhodium(I)- bis(l,5-cyclooctadiene)]-trifluoromethane sulfonate complex; [(R)-BINAPINE- rhodium-(l,5-cyclooctaidene)]-tetrafluoroborate complex; [(S)-eTCFP-(l,5- cyclooctadiene)-rhodium(I)]-tetrafluoroborate complex; and [(S)-mTCFP-(l,5- cyclooctadiene)-rhodium(I)]-tetrafluroborate complex.
[0099] For a given chiral catalyst and hydrogenation substrate (Formula 2 or 4), the molar ratio of the substrate and catalyst (s/c) may depend on, among other things, H2 pressure, reaction temperature, and solvent (if any). Usually, the substrate-to- catalyst ratio exceeds about 100:1 or 200:1, and substrate-to-catalyst ratios of about 1000: 1 or 2000: 1 are common. Although the chiral catalyst may be recycled, higher substrate-to-catalyst ratios are more useful. For example, substrate-to-catalyst ratios of about 1000:1, 10,000:1, and 20,000:1, or greater, would be useful. The asymmetric hydrogenation is typically carried out at about RT or above, and under about 10 kPa (0.1 atm) or more of H2. The temperature of the reaction mixture may range from about 20°C to about 80°C, and the H2 pressure may range from about 10 kPa to about 5000 kPa or higher, but more typically, ranges from about 10 kPa to about 100 kPa. The combination of temperature, H2 pressure, and substrate-to-catalyst ratio is generally selected to provide substantially complete conversion (i.e., about 95 wt %) of the substrate (Formula 2 or 4) within about 24 h. With many of the chiral catalysts, decreasing the H2 pressure increases the enantioselectivity.
[0100] A variety of solvents may be used in the asymmetric hydrogenation, including protic solvents, such as water, MeOH, EtOH, and z'-PrOH. Other useful solvents include aprotic polar solvents, such as THF, ethyl acetate, and acetone. The stereoselective hydrogenation may employ a single solvent or may employ a mixture of solvents, such as THF and MeOH, THF and water, EtOH and water, MeOH and water, and the like.
[0101] In some cases it may be advantageous to employ more than one chiral catalyst to carryout the asymmetric hydrogenation of the substrate (Formula 2 or 4). For example, the method may provide for reacting the enamide or enamine successively with first and second chiral catalysts to exploit the comparatively greater stereoselectivity, but lower reaction rate of the first (or second) chiral catalyst. Thus, for example, the method provides for reacting the substrate with hydrogen in the presence of a chiral catalyst comprised of (R)-BINAPINE or its opposite enantiomer, followed by reaction in the presence of a chiral catalyst comprised of (R)-mTCFP or its opposite enantiomer.
[0102] As shown in Scheme I, the method optionally provides for conversion of the hydrogenation product (Formula 3) into the optically active β-amino acid (Formula 1). For example, when R4 is C1-6 alkyl and R19 is non-hydrogen, the ester and amide moieties may be hydrolyzed by treatment with an acid or a base or by treatment with a base (or acid) followed by treatment with an acid (or base). For example, treating the compound of Formula 3 with HCl, H2SO4, and the like, with excess H2O generates the β-amino acid (Formula 1) or an acid addition salt. Treating the compound of Formula 3 with an aqueous inorganic base, such as LiOH, KOH, NaOH, CsOH, Na2CO3, K2CO3, Cs2CO3, and the like, in an optional polar solvent (e.g., THF, MeOH, EtOH, acetone, ACN, etc.) gives a base addition salt of a β-amido acid, which may be treated with an acid to generate the β-amino acid (Formula 1) or an acid addition salt. Likewise, when R19 in Formula 3 is hydrogen, the ester moiety may be hydrolyzed by treatment with an acid or base to give the β-amino acid (Formula 1) or an acid or base addition salt. The ester and amide hydrolysis may be carried out at RT or at temperatures up to reflux temperature, and if desired, treatment of the acid or base addition salts with a suitable base (e.g., NaOH) or acid (e.g., HCl) gives the free amino acid (zwitterion).
[0103] Useful compounds represented by Formula 3 include β-amino and β- amido C1-6 alkyl esters in which R1 and R2 are independently hydrogen or C1-3 alkyl, provided that R1 and R2 are not both hydrogen, and those in which R3 is C1-6 alkyl.
1 O
Useful compounds of Formula 3 also include those in which R is hydrogen, R is methyl, and R is methyl, ethyl or n-propyl, i.e., C1-6 alkyl esters of (3,S',5/?)-3-amino- 5-methyl-heptanoic acid, (35,5/?)-3-amino-5-methyl-octanoic acid, (3S,5R)-3-amhio- 5-methyl-nonanoic acid, (35,5/?)-3-acetylamino-5-methyl-heptanoic acid, (3S,5R)-3- acetylamino-5-methyl-octanoic acid, and (3S,5R)-3-acetylamino-5-methyl-nonanoic acid. Examples of useful β-amino C1-6 alkyl esters thus include (3S,5/?)-3-amino-5- methyl-heptanoic acid ethyl ester, (35',5i?)-3-amino-5-methyl-octanoic acid ethyl ester, and (35r,5i?)-3-amino-5-methyl-nonanoic acid ethyl ester. Likewise, useful β- amido C1-6 alkyl esters include (3S,5R)-3-acetylamino-5-methyl-heptanoic acid ethyl ester, (3S,5R)-3-acetylamino~5-methyl-octanoic acid ethyl ester, and (3S,5R)-3- acetylamino-5-methyl-nonanoic acid ethyl ester.
[0104] Compounds of Formula 3 also include β-amido acids in which R1 and R2 are independently hydrogen or C1-3 alkyl, provided that R1 and R2 are not both hydrogen, and those in which R3 is C1-6 alkyl. Useful β-amido acids of Formula 3 also include those in which R is hydrogen, R is methyl, and R is methyl, ethyl or n- propyl, i.e., (3S,5i?)-3-acetylamino~5-methyl-heptanoic acid, (35',5/?)-3-acetylamino- 5-methyl-octanoic acid, and (3S,5R)-3-acetylamino-5-methyl-nonanoic acid.
[0105] The compound of Formula 1, or its diastereoisomer, may be further enriched through, e.g., fractional recrystallization or chromatography or by recrystallization in a suitable solvent. In addition, compounds of Formula 1 or 3 may be enriched through treatment with an enzyme such as a lipase or amidase.
[0106] Scheme II illustrates another method for preparing the desired stereoisomer of the compound of Formula 1. The stereoselective synthesis includes reacting an optically active β-dicarbonyl (Formula 6) with hydrogen in the presence of a chiral catalyst to yield an optically active β-hydroxy carboxylic acid derivative (Formula 12) that is subsequently hydrolyzed to give the corresponding β-hydroxy acid (Formula 10). The activated acid is reacted with an amine (Formula 11) to give an optically active amide (Formula 9), which is cyclized under Mitsunobu conditions (e.g., Ph3P, DEAD, dry THF) to give a chiral lactam (Formula 8) with inversion of the stereocenter. Besides DEAD, other useful azodicarboxylates include DBAD, DIAD, and l,l'-(azodicarbonyl)dipiperidine. In addition to Mitsunobu conditions, the alcohol (Formula 9) may be activated by conversion to a sulfonate ester (e.g., reaction with MsCl and pyridine), which is subsequently cyclized by treatment with a base (e.g., a carbonate). Treatment of the lactam (Formula 8) with an acid or base gives a secondary amine (Formula 7), which is subsequently reduced via, e.g., catalytic hydrogenolysis to give the compound of Formula 1. Substituents R1, R2, and R3 in Formula 7 to 10 and Formula 12 are as defined in Formula 1; substituent R4 in Formula 12 is as defined in Formula 6; and substituent R6 in Formula 7 to 9 and Formula 11 is aryl-C1-3 alkyl (e.g., benzyl, 3,5-dimethoxybenzyl, etc.), C1-6 alkyl (e.g., methyl) or C2-6 alkenyl (e.g., allyl).
[0107] The methodology shown in Scheme II may employ many of the same reagents and conditions described in Scheme I. For example, useful reagents (substrates, chiral catalysts, solvents, etc.) and conditions (temperature, pressure, etc.) for the stereoselective hydrogenation of the β-dicarbonyl (Formula 6) to give the β- hydroxy carboxylic acid derivative (Formula 12) include the reagents and conditions described in Scheme I for the asymmetric hydrogenation of the enamide (Formula 2). However, because the formation of the lactam (Formula 8) inverts the β-carbon stereocenter, the chiral catalyst should promote the formation of a hydroxy-substituted stereocenter (Formula 12) having the opposite stereochemical configuration as that of the β-carbon of the final product (Formula 1).
[0108] Similarly, reagents and conditions for coupling the β-hydroxy carboxylic acid (Formula 10) and the primary amine (Formula 11) to give the chiral amide (Formula 9) include reagents and conditions described in Scheme I for acylation of the enamine (Formula 4). For example, the β-hydroxy carboxylic acid (Formula 10) may be activated in-situ with a coupling agent (e.g., DMT-MM) and reacted with a primary amine (e.g., BnONH2 or BnONH3 +Cl") to give the chiral amide (Formula 9 in which R6 is Bn). Useful β-hydroxy carboxylic acids (Formula 10) include (3R,5R)-3- hydroxy-5-methyl-heptanoic acid, (3/?,5i?)-3-hydroxy-5-methyl-octanoic acid, and (3/?,5i?)-3-hydroxy-5-methyl-nonanoic acid. Representative β-hydroxy amides (Formula 9) include aryl-C1-3 alkyl amides derived from the aforementioned carboxylic acids, including (3i?,5/?)-3-hydroxy-5-methyl-heptanoic acid benzyloxy- amide, (3/?,5/?)-3-hydroxy-5-methyl-octanoic acid benzyloxy-amide, and (3R,5R)-3- hydroxy-5-methyl-nonanoic acid benzyloxy-amide.
[0109] Likewise, reagents and conditions for hydrolyzing the β-hydroxy carboxylic acid derivative (Formula 12) or the lactam (Formula 8) include reagents and conditions described in Scheme I for hydrolysis of the amino acid ester (Formula 3). Useful, β-hydroxy carboxylic acid derivatives (Formula 12) include C1-6 alkyl esters of (3/?,5/?)-3-hydroxy-5-methyl-heptanoic acid, (3R,5i?)-3-hydroxy- 5-methyl-octanoic acid, and (3R,5i?)-3-hydroxy-5-methyl-nonanoic acid. Examples of useful β-hydroxy C1-6 alkyl esters include (3/?,5/?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester, (3i?,5i?)-3-hydroxy-5-methyl-octanoic acid ethyl ester, and (3R,5K)- 3-hydroxy-5-methyl-nonanoic acid ethyl ester. Representative lactams (Formula 8) include (2/?,45>l-(aryl-C1-3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-one, (2R,45)-1- (aryl-Ci-3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-one, and (2Λ,45)-l-(aryl- C1-3 alkyloxy)-4-(2-methyl-butyl)-azetidin-2-ones. These include, for example, (2R,4S)- 1 -benzyloxy-4-(2-methyl-butyl)-azetidin-2-one, (2R,4S)- 1 -benzyloxy-4-(2- methyl-pentyl)-azetidin-2-one, and (2R,4S)- 1 -benzyloxy-4-(2-methyl-hexyl)-azetidin- 2-one.
[0110] Hydrogenolysis is carried out in the presence of a catalyst and one or more polar solvents, including without limitation, alcohols, ethers, esters and acids, such as MeOH, EtOH, IPA, THF, EtOAc, and HOAc. The reaction may be carried out at temperatures ranging from about 5°C to about 1000C, though reactions at RT are common. Generally, the substrate-to-catalyst ratio may range from about 1:1 to about 1000: 1, based on weight, and H2 pressure may range from about atmospheric pressure, 0 psig, to about 1500 psig. More typically, the substrate-to-catalyst ratios range from about 4:1 to about 20:1, and H2 pressures range from about 25 psig to about 150 psig.
[0111] Useful substrates (Formula 7) include those in which R1 and R2 are independently hydrogen or C1-3 alkyl, provided that R and R are not both hydrogen, and those in which R3 is C1-6 alkyl. Representative compounds of Formula 7 include those in which R1 is hydrogen, R2 is methyl, R3 is methyl, ethyl or n-propyl, and R6 is benzyl, i.e., (3S,5R)-3-benzyloxyamino-5-methyl-heptanoic acid, (3,S,5i?)-3- benzyloxyamino-5-methyl-octanoic acid, and (3S,5i?)-3-benzyloxyamino-5-methyl- nonanoic acid.
[0112] Useful catalysts include, without limitation, heterogeneous catalysts containing from about 0.1% to about 20%, and more typically, from about 1% to about 5%, by weight, of transition metals such as Ni, Pd, Pt, Rh, Re, Ru, and Ir, including oxides and combinations thereof, which are typically supported on various materials, including Al2O3, C, CaCO3, SrCO3, BaSO4, MgO, SiO2, TiO2, ZrO2, and the like. Many of these metals, including Pd, may be doped with an amine, sulfide, or a second metal, such as Pb, Cu, or Zn. Useful catalysts thus include palladium catalysts such as Pd/C, Pd/SrCO3, PdZAl2O3, Pd/MgO, PdZCaCO3, PdZBaSO4, PdO, Pd black, PdCl2, and the like, containing from about 1% to about 5% Pd, based on weight. Other useful catalysts include Raney nickel, RhZC, RuZC, ReZC, PtO2, RhZC, RuO2, and the like. For a discussion of hydrogenolysis catalysts, see U.S. Patent No. 6,624,112 to Hasegawa et al., which is herein incorporated by reference.
[0113] Scheme III illustrates an additional method for preparing the desired stereoisomer of the compound of Formula 1. The stereoselective synthesis includes reducing an optically active β-dicarbonyl (Formula 6) by, e.g., reacting it with hydrogen in the presence of a metal catalyst, to give an optically active β-hydroxy carboxylic acid derivative (Formula 17). Activating the β-hydroxy moiety via, e.g., reaction with a compound of Formula 18, gives an intermediate (Formula 16), which undergoes elimination via treatment with a base. Reacting the resulting unsaturated acid derivative (Formula 15) with an anion of a chiral amine (Formula 14) gives, after protonation, an optically active secondary or tertiary amine (Formula 13), which is subsequently deprotected via catalytic hydrogenolysis to give the compound of Formula 37. As in Scheme I, the compound of Formula 37 is optionally hydrolyzed to the compound of Formula 1 by treatment with an acid or base. Substituents R1, R2, and R3 and substituent R in Formula 13, 15 to 17, and 37 are as defined in Formula 1 and Formula 6, respectively; substituent R7 in Formula 13 and 14 is C1-6 alkyl, C2-6 alkenyl, or aryl-C1-3 alkyl; substituent R8 in Formula 16 is a leaving group (e.g., R9O-); substituent R9 in Formula 18 is tosyl, mesyl, brosyl, closyl (p-chloro- benzenesulfonyl), nosyl, or triflyl; and substituent X2 in Formula 18 is halogeno or R9O-.
Figure imgf000049_0001
Figure imgf000049_0002
10
Cyclization Conditions
Figure imgf000049_0003
Hydrolysis
Figure imgf000049_0004
Figure imgf000049_0005
Hydrogenolysis
Figure imgf000049_0006
Scheme II
^8— [0114] The methodology shown in Scheme III may employ many of the same reagents and conditions described in Scheme II. For example, useful reagents (catalysts, solvents, etc.) and conditions (temperature, pressure, etc.) for the catalytic reduction of the β carbonyl and substituted amino moieties of the compounds of Formula 6 and Formula 13, respectively, include the reagents and conditions described in Scheme II for the catalytic hydrogenolysis of the secondary amine (Formula 7). Representative optically active secondary or tertiary amines (Formula 13) include β-amino C1-6 alkyl esters of (lS,3S,5R)-3-[benzyl-(l-phenyl- ethyl)-amino]-5-methyl-heptanoic acid, (15',35',5/?)-3-[benzyl-(l-phenyl-ethyl)- amino]-5-methyl-octanoic acid, and (15r,35,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5- methyl-nonanoic acid. Examples of useful β-amino C1-6 alkyl esters thus include (15,31Sr,5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-heptanoic acid ethyl ester, (15,3iS',5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester, and (15',35,5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester.
[0115] As shown in Scheme III, the β-hydroxy moiety of the compound of Formula 17 is activated via reaction with the compound of Formula 18. Useful β- hydroxy carboxylic acid derivatives (Formula 17) include C1-6 alkyl esters of (5i?)-3- hydroxy-5-methyl-heptanoic acid, (5i?)-3-hydroxy-5-methyl-octanoic acid, and (5R)- 3-hydroxy-5-methyl-nonanoic acid. Representative β-hydroxy C1-6 alkyl esters thus include (52?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester, (5/?)-3-hydroxy-5- methyl-octanoic acid ethyl ester, and (5i?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester.
[0116] Useful compounds of Formula 18 include sulfonylating agents, such as TsCl, MsCl, BsCl, NsCl, TfCl, and the like, and their corresponding anhydrides (e.g., /7-toluenesulfonic acid anhydride). Thus, for example, compounds of Formula 17 may be reacted with TsCl in the presence of pyridine and an aprotic solvent, such as ethyl acetate, MeCl2, ACN, THF, and the like, to give C1-6 alkyl esters of (5R)-5-methyl-3- (toluene-4-sulfonyloxy)-heptanoic acid, (5/?)-5-methyl-3-(toluene-4-sulfonyloxy)- octanoic acid, and (5i?)-5-methyl-3-(toluene-4-sulfonyloxy)-nonanoic acid. Likewise, compounds of Formula 17 may be reacted with MsCl in the presence of a an aprotic solvent and a strong or hindered base, such as Et3N, to give C1-6 alkyl esters of (5R)-3- methanesulfonyloxy-5-methyl-heptanoic acid, (5/?)-3-methanesulfonyloxy-5-methyl- octanoic acid, and (5/?)-3-methanesulfonyloxy-5-methyl-nonanoic acid.
[0117] Upon activation of the β-hydroxy moiety, the resulting intermediate (Formula 16) is reacted with a base to give an unsaturated carboxylic acid derivative (Formula 15). The reaction is typically carried out at RT or above and in the presence of an aprotic solvent, such as ethyl acetate, THF, MeCl2, ACN, and the like. Useful bases include strong or hindered bases (i.e., non-nucleophilic bases) such as Et3N, t- BuOK, DBN, DBU, and the like.
[0118] As indicated above, conjugate addition of a chiral amine (Formula 14) to an unsaturated carboxylic acid derivative (Formula 15) gives an optically active secondary or tertiary amine (Formula 13). The stereochemistry of the chiral amine (Formula 14) determines the stereochemical configuration of the amino-substituted stereocenter (Formula 13). Useful substrates for the conjugate addition include Z- or E-isomers or a mixture of Z- and E- isomers of the unsaturated carboxylic acid derivative (Formula 15) and include C1-6 alkyl esters of the Z- and E-isomers of (R)-5- methyl-hept-2-enoic acid, (/?)-5-methyl-oct-2-enoic acid, and (i?)-5-methyl-non~2- enoic acid. Examples include the Z- and E-isomers of (/?)-5-methyl-hept-2~enoic acid ethyl ester, (/?)-5-methyl-oct~2~enoic acid ethyl ester, and (i?)-5-methyl-non-2-enoic acid ethyl ester. Useful chiral amines (Formula 14) include (i?)-(+)-N-benzyl-α- methylbenzylamine, (5>(-)-N-benzyl-α-methylbenzylamine, and the like. See S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry 2(3): 183-186 (1991); and /. Chem. Soc, Perkins Trans. 1 2931-2938 (2001).
Figure imgf000052_0001
Scheme III
[0119] To carryout the conjugate addition, the chiral amine (Formula 14) is typically treated with a strong base, such as n-BuLi and the like, in an ethereal solvent, such as Et2O, THF, etc., and at a temperature of about -78°C to RT. The resulting deprotonated amine is subsequently reacted with the unsaturated carboxylic acid derivative (Formula 15) to give the optically active secondary or tertiary amine (Formula 13) having the desired stereochemical configuration.
[0120] Scheme III shows an< alternative method for preparing the compound of Formula 15. The method includes reacting a sorbate ester (Formula 38) or amide with a Grignard reagent (Formula 29) and a catalytic amount of another metal (e.g., copper salt) and an optional chiral catalyst. The resulting enantiomerically enriched compound (Formula 39) is subsequently isomerized by treatment with a base (e.g., triethylamine) in a polar solvent (e.g., THF) to give the compound of Formula 15. Alternatively, the compound of Formula 39 may be isomerized by treatment with a metal catalyst, including Ru, Rh or Pd salts complexed with a counterion, such as a halogen anion, COD, and the like. Compounds of Formula 15 and 39 may also be enantiomerically enriched by treatment with a lipase under standard conditions. The optional chiral catalysts may include those described above in connection with the asymmetric hydrogenation of the enamide (Formula 2) and enamine (Formula 4) in Scheme I.
[0121] Substituents R1, R2, and R3 and substituent R4 in Formula 29, 38 and 39 are as defined in Formula 1 and Formula 6, respectively, and substituent X4 in Formula 29 is halogeno. Useful compounds of Formula 39 thus include, without limitation, C1-6 alkyl esters of the Z- and E-isomers of (i?)-5-methyl-hept-3-enoic acid, (/?)-5-methyl-oct-3-enoic acid, and (i?)-5-methyl-non-3-enoic acid. Examples include the Z- and E-isomers of (/?)-5-methyl-hept-3-enoic acid ethyl ester, (/?)-5-methyl-oct- 3-enoic acid ethyl ester, and (i?)-5-methyl-non-3-enoic acid ethyl ester.
[0122] In addition to the methodology shown in Scheme III, the compound of Formula 37 may be prepared from the compound of Formula 15 by catalytic asymmetric conjugate addition of an amine. See, e.g., Hamashima et al., Organic Letters 6:1861-1864 (2004), the complete disclosure of which is herein incorporated by reference.
[0123] Scheme IV illustrates a method for preparing β-dicarbonyls (Formula 6) used in Scheme I, II, and III. The method includes activating a chiral alcohol (Formula 25) via, e.g., reaction with a sulfonylating agent (Formula 26), to give an intermediate (Formula 24), which is subsequently treated with a source of cyanide ion to yield an optically active nitrile (Formula 23). Hydrolyzing the nitrile (Formula 23) through contact with an acid gives a chiral carboxylic acid (Formula 22 or salt), which is subsequently activated through, e.g., reaction with a coupling agent such as CDI. The activated carboxylic acid derivative (Formula 20) is reacted with a malonic acid salt or ester (Formula 21) in the presence of a base to give an α- substituted malonic acid intermediate (Formula 19), which is decarboxylated by treatment with an acid to provide the desired β-dicarbonyl (Formula 6). Useful sulfonylating agents include those described in connection with Formula 18; useful sources of cyanide ion include, without limitation, sodium cyanide, potassium cyanide, zinc cyanide, hydrogen cyanide, acetone cyariohydrin, and the like, either alone or in combination.
[0124] Instead of the chiral alcohol (Formula 25), the method may employ an activated prochiral enoate (Formula 30), which is reacted with a deprotonated chiral oxazolidinone to give an TV-acylated oxazolidinone (Formula 28). The deprotonated oxazolidinone may be prepared from a chiral oxazolidinone (Formula 31) by separate treatment with a strong base (e.g., /i-BuLi) or by in-situ treatment with a hindered base (e.g., Et3N). The JV-acylated oxazolidinone (Formula 28) is subsequently reacted with a Grignard reagent (Formula 29) in the presence of a copper salt (e.g., CuBrDMS) to give a conjugate addition product (Formula 27). As indicated in Scheme IV, the conjugate addition product (Formula 27 or Formula 20 in which R10 is a chiral oxazolidin-2-one-3-yl) may be reacted with the malonic acid derivative (Formula 21) to give the α-substituted malonic acid intermediate (Formula 19). Alternatively, the chiral side chain may be cleaved following asymmetric synthesis via, e.g., acid or base hydrolysis, using for instance, an alkali metal hydroxide or peroxide such as LiOOH in aq. THF followed by reduction, to give the carboxylic acid of Formula 22 or a salt thereof and to regenerate the chiral auxiliary
(Formula 31). For additional methods of cleaving the chiral side, see U.S. Patent No.
5,801,249 to Davies et al. and references cited therein.
[0125] In Scheme IV, substituents R1, R2, and R3 in Formula 19, 20, 22 to 25, and 27, 28 and 30 are as defined above in Formula 1; R4 in Formula 19 and 21 is as defined in Formula 2; R10, R11, and R17 in Formula 20, 24, and 30 are leaving groups, which may be the same or different; R12 in Formula 26 is a tosyl, mesyl, brosyl, closyl, nosyl, or triflyl; X3 in Formula 26 is halogeno; and R13, R14, R15, and R16 in Formula 27, 28, and 31 are independently hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, or aryl-C1-3 alkyl, provided that R15 and R16 are not both hydrogen atoms.
[0126] For the methodology shown in Scheme IV, representative chiral alcohols (Formula 25) and corresponding activated forms (Formula 24) include, without limitation, (2?)-2-methyl-butanol, (/?)-2-methyl~pentanol, (/?)-2-methyl-hexanol, (R)-2- methyl- 1 -(toluene-4-sulf onyloxy)-butane, (/?)-2-methyl- 1 -(toluene-4-sulf onyloxy)- pentane, (R)-2-methyl- 1 -(toluene-4-sulfonyloxy)-hexane, (R)- 1 -methanesulf onyloxy- 2-methyl-butane, (R)-I -methanesulf onyloxy-2-methyl-pentane, and (R)-I- methanesulfonyloxy-2-methyl-hexane. Representative nitriles (Formula 23), chiral carboxylic acids (Formula 22) and corresponding activated forms (Formula 20) include, without limitation, (/?)-3-methyl-pentanenitrile, (i?)-3-methyl-hexanenitrile, (R)-3 -methyl-heptanenitrile, (R)- 1 -imidazol- 1 -yl-3 -methyl-pentan- 1 -one, (R)- 1 - imidazol- 1 -yl-3 -methyl-hexan- 1 -one, and (R)- 1 -imidazol- 1 -yl-3 -methyl-heptan- 1 -one.
Figure imgf000056_0001
28
Activate
Figure imgf000056_0002
Figure imgf000056_0003
19
Scheme IV
[0127] In addition, representative activated prochiral enoates (Formula 30) include, without limitation, acid halides of the Z- and E- isomers of but-2-enoic acid, such as but-2-enoyl chloride. Representative chiral oxazolidinones (Formula 31) include, without limitation, (7?)-4-isopropyl-oxazolidin-2-one, (/?)-4-phenyl- oxazolidin-2-one, (R)-4-benzyl-oxazolidin-2-one, and (4/?,5S)-4-methyl-5-phenyl- oxazolidin-2-one. Thus, representative N-acylated oxazolidinones (Formula 28) include, without limitation, the Z- and E-isomers of (i?)-3-(but-2-enoyl)-4-isopropyl- oxazolidin-2-one, (i?)~3-(but-2-enoyl)-4-phenyl-oxazolidin-2-one, (i?)-4-benzyl-3- (but-2-enoyl)-oxazolidin-2-one, and (4/?,55')-3-(but-2-enoyl)-4-methyl-5-phenyl- oxazolidin-2-one. Likewise, representative Michael adducts (Formula 27 or Formula 20) include, without limitation, (i?,/?)-4-isopropyl-3-(3-methyl-pentanoyl)- oxazolidin-2-one, (/?,/?)-4-isopropyl-3-(3-methyl-hexanoyl)-oxazolidin-2-one, (R,R)- 4-isopropyl-3-(3-methyl-heptanoyl)-oxazolidin-2-one, (7?,/?)-3-(3-methyl-pentanoyl)- 4-phenyl-oxazolidin-2-one, (R,i?)-3-(3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one, (i?,/?)-3-(3-methyl-heptanoyl)-4-phenyl-oxazolidin-2-one, (i?,i?)-4-benzyl-3-(3- methyl-pentanoyl)-oxazolidin-2-one, (i?,2?)-4-benzyl-3-(3-methyl-hexanoyl)- oxazolidin-2-one, (/?,/?)~4-benzyl-3-(3-methyl-heptanoyl)-oxazolidin-2-one, (3i?,4i?,51S')-4-methyl-3-(3-methyl-ρentanoyl)-5-phenyl-oxazolidin-2-one, (3R,4R,5S)- 4-methyl-3-(3-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one, and (3/?,4/?,5S)-4- methyl-3-(3-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one.
[0128] Scheme V illustrates another method for preparing the β-dicarbonyl (Formula 6) used in Scheme I, II, and III. The method includes activating a chiral alcohol (Formula 34) via, e.g., reaction with a sulfonylating agent (Formula 26), to give an intermediate (Formula 32), which is subsequently reacted with a deprotonated acetoacetate derivative (Formula 36). The resulting chiral anion (Formula 35) or a corresponding salt is treated with an acid to yield, via tautomerization, the desired β- dicarbonyl (Formula 6). As shown in Scheme V, the displacement of substituent R18 (Formula 32) results in inversion of the stereogenic center and occurs via attack by a dianion intermediate (Formula 36 or corresponding salt). The dianion (Formula 36) may be prepared by treating an acetoacetate derivative (Formula 33) successively with one or more equivalents of a first base (e.g., LiH, NaH, etc.) and a second base (e.g., BuLi) that are strong enough to deprotonate, respectively, the central methylene and terminal methyl groups. Alternatively, the acetoacetate derivative may be treated with two or more equivalents of a single base that can deprotonate the terminal methyl group. In Scheme V, substituents R , R , and R in Formula 32 and 34 are as defined above in Formula 1; R4 in Formula 33 and 36 is as defined above in Formula 2; and R18 is a leaving group.
Figure imgf000058_0001
Scheme V
[0129] For the methodology shown in Scheme V, representative chiral alcohols (Formula 34) and corresponding activated forms (Formula 32) include, without limitation, (S)-butan-2-ol, (5)-pentan-2-ol, (S)-hex-2-ol, (5)-2-(toluene-4- sulfonyloxy)-butane, (ιS)-2-(toluene-4-sulfonyloxy)-pentane, (ιS)-2-(toluene-4- sulfonyloxy)-hexane, (S)-2-(chlorobenzene~4~sulfonyloxy)~butane, (S)-2- (chlorobenzene-4-sulfonyloxy)-pentane, (>S')-2-(chlorobenzene-4-sulfonyloxy)-hexane, (5)-2-methanesulfonyloxy-butane, (5)-2-methanesulfonyloxy-pentane, and (S)-2- methanesulfonyloxy-hexane. Representative acetoacetate derivatives (Formula 33) include, without limitation, C1-6 alkyl esters of acetoacetate, including acetoacetate ethyl ester. Representative dianions (Formula 36) include, without limitation, Z- and E-isomers of 1-C1-6 alkoxy-buta-l,3-diene-l,3-diol dianions, such as (Z)- and (E)-I- ethoxy-buta-l,3-diene-l,3-diol dianion. Similarly, representative chiral anions (Formula 35) include, without limitation, Z- and E-isomers of (R)-I-C1-6 alkoxy-4- methyl-hex-l-en-2-ol anion, (R)-I-C1-6 alkoxy-4-methyl-hept-l-en-2-ol anion, and (R)-I-C1-6 alkoxy-4-methyl-oct-l-en-2-ol anion, which include Z- and E-isomers of (R)- 1 -ethoxycarbonyl-4-methyl-hex- 1 -en-2-ol anion, (R)- 1 -ethoxycarbonyl-4-methyl- hept-l-en-2-ol anion, and (R)- l-ethoxycarbonyl-4-methyl-oct-l -en-2-ol anion.
[0130] The activation of the chiral alcohol (Formula 34), subsequent displacement of R18 (Formula 32), and treatment of the chiral anion (Formula 35) with acid may be carried out at about -5O0C to reflux, while the preparation of the dianion (Formula 36) generally occurs at temperatures less than about 00C, and more typically, at temperatures less than about -3O0C but greater than about -800C.
[0131] Many of the compounds described herein are capable of forming pharmaceutically acceptable salts. These salts include, without limitation, acid addition salts (including di-acids) and base salts. Pharmaceutically acceptable acid addition salts include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
[0132] Pharmaceutically acceptable base salts include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines. Examples of suitable metal cations include, without limitation, sodium cations (Na+), potassium cations (K+), magnesium cations (Mg2+), calcium cations (Ca2+), and the like. Examples of suitable amines include, without limitation, iV,iV'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. For a discussion of useful acid addition and base salts, see S. M. Berge et al., "Pharmaceutical Salts," 66 /. ofPharm. ScL, 1-19 (1977); see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).
[0133] One may prepare an acid addition salt (or base salt) by contacting a compound's free base (or free acid) with a sufficient amount of a desired acid (or base) to produce a nontoxic salt. One may then isolate the salt by filtration if it precipitates from solution, or by evaporation to recover the salt. One may also regenerate the free base (or free acid) by contacting the acid addition salt with a base (or the base salt with an acid). Certain physical properties (e.g., solubility, crystal structure, hygroscopicity, etc.) of a compound's free base, free acid, or zwitterion may differ from its acid or base addition salt. Generally, however, references to the free acid, free base or zwitterion of a compound would include its acid and base addition salts.
[0134] Disclosed and claimed compounds may exist in both unsolvated and solvated forms and as other types of complexes besides salts. Useful complexes include clathrates or compound-host inclusion complexes where the compound and host are present in stoichiometric or non-stoichiometric amounts. Useful complexes may also contain two or more organic, inorganic, or organic and inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. K. Haleblian, /. Pharm. Sci. 64(8): 1269-88 (1975). Pharmaceutically acceptable solvates also include hydrates and solvates in which the crystallization solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6- DMSO, etc. Generally, for the purposes of this disclosure, references to an unsolvated form of a compound also include the corresponding solvated or hydrated form of the compound. [0135] The disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as H and H; isotopes of carbon, such as 13C and 14C; isotopes of nitrogen, such as 15N; isotopes of oxygen, such as 17O and 18O; isotopes of phosphorus, such as 31P and 32P; isotopes of sulfur, such as 35S; isotopes of fluorine, such as F; and isotopes of chlorine, such as 36Cl. Use of isotopic variations (e.g., deuterium, H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3H, or 1 C), which may be useful in drug and/or substrate tissue distribution studies.
EXAMPLES
[0136] The following examples are intended as illustrative and non-limiting, and represent specific embodiments of the present invention.
EXAMPLE 1. Preparation of (i?)-3-methyl-hexanoic acid from (i?)-2-methyl-pentan- l-ol via (/?)-3-methyl-hexanenitrile
[0137] A mixture of (i?)-2-methyl-pentan-l-ol , MeCl2 and pyridine is cooled to O0C to 1O0C. To this mixture is added toluenesulfonyl chloride and the resulting reaction mixture is allowed to warm to RT overnight. The reaction is quenched by the addition of water and the mixture is separated into upper and lower layers. The lower layer is washed with dilute aq HCl. The organic layer is concentrated to an oil by vacuum distillation, then diluted with DMSO and reacted by adding sodium cyanide and heating to 5O0C for 3 hours. After cooling to RT, the reaction mixture is diluted with hexane and water and the upper layer is washed with water. The hexane layer is concentrated by vacuum distillation giving (i?)-3-methyl-hexanenitrile as an oil. The oil is reacted by adding aq HCl and heating the mixture to 5O0C to 600C for 6 hours. The reaction mixture is extracted with diethyl ether and the organic layer is concentrated by vacuum distillation, which provides the titled compound as an oil.
EXAMPLE 2. Preparation of (i?)-5-methyl-3-oxo-octanoic acid ethyl ester from (R)- methyl-hexanoic acid and potassium ethyl malonate
[0138] To a stirred mixture of N,N carbonyldiimidazole (26.4 g) in THF (175 rnL) was added (i?)-3-methyl-hexanoic acid (20 g) at RT. The reaction mixture cleared upon stirring for 4 hours at RT to give an activated carboxylic acid solution. To a stirred mixture of ethyl malonate potassium salt (49.6 g) in acetonitrile (265 rnL) was added Et3N (21.4 rnL). To this mixture was added anhydrous magnesium chloride powder (35.Ig) in portions while keeping the temperature at 15°C to 25°C. The resulting slurry was allowed to warm to RT and was stirred for 4 hours. The activated carboxylic acid solution was added to the slurry and the mixture was stirred at RT for 17 hours. The reaction was quenched with aqueous HCl and extracted with MTBE. The organic layer was washed with sodium bicarbonate and NaCl/H2O/HCl solutions. The solvents were removed by vacuum distillation to give the titled compound as a yellow oil (36 g). 1H NMR (400 MHz, CDCl3) δ 4.20 (q, 2H), 3.42 (S, 2H), 2.52 (dd, IH), 2.33 (dd, IH), 2.03 (m, IH), 1.3 (m, 3H), 1.28 (t, 3H), 1.16 (m, IH), 0.9 (m, 6H).
EXAMPLE 3. Preparation of (i?)-5-methyl-3-oxo-octanoic acid ethyl ester from (R)- methyl-hexanoic acid and potassium ethyl malonate
[0139] To a stirred mixture of N,N carbonyldiimidazole (33 kg) in EtOAc (217 L) was added (/?)~3~methyl-hexanoic acid (25 kg) dissolved in EtOAc (30 L) at RT. The reaction mixture cleared upon stirring for 1 hour at RT to give an activated carboxylic acid solution. To a stirred mixture of ethyl malonate potassium salt (45.8 kg) and magnesium chloride (25.6 kg) in EtOAc (320 L) was added Et3N (31.1 kg). The activated carboxylic acid solution was added to this slurry and the resulting mixture was stirred at 40°C to 50°C for 11 hours. The mixture was cooled to 1O0C to 15°C, and the reaction was quenched with aqueous HCl. The organic layer was washed successively with water and aq sodium bicarbonate and then concentrated by vacuum distillation to give the titled compound as a yellow oil (38.2 kg, 100% yield of 92% pure product).
EXAMPLE 4. Preparation of (R)-5-methyl-3-oxo-octanoic acid ethyl ester from (/?,/?)-4-methyl-3-(3-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one and potassium ethyl malonate
[0140] To a stirred mixture containing (/?,/?)-4-methyl-3-(3-methyl-hexanoyl)-5- phenyl-oxazolidin-2-one (34 g) and ethyl malonate potassium salt (40 g) in acetonitrile (250 mL), was added magnesium chloride (45 g) in portions while keeping the temperature below 6O0C. The slurry was diluted with Et3N (35 mL) and heated to 60°C for 16 hours. After cooling to RT, the reaction was quenched with aq HCl and extracted with ethyl acetate. The organic layer was washed with aq sodium bicarbonate and with water. The solvents were removed by vacuum distillation, and the resulting solids were slurried in hexanes (300 mL) and filtered. The solids were 90% pure recovered (4/?,5S)-4-methyl-5-phenyl-oxazolidin-2-one. The filtrate was concentrated by vacuum distillation resulting in the titled compound (14 g, 94% pure via vapor phase chromatography). The product could be further purified by vacuum distillation.
EXAMPLE 5. Preparation of (/?)-5-methyl-3-oxo-octanoic acid ethyl ester from (/?,/?)-3-(3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one and potassium ethyl malonate
[0141] To a stirred mixture containing (/?,/?)-3-(3-methyl-hexanoyl)-4-phenyl- oxazolidin-2-one (5 g) and ethyl malonate potassium salt (6 g) in acetonitrile (50 mL), was added anhydrous magnesium chloride (7.8 g) in portions while keeping the temperature below 60°C. The slurry was diluted with Et3N (5 mL) and heated to 60°C for 16 hours. After cooling to RT, the reaction was quenched with aqueous HCl and the upper layer concentrated to an oil, then extracted with hexane. The solvent was removed by vacuum distillation to yield titled compound as an oil (2.3 g). The product could be further purified by vacuum distillation. EXAMPLE 6. Preparation of (i?)-5-methyl-3-oxo-octanoic acid ethyl ester from (S)- pentan-2-ol and acetoacetate ethyl ester
[0142] To a 250 mL round bottom flask containing 4-chlorobenzenesulfonyl chloride (25.18 g, 0.12 mol) and (S)-pentan-2-ol (10 g, 0.11 mol) in MeCl2 (50 mL) was added Et3N (22.14 mL, 0.15 mol) and DMAP (0.69 g, 0.0057mol). The mixture was stirred at 40°C for at least 3 hours. After the reaction was completed, 37% HCl (4.7 mL) and water (10 mL) were added to the reaction mixture. The organic layer was separated and washed with water (25 mL x 2). The solvent was removed by distillation at ambient pressure. THF (10 mL x 2) was added to remove residual MeCl2 under vacuum to give (S)-2-(chlorobenzene-4-sulfonyloxy)-pentane as an oil.
[0143] To a 1 L round bottom flask containing diisopropylamine (46.7 g, 0.45 mol) in THF (50 mL), which was cooled to -20°C, was slowly added n-BuLi (138.9 g, 0.45 mol) while maintaining the temperature below -1O0C. The mixture was cooled to -4O0C. After the addition was completed, acetoacetate ethyl ester (29.5 g, 0.22 mol) was slowly added while maintaining the temperature below -300C to give 1 -ethoxy-buta- 1 ,3 -diene- 1 ,3-diol dianion.
[0144] To the ethyl acetoacetate dianion was added the pentyl closylate oil (30 g, 0.11 mol) in a single addition. The mixture was allowed to warm to 25°C and was stirred for at least 3 hours. Following completion of the reaction, an HCl solution (89.4 g in 200 mL water) was added to the cold reaction mixture at O0C to quench the reaction. After separating the organic layer, the aqueous layer was extracted with hexane (50 mL). The combined organic layers were washed with NaHCO3 solution (10 g in 100 mL water) and 10% brine (10 g NaCl and 3mL of 37% HCl in 100 mL water). The solvent was removed by vacuum distillation. The titled compound was distilled under vacuum at 400C to 450C (26% yield). EXAMPLE 7. Preparation (R)-3-methyl-heptanoic acid from (R,R)-3-(3-methyl- heptanoyl)-4-phenyl-oxazolidin-2-one
[0145] To a solution of (R,R)-3-(3-methyl-heptanoyl)-4-phenyl-oxazolidin-2-one (24.6 kg) in THF (180 L) and water (30 L), was added lithium hydroperoxide, which was prepared by combining aq LiOH (6.6 kg of LiOH monohydrate dissolved in 130 L of water) and 35 % aq hydrogen peroxide (33 kg) at 5+5°C. After stirring for at least 4 hours, the reaction was quenched by the addition of aq sodium bisulfite (42 kg NaHSO3 dissolved in 140 L water) and was diluted with ethyl acetate (150 kg). The layers were separated and the lower layer was extracted with ethyl acetate (60 kg). The ethyl acetate layers were combined and washed with brine and then concentrated by vacuum distillation. The residue was dissolved in hexanes (280 L) and cooled to crystallize out (R)-4-phenyl-oxazolidin-2-one, which was collected by filtration. The filtrate was concentrated by vacuum distillation to give the titled compound, which was carried directly into the next reaction.
EXAMPLE 8. Preparation of (/?)-5-methyl-3-oxo-nonanoic acid ethyl ester from (R)- 3-methyl-heptanoic acid and potassium ethyl malonate
[0146] To a stirred mixture of CDI (13.2 g) in ethyl acetate (50 mL) was added (i?)-3-methyl-heptanoic acid (11.1 g). The mixture was allowed to stir for 4 hours at RT to give an activated acid solution. To a stirred mixture of ethyl malonate potassium salt (18.3 g) in ethyl acetate (125 mL) was added Et3N (12.4 g). To this mixture was added anhydrous magnesium chloride powder (10.3 g) in portions while keeping the temperature at 15°C to 250C. The slurry was allowed to warm to RT and continued to stir for 1 hour. The activated acid solution was subsequently added to the slurry and the mixture was stirred at RT for 17 hours. The reaction was quenched with aqueous HCl. The organic layer was washed with sodium bicarbonate and brine solutions and the solvents were removed by vacuum distillation to yield the titled compound as a yellow oil (15.9 g, 96%yield). 1H NMR (400 MHz, CDCl3) δ 4.20 (q, 2H), 3.42 (S, 2H), 2.52 (dd, IH), 2.33 (dd, IH), 2.03 (m, IH), 1.3 - 1.1 (m, 6H), 1.28 (t, 3H), 0.9 (m, 6H). EXAMPLE 9. Preparation of (R,E)-5-methyl-oct-2-eneoic acid ethyl ester from (R)- 5-methyl-3-oxo-octanoic acid ethyl ester
[0147] To a reactor containing (R)-5-methyl-3-oxo-octanoic acid ethyl ester (15 kg, 75 mol) in EtOH (90 kg) was added dichloro-tris(triphenylphosphine)- ruthenium (190 g) followed by 10% aq HCl (0.7 kg). The reactor contents were heated to 50+50C and reacted under 50 psig of hydrogen for 20 hours. The reactor was subsequently purged with nitrogen and its contents filtered and concentrated to an oil by vacuum distillation. The oil was diluted with ethyl acetate (60 L), concentrated by vacuum distillation, again diluted with EtOAc (60 L), cooled to -100C to -20 C and further diluted with methanesulfonyl chloride (12.1 kg). The resulting solution was cooled to -10°C to -20 C and Et3N (26 kg) was slowly added while maintaining the temperature below 20°C. The solution was warmed to 40°C to 6O0C for at least 12 hours, then cooled to O0C to 100C, and quenched by the addition of aq HCl. The organic solution was washed with water and concentrated by vacuum distillation resulting in an oil. Hexane was added and the solution concentrated by vacuum distillation to give the titled compound (11 kg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 6.94 (dt, IH), 5.80 (d, IH), 4.18 (q, 2H), 2.19 (m, IH), 2.05 (m, IH), 1.63 (m, IH), 1.3 - 1.1 (m, 4H), 1.29 (t, 3H), 0.9 (m, 6H).
EXAMPLE 10. Preparation of (l>S,35',5R)-3-[benzyl-(l-phenyl-ethyl)-amino]-5- methyl-octanoic acid ethyl ester from (R)-5-methyl-oct-2-eneoic acid ethyl ester
[0148] To a cooled solution of OS)-benzyl-(l-phenyl-ethyl)-amine (21.3 kg) in THF (77 L) was added 24% n-BuLi (27 kg) at -200C to -3O0C. The resulting solution was cooled to -7O0C to -9O0C and (R,E)-5-methyl-oct-2-eneoic acid ethyl ester (15 kg) in THF (10 L) was slowly added over about 1 hour. The reaction mixture was stirred for an additional 5 to 15 minutes at -65°C to -750C. The reaction was subsequently quenched by the addition of aq HCl and the mixture partitioned into upper and lower layers. The upper layer was washed two times with water and the organic layer was concentrated by vacuum distillation to give the titled compound as an oil (30 kg, 93% yield). EXAMPLE 11. Preparation of (3S,5R)-3-amino-5-methyl-octanoic acid HCl from (15l,35r,5R)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester
[0149] A slurry of 20% Pd/C (10 kg, 50% water wet), (lS,3S,5i?)-3-[benzyl-(l- phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester (31 kg) in EtOH (100 L), and acetic acid (10 kg), was reacted with hydrogen (50 psig) at 45°C to 55°C for at least 16 hours. Following reaction, the reactor was vented and purged with nitrogen and the contents were filtered. The filtrate was diluted with aq HCl, concentrated by vacuum distillation, and diluted with 35% HCl (30 kg) and water (100 kg). The resulting solution was heated to 80°C to 100°C for a minimum of 12 hours and admixed with toluene. The solution was partitioned into upper and lower layers. The lower layer was separated and concentrated by vacuum distillation to a volume of about 50 L. The solution was cooled and the resulting precipitate was collected by filtration, washed with toluene, then dried under vacuum to provide an off-white solid (7 kg). The solid was recrystallized from isopropanol and toluene to give the titled compound as a white product (5 kg, 30% yield). 1H NMR (400 MHz, D6DMSO) δ 12.71 (bs, IH) 8.16 (bs, 3H), 3.38 (m, IH), 2.68 (dd, IH), 2.53 (dd, IH), 1.61 (m, 2H), 1.3 - 1.1 (m, 5H), 0.83 (m, 6H).
EXAMPLE 12. Preparation of (i?,E)-5-methyl-non-2-eneoic acid ethyl ester from (i?)-5-methyl-3-oxo-nonanoic acid ethyl ester
[0150] To a reactor containing (R)-5-methyl-3-oxo-nonanoic acid ethyl ester (16 kg, 75 mol) in EtOH (90 kg) was added dichloro-tris(triphenylphosphine)- ruthenium (96 g) followed by 10% aq HCl (0.7 kg). The contents of the reactor were heated to 50+50C under 50 psig of hydrogen for 20 hours. Following reaction, the reactor was purged with nitrogen and the contents were filtered and concentrated to an oil by vacuum distillation. The oil was diluted with ethyl acetate (60 L), concentrated by vacuum distillation, diluted again with EtOAc (60 L), cooled to -10 to -20 C, and further diluted with methanesulfonyl chloride (12.1 kg). The solution was cooled to -10°C to -200C and Et3N (23 kg) was slowly added while maintaining the temperature below 2O0C. The solution was warmed to about 5O0C for at least 12 hours, cooled to 0°C to 1O0C, and quenched with aq HCl. The organic solution was washed with water and concentrated by vacuum distillation resulting in an oil. Hexane was added and the solution concentrated by vacuum distillation to give the titled compound (11 kg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 6.94 (dt, IH), 5.80 (d, IH), 4.18 (q, 2H), 2.20 (m, IH), 2.05 (m, IH), 1.60 (m, IH), 1.3 - 1.1 (m, 6H), 1.29 (t, 3H), 0.9 (m, 6H).
EXAMPLE 13. Preparation of (l£3S,5R)-3-[benzyl-(l-ρhenyl-ethyl)-amino]-5- methyl-nonanoic acid ethyl ester from (i?)-5-methyl-non-2-eneoic acid ethyl ester
[0151] To a cooled solution of (S)-benzyl-(l-phenyl-ethyl)-amine (29 kg) in THF (250 L) was added 24% Ti-BiLi (34.5 kg) at -20°C to -30°C. The resulting solution was cooled to -70°C to -90°C and (i?)-5-methyl-non-2-eneoic acid ethyl ester (19.5 kg) in THF (70 L) was slowly added over about 1 hour. The reaction mixture was stirred for an additional 5 to 15 minutes at -65°C to -75°C. The reaction was quenched by the addition of aqueous HCl and the mixture was partitioned between upper and lower layers. The upper layer was washed two times with water and the organic layer was concentrated by vacuum distillation to give the titled compound as an oil (32 kg, 79% yield).
EXAMPLE 14. Preparation of (3S,5i?)-3-amino-5-methyl-nonanoic acid HCl from (15r,35,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester
[0152] A slurry of 20% Pd/C (20 kg, 50% water wet), (lS,3S,5R)-3-[benzyl-(l- phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester (50 kg) in EtOH (312 L), and acetic acid (15 kg) acetic acid, was reacted with hydrogen (50 psig) at 45°C to 55°C for at least 16 hours. Following reaction, the reactor was vented and purged with nitrogen and the contents were filtered. The filtrate was diluted with aq HCl, concentrated by vacuum distillation, and diluted with 50 Kg 35% HCl (50 kg) and 100 Kg water (100 kg). The solution was heated to 80°C to 100°C for a minimum of 12 hours and then admixed with toluene. The solution was partitioned into upper and lower layers. The lower layer was separated and concentrated by vacuum distillation to a volume of about 100 L. The solution was diluted with concentrated aq. HCl (12 kg) and cooled. The resulting precipitate was collected by filtration, washed with toluene, then dried under vacuum to give an off-white solid (21 kg). The solid was recrystallized twice from aq HCl to provide the titled compound as a white solid (11 kg, 40% yield). 1H NMR (400 MHz, D6DMSO) δ 12.77 (bs, IH), 8.14 (bs, 3H), 3.36 (m, IH), 2.67 (dd, IH), 2.53 (dd, IH), 1.60 (m, 2H), 1.3 - 1.1 (m, 7H), 0.83 (m, 6H).
EXAMPLE 15. Preparation of (35',5R)-3-amino-5-methyl-nonanoic acid from (3S,5R)-3-amino-5-methyl-nonanoic acid HCl
[0153] (3S,5/?)-3-amino-5-methyl-nonanoic acid HCl (11 kg) was dissolved in water (45 L), filtered to remove particulates, and diluted with aq 5 N NaOH (10 L) to give a slurry having a pH between 5 and 7. The solids were dissolved by MTBE (50 L) and the solution cooled to -5°C to 5 C. The resulting precipitate was collected by filtration and washed with cooled MTBE. The solids were slurried in water (about 50 L), collected by filtration, washed with MTBE, then dried in a vacuum oven to give the titled compound as a white solid (3.8 kg, 42% yield). 1H NMR (400 MHz, CD3OD) 64.93 (bs, 2H), 3.42 (m, IH), 2.46 (dd, IH), 2.28 (dd, IH), 1.61 (m, 2H), 1.5 - 1.1 (m, 7H), 0.9 (m, 6H).
EXAMPLE 16. Preparation of (i?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester from (/?)-5-methyl-3-oxo-octanoic acid ethyl ester
[0154] (i?)-5-Methyl-3-oxo-octanoic acid ethyl ester (20 g) and ammonium acetate (16.2 g) were heated in EtOH (150 mL) at 60°C for 3 hours, then cooled and concentrated to an oil by vacuum distillation. The material was dissolved in toluene and concentrated by vacuum distillation. After adding toluene and cooling to 15°C to 25°C, the slurry was filtered, diluted with additional toluene, and reacted further by adding acetic anhydride (20 g) and pyridine (21.3 mL) and heating the mixture at 100°C to HO0C for 16 hours. The reaction mixture was cooled to 1O0C to 2O0C and the reaction was quenched by the addition of water. The mixture was partitioned into upper and lower layers, and the upper layer was washed with dilute aqueous sulfuric acid followed by water. The product was concentrated by vacuum distillation, dissolved in EtOH, and concentrated again to give the titled compound as an oil (21 g, 88% yield). 1H NMR (CDCl3) δ 4.90 (s, IH), 4.17 (q, J= 8 Hz, 2H), 2.88 (m, IH), 2.34 (m, IH), 2.14 (s, 3H), 1.79 (m, IH), 1.30 (m, 7H), 0.89 (m, 6H).
EXAMPLE 17. Preparation of (35',5/?)-3-acetylamino-5-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (i?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (i?,i?,5',5')-TangPhos-Rh catalyst
[0155] A 250 mL 3NRB glass flask fitted with a magnetic stirrer, a rubber septum, a glass stopper, and a gas inlet adapter, was purged by evacuating and filling the flask with nitrogen four times. The flask was then placed in a nitrogen-filled glove bag along with a vial containing bis(l,5-cyclooctadiene)Rh(I)trifluoromethane sulfonate (0.123 g, 0.263 mmol, 1.00 mol%) and a vial containing (R,R,S,S)- TangPhos (0.070 g, 0.245 mmol, 0.93 mol%). The vials were opened and their contents were charged to the flask. The flask, which contained the catalyst precursors, was sealed, moved to a hood, purged again with vacuum and nitrogen, and held under a positive nitrogen pressure.
[0156] To a separate 250 mL 3NRB glass flask fitted with a magnetic stir bar was charged (/?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester (6.33 g, 26.2 mmol) and MeOH (120 mL). This flask was sealed with a rubber septum, a glass stopper, and a gas inlet adapter with a PTFE stopcock. While stirring its contents, the flask was purged four times by evacuating and filing the flask with nitrogen. The flask was then held under a positive nitrogen pressure and its contents were transferred, via syringe, to the reaction flask, which contained the catalyst precursors.
[0157] The reaction flask was again inerted (with agitation) using several vacuum/nitrogen purges. Hydrogen was then introduced as a rapid stream that was vented through a bubbler. After about 10 minutes the hydrogen flow rate was reduced so that it maintained a small positive pressure, estimated at about 5 psig to about 10 psig, as indicated by the bubbler. The reaction was run at ambient temperature, without heating or cooling to give the titled compound. Samples were taken via syringe for TLC and chiral GC analysis, and the reaction was found to be complete after about 4 hours (97.1% de via chiral GC). 1H NMR (D6DMSO) δ 7.66 (d, J = 8 Hz, IH), 4.13 (m, IH), 4.01 (q, /= 7 Hz, 2H), 2.34 (m, 2H), 1.75 (s, 3H), 1.40 (m, 2H), 1 - 1.3 (m, 8H), 0.8 (m, 6H).
EXAMPLE 18. Preparation of (S^SR^-acetylamino-S-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (R)-BINAPINE-Rh catalyst
[0158] (R,Z)-3-Acetylamino-5-methyl-oct-2-enoic acid ethyl ester (5 g) was dissolved in methanol (15 mL) and the solution thoroughly degassed and inerted with argon. (R)-BINAPINE-Rh(COD)BF4 (30 mg) was added in a glove box, and the vessel sealed and placed under hydrogen (75 psig). The reaction was stirred vigorously and warmed to 30°C. Following completion of the reaction, the reaction mixture was concentrated to give the titled compound as an oil (5 g, 96% de).
EXAMPLE 19. Preparation of (3lS',5R)-3-acetylamino-5-methyl-octanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester using (R)-mTCFP-Rh catalyst
[0159] (R,Z)-3-Acetylamino-5-methyl-oct-2-enoic acid ethyl ester (52 g) was dissolved in methanol (150 mL) and the solution thoroughly degassed and inerted with argon. (R)-mTCFP-Rh(COD)BF4 (178 mg) was added in a glove box, and the vessel sealed and placed under hydrogen (10 psig). The reaction was stirred vigorously and warmed to 350C. Following completion of the reaction, the reaction mixture was concentrated to give the titled compound as an oil (52 g, 93.2% de). 1H NMR (CDCl3) δ 5.98 (d, IH), 4.35 (m, IH), 4.15 (q, 2H), 2.47 (m, 2H), 1.97 (s, 3H), 1.57 (m, IH), 1 - 1.4 (m, 8H), 0.9 (m, 6H).
EXAMPLE 20. Preparation of (3»S,5R)-3-ammo-5-methyl-octanoic acid HCl from (3S,5R)-3-acetylamino-5-methyl-octanoic acid ethyl ester
[0160] (35,5^-3 -Acetylamino-5-methyl-octanoic acid ethyl ester (4.5 g) was diluted with 35% aq HCl (4 mL) and water (8 mL) and heated to 950C to 105°C for 3 days. Toluene (10 mL) was added to the mixture, which was cooled to 5°C. The product was collected by filtration, and washed with toluene resulting in the titled compound (2.6 g). The product may be further purified by recrystallizing from aqueous HCl or toluene/isopropanol, and then filtered, washed with toluene, and dried under vacuum. 1H NMR (D6DMSO) δ 12.7 (bs, IH), 8.17 (bs, 3H), 3.38 (m, IH), 2.69 (dd, / = 6, 17 Hz, IH), 2.53 (dd, / = 7, 17 Hz, IH), 1.61 (m, 2H), 1.2 (m, 4H), 1.1 (m, IH), 0.8 (m, 6H).
EXAMPLE 21. Preparation of (/?,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester from (2?)-5-methyl-3-oxo-nonanoic acid ethyl ester via (i?,Z)-3-amino-5-methyl- non-2-enoic acid ethyl ester
[0161] (i?)-5-Methyl-3-oxo-nonanoic acid ethyl ester (30 g) and ammonium acetate (22 g) were heated in EtOH (150 mL) at 60°C for 16 hours, then cooled and concentrated by vacuum distillation. The material was dissolved in toluene and concentrated by vacuum distillation. The resulting concentrate was dissolved in toluene, filtered to remove solids, and concentrated by vacuum distillation to give (/?,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester as an oil (29 g). A portion of the enamine (25 g) was dissolved in toluene (150 mL), and reacted further by adding acetic anhydride (24 g) and pyridine (24 mL) and heating the mixture at 100°C to 110°C for 16 hours. The reaction mixture was cooled to 10°C to 2O0C and quenched by the addition of water. The reaction mixture was partitioned into upper and lower layers and the upper layer was washed with dilute aqueous NaHSO4, water, and was concentrated to give the titled compound as an oil (26 g). 1H NMR (CDCl3) δ 11.2 (s, 1 H), 4.90 (s, IH), 4.17 (q, J = 8 Hz, 2H), 2.88 (dd, IH, J= 8, 16 Hz), 2.34 (dd, IH, J= 12, 8 Hz), 2.14 (s, 3H), 1.79 (m, IH), 1.30 (m, 7H), 0.89 (m, 6H); 13C NMR (CDCl3) 169.1, 1668.3, 157.8, 97.2, 59.8, 42.7, 36.3, 31.4, 29.0, 28.8, 22.9, 22.7, 19.0, 14.2, 14.0.
EXAMPLE 22. Preparation of (/?,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester from (/?)-5-methyl-3-oxo-nonanoic acid ethyl ester
[0162] A pressure vessel was charged with (/?)-5-Methyl-3-oxo-nonanoic acid ethyl ester (50 g), EtOH (250 mL), and ammonia (about 8 g). The resulting mixture was allowed to react at 50°C for about 20 hours. The mixture was subsequently cooled to RT and concentrated by vacuum distillation. The resulting concentrate was dissolved in octane and concentrated by vacuum distillation to give the titled compound as an oil (50 g).
EXAMPLE 23. Preparation of (3S,5R)-3-acetylamino-5-methyl-nonanoic acid HCl via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester using (R)-BINAPINE-Rh catalyst
[0163] (R,Z)-3-Acetylamino-5-methyl-non-2-enoic acid ethyl ester (0.64 g) and (R)-BINAPINE-Rh(COD)BF4 (5.2 mg) were dissolved under inert conditions in MeOH (3 mL) and were reacted with hydrogen (30 psig) at 30°C. Following completion of the reaction, the mixture was concentrated to an oil and diluted with 35% aq HCl (0.6 g) and water (0.6 mL) and heated at 100°C to 1050C for 50 hours. The solution was cooled to 0°C to 1O0C and filtered to give the titled compound.
EXAMPLE 24. Preparation of (3S,5R)-3-acetylamino-5-methyl-nonanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester using (R)-BINAPINE-Rh catalyst and (R)-mTCFP-Rh catalyst
[0164] A pressure vessel was charged with (R,Z)-3-acetylamino-5-methyl-non-2- enoic acid ethyl ester (100 kg) and MeOH (320 kg) and was purged with nitrogen. (R)-BINAPINE-Rh(COD)BF4 (500 g) was added and rinsed into the vessel using nitrogen-purged MeOH (20 L). The reaction vessel was purged with hydrogen and the contents allowed to react at 350C under 25 psig H2 for 2 to 5 days. (R)-mTCFP- Rh(COD)BF4 (about 60 g) was added and rinsed into the vessel using nitrogen-purged MeOH (20 L). The reaction was allowed to continue at 35°C under 25 psig H2. Following completion of the reaction, the mixture was concentrated by vacuum distillation to give the titled compound as an oil. 1H NMR (CDCl3) δ 5.97 (d, IH), 4.35 (m, IH), 4.15 (q, 2H), 2.56 (dd, IH), 2.47 (dd, IH), 1.97 (s, 3H), 1.57 (m, IH), 1.42 (m, IH), 1.1 - 1.3 (m, 10H), 0.9 (m, 6H).
EXAMPLE 25. Preparation of (3S,5R)-3-amino-5-methyl-nonanoic acid HCl salt from (35,5R)-3-acetylamino-5-methyl-nonanoic acid ethyl ester [0165] (3S,5R)-3-Acetylamino-5-methyl-nonanoic acid ethyl ester (150 kg) was diluted with 35% aq HCl (150 L) and water (300 L). The resulting mixture was heated and stirred at 100°C to 115°C for at least 48 hours while distilling off a portion of the solvent (about 100 L). The solution was cooled to 35°C to 50°C, washed with toluene (300 L), and concentrated slightly by vacuum distillation. The resulting concentrate was diluted with toluene (300 L). Adding 35% aq HCl (150 L) and slowly cooling the solution to about 10°C resulted in a solid precipitate, which was collected by filtration and washed with hexane and dried. The solids were dissolved in /-PrOH and were recrystallized by adding hexanes and slowly cooling the solution. The solids were collected by filtration, washed with hexanes, and then dried to give the titled compound as a solid (51 kg, 39% yield). 1H NMR (400 MHz, D6DMSO) δ 12.7 (bs, IH), 8.14 (bs, 3H), 3.36 (m, IH), 2.67 (dd, IH), 2.53 (dd, IH), 1.60 (m, 2H), 1.3 - 1.1 (m, 7H), 0.84 (m, 6H).
EXAMPLE 26. Preparation of (35',5i?)-3-amino-5-methyl-nonanoic acid (zwitterion) from (35,5i?)-3-amino-5-methyl-nonanoic acid HCl salt
[0166] (3iS',5il?)-3-Amino-5-methyl-nonanoic acid HCl salt (51 kg) was dissolved in water (170 L), passed through a polish filter, and titrated with aq NaOH until the pH of the solution was 5.5 to 7.5. MTBE (200 L) was added and the resulting mixture was warmed to 250C to 35°C and slowly cooled to O0C to 1O0C to form a solid precipitate. The precipitate was collected by filtration, washed successively with a small amount of water and with MTBE and then dried to give the titled compound as a white solid (41 kg, 95% yield). 1H NMR (400 MHz, CD3OD) δ 4.93 (bs, 2H), 3.42 (m, IH), 2.46 (dd, IH), 2.28 (dd, IH), 1.61 (m, 2H), 1.5 - 1.1 (m, 7H), 0.9 (m, 6H).
EXAMPLE 27. Preparation of (3S,5R)-3-amino-5-methyl~nonanoic acid HCl salt from (35',5i?)-3-acetylamino-5-methyl-nonanoic acid ethyl ester via (3S,5R)-3- acetylamino-5 -methyl-nonanoic acid
[0167] To a solution containing (3>S,5i?)-3-acetylamino-5-methyl-nonanoic acid ethyl ester in MeOH is added aq NaOH. The resulting mixture is stirred for 2 hours or until complete to give (35,5i?)-3-acetylamino-5-methyl-nonanoic acid sodium salt. The amide acid salt is concentrated by vacuum distillation to about one-third of its volume. Water and toluene are added to the concentrate and the phases separated. Aq HCl is added to the lower layer and the resulting solution is heated to 100°C to 110 C for at least 36 hours. The solution is cooled to precipitate a solid, which is collected by filtration and washed with hexane to give the above-titled compound.
EXAMPLE 28. Preparation of (35',5R)-3-amino-5-methyl-nonanoic acid ethyl ester via asymmetric hydrogenation of (R,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester
[0168] A pressure vessel is charged with (i?,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester (10 g) and 2,2,2-trifluoroethanol (32 g) and the contents are purged with nitrogen. To the vessel is added (R)-(S)- JOSIPHOS-Rh(COD)BF4 (50 mg). The vessel contents are purged with hydrogen and are reacted at 50°C under 100 psig H2 for 1 to 2 days or until the reaction is complete. The mixture is concentrated by vacuum distillation to give the above titled compound.
EXAMPLE 29. Preparation of (3S,5R)-3-amino-5-methyl-nonanoic acid from (35',5/?)-3-amino-5-methyl-nonanoic acid ethyl ester
[0169] (35',5i?)-3-Amino-5-methyl-nonanoic acid ethyl ester (10 g) is diluted with 35% aq HCl (10 mL) and water (20 mL) and is heated with stirring at 1000C to 115°C for at least 6 hours while distilling off about 2 mL of solvent. The solution is cooled to 350C to 50°C and is washed with toluene (20 mL). The solution is concentrated slightly by vacuum distillation and is diluted with toluene (20 mL). Concentrated aq HCl (10 ml, 35%) is added and the solution is cooled slowly to about 10°C to precipitate the above titled compound, which is collected by filtration, washed with hexane, and dried. The solid may be recrystallized from /-PrOH and hexanes.
[0170] It should be noted that, as used in this specification and the appended claims, singular articles such as "a," "an," and "the," may refer to one object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "a compound" may include a single compound or two or more compounds. [0171] It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. The scope of the invention should, therefore, be determined not with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent applications, granted patents, and publications, are incorporated herein by reference in their entirety and for all purposes.

Claims

WHAT IS CLAIMED IS:
1. A method of making a compound of Formula 1 ,
Figure imgf000077_0001
or a diastereomer thereof or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, wherein
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; the method comprising: reacting a compound of Formula 2,
Figure imgf000077_0002
or Formula 4,
Figure imgf000078_0001
with H2 in the presence of a chiral catalyst to give a compound of Formula 3,
Figure imgf000078_0002
or a diastereomer thereof, wherein R1, R2, and R3 in Formula 2, Formula 3, and Formula 4 are as defined in Formula 1; R4 in Formula 2, Formula 3, and Formula 4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and R5 in Formula 2 and R19 in Formula 3 are independently hydrogen atom, carboxy, C1-7 alkanoyl, C2-7 alkenoyl, C2-7 alkynoyl, C3-7 cycloalkanoyl, C3-7 cycloalkenoyl, halo-C1-7 alkanoyl, halo-C2-7 alkenoyl, halo-C2-7 alkynoyl, C1-6 alkoxycarbonyl, halo- C1-6 alkoxycarbonyl, C3-7 cycloalkoxycarbonyl, aryl-C1-7 alkanoyl, aryl-C2-7 alkenoyl, aryl-C2-7 alkynoyl, aryloxycarbonyl, or aryl-C1-6 alkoxycarbonyl, provided that R5 is not a hydrogen atom; optionally converting the compound of Formula 3 or its diastereomer to the compound of Formula 1 or its diastereomer or to a pharmaceutically acceptable complex, salt, solvate or hydrate of the compound of Formula 1 or its diastereomer.
2. The method of claim 1, wherein the chiral catalyst comprises a chiral ligand bound to a transition metal through one or more phosphorus atoms.
3. The method of claim 2, wherein the chiral ligand is (R,R,$,S)- TANGPhos, (R)-BINAPINE, (R)-eTCFP, or (R)-mTCFP, or stereoisomers thereof.
4. A method of making a compound of Formula 1 ,
Figure imgf000079_0001
or a diastereomer thereof or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, wherein
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; the method comprising: reducing an amino moiety of a compound of Formula 7,
Figure imgf000079_0002
or a diastereomer thereof or a salt thereof to give the compound of Formula 1, wherein R1, R2, and R3 in Formula 7 are as defined in Formula 1 and R6 is C1-6 alkyl, C2-6 alkenyl or aryl-C1-3 alkyl; and optionally converting the compound of Formula 1 or its diastereomer to a pharmaceutically acceptable complex, salt, solvate or hydrate.
5. A method of making a compound of Formula 1 ,
Figure imgf000080_0001
or a diastereomer thereof or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, wherein
R and R are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; the method comprising: reducing an amine moiety of a compound of Formula 13,
Figure imgf000081_0001
or a diastereomer thereof, to give a compound of Formula 37,
Figure imgf000081_0002
1 9 ^ or a diastereomer thereof, wherein R , R , and R in Formula 37 and Formula 13 are as defined in Formula 1, R in Formula 37 and Formula 13 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo- C1-7 alkyl, halo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion, and R7 in Formula 13 is C1-6 alkyl, C2-6 alkenyl or aryl-C1-3 alkyl; and optionally converting the compound of Formula 37 or its diastereomer to the compound of Formula 1 or its diastereomer or to a pharmaceutically acceptable complex, salt, solvate or hydrate of the compound of Formula 1 or its diastereomer.
6. A method of making a compound of Formula 6,
Figure imgf000081_0003
wherein
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; and
R4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; the method comprising treating a compound of Formula 19,
Figure imgf000082_0001
19
or a salt thereof with an acid, wherein R , R , R , and R in Formula 19 are as defined in Formula 6.
7. A method of making a compound of Formula 6,
Figure imgf000082_0002
wherein R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom; and
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; and
R4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, 1IaIo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; the method comprising treating a compound of Formula 33,
Figure imgf000083_0001
33
with a base to generate a dianion; reacting the dianion with a compound of Formula 32,
Figure imgf000083_0002
32
to give an intermediate; and treating the intermediate with an acid, wherein R1, R2, and R3 in Formula 32 and R4 in Formula 33 are as defined in Formula 6 and R18 in Formula 32 is a leaving group.
8. A compound of Formula 40,
Figure imgf000084_0001
40 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which:
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom;
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms;
R20 is a hydrogen atom, hydroxy, R6-O-NH-, R9O- or R19-NH-, or
Figure imgf000084_0002
R21 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, halo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion, a secondary ammonium ion or R6-O-NH-; wherein:
R6 and R7 are independently C1-6 alkyl, C2-6 alkenyl or aryl-C1-3 alkyl;
R9 is tosyl, mesyl, brosyl, closyl, nosyl, or triflyl; and
R19 is hydrogen atom, carboxy, C1-7 alkanoyl, C2-7 alkenoyl, C2-7 alkynoyl, C3-7 cycloalkanoyl, C3-7 cycloalkenoyl, halo-C1-7 alkanoyl, 1IaIo-C2-7 alkenoyl, halo- C2-7 alkynoyl, C1-6 alkoxycarbonyl, halo-C1-6 alkoxycarbonyl, C3-7 cycloalkoxycarbonyl, aryl-C1-7 alkanoyl, aryl-C2-7 alkenoyl, aryl-C2-7 alkynoyl, aryloxycarbonyl, or aryl-C1-6 alkoxycarbonyl. 9. A compound of Formula 39,
Figure imgf000085_0001
39 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which:
1 0
R and R are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R is not a hydrogen atom;
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R3 is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; and
R4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, ImIo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion.
10. A compound of Formula 41 ,
Figure imgf000085_0002
41 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which: R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom;
R3 is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R is optionally substituted with one to five fluorine atoms, and each aryl of R3 is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms;
R4 is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, halo-C1-7 alkyl, 1IaIo-C2-7 alkenyl, halo-C2-7 alkynyl, aryl-C1-6 alkyl, aryl-C2-6 alkenyl, or aryl-C2-6 alkynyl or a cation selected from a Group 1 metal ion, a Group 2 metal ion, a primary ammonium ion or a secondary ammonium ion; and
R22 is a hydrogen atom or carboxy.
11. A compound of Formula 42,
Figure imgf000086_0001
42 including complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof, in which:
R1 and R2 are independently hydrogen atoms or C1-3 alkyl optionally substituted with one to five fluorine atoms, provided that when R1 is a hydrogen atom, R2 is not a hydrogen atom;
R is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl-C1-3 alkyl, or arylamino, wherein each alkyl of R is optionally substituted with one to five fluorine atoms, and each aryl of R is optionally substituted with from one to three substituents independently selected from chloro, fluoro, amino, nitro, cyano, C1-3 alkylamino, C1-3 alkyl optionally substituted with one to three fluorine atoms, and C1-3 alkoxy optionally substituted with from one to three fluorine atoms; and
R is a hydrogen atom or a chiral oxazolidin-2-one-3-yl.
12. A compound selected from: (7?)-5-methyl-3-oxo-heptanoic acid ethyl ester; (7?)-5-methyl-3-oxo-octanoic acid ethyl ester; (i?)-5-methyl-3-oxo-nonanoic acid ethyl ester; (i?,Z)-3-amino-5-methyl-hept-2-enoic acid ethyl ester; (R,Z)-3-amino-5-methyl-oct-2-enoic acid ethyl ester; (R,Z)-3-amino-5-methyl-non-2-enoic acid ethyl ester; (R,Z)-3-acetylamino-5-methyl-hept-2-enoic acid ethyl ester; (/?,Z)-3-acetylamino-5-methyl-oct-2-enoic acid ethyl ester; (i?,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester; (35,5i?)-3-amino-5-methyl-heptanoic acid ethyl ester; (3ιS',5/?)-3-amino-5-methyl-octanoic acid ethyl ester; (3S,5i?)-3-amino-5-methyl-nonanoic acid ethyl ester; (3ιS,5R)-3-acetylamino-5-methyl-heptanoic acid ethyl ester; (35',5/?)-3-acetylamino-5-methyl-octanoic acid ethyl ester; (35',5/?)-3-acetylamino-5-methyl-nonanoic acid ethyl ester; (3S,5R)-3-acetylamino-5-methyl-heptanoic acid; (3S,5R)-3-acetylamino-5-methyl-octanoic acid; (3 S ,5R)-3 -acetylamino-5 -methyl-nonanoic acid; (3i?,5/?)-3-hydroxy-5-methyl-heptanoic acid; (3i?,5i?)-3-hydroxy-5-methyl-octanoic acid; (3i?,5i?)-3-hydroxy-5-methyl-nonanoic acid; (3i?,5i?)-3-hydroxy-5-methyl-heptanoic acid benzyloxy-amide; (3i?,5i?)-3-hydroxy-5-methyl-octanoic acid benzyloxy-amide; (3i?,5i?)-3-hydroxy-5-methyl-nonanoic acid benzyloxy-amide; (3i?,5/?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester; (3i?,5i?)-3-hydroxy-5-methyl-octanoic acid ethyl ester; (3i?,5i?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester; (2R,4S)- 1 -benzyloxy-4-(2-methyl-butyl)-azetidin-2-one; (2Z?,^)- 1 -benzyloxy-4-(2-methyl-pentyl)-azetidin-2-one; (2/?,45)-l-benzyloxy-4-(2-methyl-hexyl)-azetidin-2-one; (3S,5R)-3-benzyloxyamino~5-methyl-heptanoic acid; (3S,5R)-3-benzyloxyamino-5-methyl-octanoic acid;
(35',5R)-3-benzyloxyamino-5-methyl-nonanoic acid;
(lS^S^^-S-Cbenzyl-Cl-phenyl-ethyO-aminoJ-S-methyl-heptanoic acid ethyl ester;
(15',3lS',5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester;
(15',35',5/?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester;
(5i?)-3-hydroxy-5-methyl-heptanoic acid ethyl ester;
(5R)-3-hydroxy-5-methyl-octanoic acid ethyl ester;
(5jR)-3-hydroxy-5-methyl-nonanoic acid ethyl ester;
(i?,E)-5-methyl-hept-2-enoic acid ethyl ester;
(/?,E)-5-methyl-oct-2-enoic acid ethyl ester;
(2?,E)-5-methyl-non-2-enoic acid ethyl ester;
(R,E)-5-methyl-hept-3-enoic acid ethyl ester;
(i?,E)-5-methyl-oct-3-enoic acid ethyl ester;
(/?,E)-5-methyl-non-3-enoic acid ethyl ester;
(5i?)-5-methyl-3-(toluene-4-sulfonyloxy)-heptanoic acid ethyl ester;
(5R)-5-methyl-3-(toluene-4-sulfonyloxy)-octanoic acid ethyl ester;
(5/?)-5-methyl-3-(toluene-4-sulfonyloxy)-nonanoic acid ethyl ester;
(5i?)-3-methanesulfonyloxy-5-methyl-heptanoic acid ethyl ester;
(5i?)-3-methanesulfonyloxy-5-methyl-octanoic acid ethyl ester;
(/?)-3-methanesulfonyloxy-5-methyl-nonanoic acid ethyl ester;
(R)- 1 -imidazol- 1 -yl-3-methyl-pentan- 1 -one;
(R)- 1 -imidazol- l-yl-3-methyl-hexan- 1 -one;
(R)-l-imidazol-l-yl-3-methyl-heptan-l-one; and the pharmaceutically acceptable complexes, salts, solvates, hydrates, opposite enantiomers, diastereomers, geometric isomers, and mixtures thereof.
PCT/IB2005/001966 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein Ceased WO2006008612A2 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
MXPA06014662A MXPA06014662A (en) 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein.
BRPI0513028-0A BRPI0513028A (en) 2004-07-09 2005-06-27 preparation of beta amino acids having affinity for alpha-2-delta protein
EP05754890A EP1768952A2 (en) 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein
RU2007100355/04A RU2007100355A (en) 2004-07-09 2005-06-27 Obtaining beta-amino acids possessing affinity for alpha-2-delta protein
JP2007519908A JP2008505879A (en) 2004-07-09 2005-06-27 Production of beta-amino acids with affinity for alpha-2-delta protein
CA002573128A CA2573128A1 (en) 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein
US11/909,318 US20090247743A1 (en) 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein
IL179851A IL179851A0 (en) 2004-07-09 2006-12-05 Preparation of beta-amino acids having affinity for the alpha-2-delta protein
NO20065643A NO20065643L (en) 2004-07-09 2006-12-06 Preparation of beta-amino acids having affinity for the alpha-2-delta protein

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US58651204P 2004-07-09 2004-07-09
US60/586,512 2004-07-09
US66504105P 2005-03-24 2005-03-24
US60/665,041 2005-03-24

Publications (2)

Publication Number Publication Date
WO2006008612A2 true WO2006008612A2 (en) 2006-01-26
WO2006008612A3 WO2006008612A3 (en) 2006-04-20

Family

ID=35033554

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/001966 Ceased WO2006008612A2 (en) 2004-07-09 2005-06-27 Preparation of beta-amino acids having affinity for the alpha-2-delta protein

Country Status (13)

Country Link
US (1) US20090247743A1 (en)
EP (1) EP1768952A2 (en)
JP (1) JP2008505879A (en)
KR (1) KR20080019732A (en)
AR (1) AR049968A1 (en)
AU (1) AU2005264036A1 (en)
BR (1) BRPI0513028A (en)
CA (1) CA2573128A1 (en)
IL (1) IL179851A0 (en)
MX (1) MXPA06014662A (en)
RU (1) RU2007100355A (en)
TW (1) TW200616935A (en)
WO (1) WO2006008612A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010500403A (en) * 2006-08-16 2010-01-07 エルジー ライフサイエンス リミテッド Novel process for producing 3-amino-5-fluoro-4-dialkoxypentanoic acid ester

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801724A (en) * 1987-06-05 1989-01-31 Hoffmann-La Roche Inc. Vitamin E intermediate
US4942249A (en) * 1987-06-05 1990-07-17 Hoffmann-La Roche Inc. Process for producing vitamin E
US4877890A (en) * 1987-06-05 1989-10-31 Hoffmann-La Roche Inc. Vitamin E intermediate
JP2627679B2 (en) * 1990-10-19 1997-07-09 高砂香料工業株式会社 Optically active compound, liquid crystal composition containing the same, and liquid crystal electro-optical element
GB9326432D0 (en) * 1993-12-24 1994-02-23 Oxford Asymmetry Ltd Improvements in or relating to chiral anxiliaries
JP3798949B2 (en) * 2001-03-06 2006-07-19 エヌ・イーケムキャット株式会社 Hydrocracking catalyst
NI200300043A (en) * 2002-03-28 2003-11-05 Warner Lambert Co AMINO ACIDS WITH AFFINITY FOR THE PROTEIN a2DELTA.
US20040092522A1 (en) * 2002-08-15 2004-05-13 Field Mark John Synergistic combinations
GB0219024D0 (en) * 2002-08-15 2002-09-25 Pfizer Ltd Synergistic combinations
AP2006003544A0 (en) * 2003-09-25 2006-04-30 Warner Lambert Co Amino acids with affinity for the alpha2delta-protein.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010500403A (en) * 2006-08-16 2010-01-07 エルジー ライフサイエンス リミテッド Novel process for producing 3-amino-5-fluoro-4-dialkoxypentanoic acid ester

Also Published As

Publication number Publication date
EP1768952A2 (en) 2007-04-04
RU2007100355A (en) 2008-07-20
MXPA06014662A (en) 2007-02-12
BRPI0513028A (en) 2008-04-22
TW200616935A (en) 2006-06-01
US20090247743A1 (en) 2009-10-01
AR049968A1 (en) 2006-09-20
WO2006008612A3 (en) 2006-04-20
KR20080019732A (en) 2008-03-04
AU2005264036A1 (en) 2006-01-26
JP2008505879A (en) 2008-02-28
IL179851A0 (en) 2007-05-15
CA2573128A1 (en) 2006-01-26

Similar Documents

Publication Publication Date Title
Ojima et al. New and effective routes to fluoro analogs of aliphatic and aromatic amino acids
US20090124820A1 (en) C1-Symmetric Bisphospine Ligands and Their Use in the Asymmetric Synthesis of Pregabalin
RS51210B (en) OBTAINING PREGABALLINS AND RELATED UNITS
EP2173698A2 (en) Process for the synthesis of intermediates of renin inhibitors such as aliskiren
US7179934B2 (en) Amino acids with affinity for the α2δ-protein
TW201718462A (en) Process for the manufacture of organic compounds and intermediates
EP1768952A2 (en) Preparation of beta-amino acids having affinity for the alpha-2-delta protein
WO2006100606A2 (en) Preparation of beta-amino acid precursors via indium (iii) mediated markovnikov addition and knoevenagel condensation
EP2017259A2 (en) Preparation of gamma-amino acids having affinity for the alpha-2-delta protein
US20080194841A1 (en) Preparation of Optically Pure Beta-Amino Acids Having Affinity for the Alpha-Delta Protein
CN101027278A (en) Preparation of beta-amino acids having affinity for the alpha-2-delta protein
KR20070019787A (en) Method for preparing beta-amino acid having affinity for alpha-2-delta protein
HK1105407A (en) Preparation of beta-amino acids having affinity for the alpha-2-delta protein
RU2529996C2 (en) Method for enantioselective synthesis of (s)-pregabalin
RU2643373C2 (en) Method of producing (s)-3-aminomethyl-5-methylhexanoic acid
CA2615490A1 (en) Stereoselective synthesis of 3,4-disubstituted cyclopentanones and related compounds
WO2017051326A1 (en) New processes and intermediates useful in synthesis of nep inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006/10148

Country of ref document: ZA

Ref document number: 200610148

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 179851

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 551896

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2005264036

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: PA/a/2006/014662

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 7956/DELNP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 06130664

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 12007500066

Country of ref document: PH

Ref document number: 2573128

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1020077000450

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 200580023175.3

Country of ref document: CN

Ref document number: 2007100355

Country of ref document: RU

Ref document number: 2007519908

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

ENP Entry into the national phase

Ref document number: 2005264036

Country of ref document: AU

Date of ref document: 20050627

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2005754890

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2005264036

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1200700294

Country of ref document: VN

WWP Wipo information: published in national office

Ref document number: 1020077000450

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2005754890

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 11909318

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0513028

Country of ref document: BR