WO2006100606A2 - Preparation de precurseurs de beta-aminoacide par addition de markovnikov et condensation de knoevenagel a mediation assuree par de l'indium (iii) - Google Patents

Preparation de precurseurs de beta-aminoacide par addition de markovnikov et condensation de knoevenagel a mediation assuree par de l'indium (iii) Download PDF

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WO2006100606A2
WO2006100606A2 PCT/IB2006/001126 IB2006001126W WO2006100606A2 WO 2006100606 A2 WO2006100606 A2 WO 2006100606A2 IB 2006001126 W IB2006001126 W IB 2006001126W WO 2006100606 A2 WO2006100606 A2 WO 2006100606A2
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formula
alkyl
methyl
compound
phenyl
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PCT/IB2006/001126
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WO2006100606B1 (fr
WO2006100606A3 (fr
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Paul Timothy Angell
Peter Garth Blazecka
Ji Zhang
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Warner-Lambert Company Llc
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/125—Halogens; Compounds thereof with scandium, yttrium, aluminium, gallium, indium or thallium
    • 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
    • C07C229/04—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 saturated
    • C07C229/06—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 saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—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 saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • 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
    • C07C229/04—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 saturated
    • C07C229/06—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 saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—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 saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—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 saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • 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
    • 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
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
    • 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
    • C07C69/593—Dicarboxylic 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
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
    • 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
    • C07C69/73—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 unsaturated acids
    • C07C69/734—Ethers
    • 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 malonic acid derivatives, which may be used to prepare optically-active ⁇ -amino acids that bind to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of a calcium channel.
  • the ⁇ -amino acids are useful for treating pain, fibromyalgia, and a variety of psychiatric and sleep disorders.
  • These compounds may be used to treat a number of disorders, conditions, and diseases, including 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.
  • 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.
  • ⁇ -amino acids described in the '251 and 668 applications 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.
  • the '251 and 668 applications describe useful methods for preparing optically-active ⁇ -amino acids at laboratory bench scale. However, many of the methods employ chiral auxiliary strategies for preparing optically-active starting materials or precursors. Such strategies add to the costs of the methods and potentially render them problematic for pilot- or full-scale production. Thus, improved methods for preparing precursors of the optically-active ⁇ -amino acids would be desirable.
  • This invention provides comparatively efficient and cost-effective methods for preparing precursors of compounds of Formula 1,
  • R 1 and R 2 are each independently selected from hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C ⁇ e alkyl, aryl, aryl-C 1-3 alkyl, and arylamino, wherein each alkyl or cycloalkyl moiety is optionally substituted with from one to five fluorine atoms, and each aryl 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, provided that R 1 and R 2 are not both hydrogen atoms and that when R 1 is a hydrogen atom, R 2 is not methyl.
  • One aspect of the invention provides a method of making a compound of Formula 4,
  • R 1 and R 2 are as defined for Formula 1, above;
  • R 3 and R 4 are each independently selected from 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, and aryl-C 2-6 alkynyl, provided that R 3 and R 4 are not both hydrogen atoms; the method comprising: reacting a compound, of Formula 2,
  • Another aspect of the invention provides for converting the compounds of Formula 4 or Formula 5 to provide the compounds of Formula 1, stereoisomers thereof, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof.
  • a further aspect of the invention provides compounds of Formula 4 and Formula 5, including the following compounds, their mono- and di-C 1-6 alkyl (e.g., dimethyl and diethyl) esters, and their complexes, salts, solvates, and hydrates:
  • 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 ZlE isomers and tautomeric forms, whether they are pure, substantially pure, or mixtures.
  • the present invention includes all complexes, salts, solvates, and hydrates, whether pharmaceutically acceptable or not, and all polymorphic (crystalline and amorphous) forms of the disclosed and recited compounds and their stereoisomers, including opposite enantiomers, diastereomers, and geometrical isomers.
  • the phrase "complexes, salts, solvates, and hydrates thereof refers to the recited compounds and to their stereoisomers.
  • ww> 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.
  • 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 methyl, ethyl, n-propyl, /-propyl, n-butyl, s-butyl, /-butyl, t-butyl, pent-1-yl, pent-2-yl, ⁇ ent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2- trimethyleth-1-yl, w-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 ethenyl, 1- propen-1-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, l-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl-l-propen-l-yl, 2-methyl-2-propen- 1-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 ethynyl, 1-propyn-l-yl, 2-propyn- 1-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 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. Examples of alkenoyl groups include 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 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 methoxy, ethoxy, n-propoxy, ⁇ -propoxy, n-butoxy, s-butoxy, t-butoxy, /r-pentoxy, s- pentoxy, and the like.
  • alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, z ' -propoxycarbonyl, ?i-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 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.
  • any of the ring members may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Examples of bicyclic cycloalkyl groups include 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[
  • 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.
  • any of the ring members may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Useful substituents include 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 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 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 cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, 1-cyclobutenoxycarbonyl, 2- cyclobutenoxycarbonyl, 1-cyclopentenoxycarbonyl, 2-cyclopentenoxycarbonyl, 3- cyclopentenoxycarbonyl, 1-cyclohexenoxycarbonyl, 2-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 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 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.
  • any of the carbon or nitrogen ring members may include a non-hydrogen substituent unless such substitution would violate valence requirements.
  • Useful substituents include 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 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 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 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, lH-indazolyl, indolenyl, indolinyl, in
  • ⁇ 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 “heteroarylallcyl” refer, respectively, to aryl-alkyl and heteroaryl-alkyl, where aryl, heteroaryl, and alkyl are defined above. Examples include 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 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, (
  • Arylalkoxy and “heteroarylalkoxy” refer, respectively, to aryl-alkoxy and heteroaryl-alkoxy, where aryl, heteroaryl, and alkoxy are defined above. Examples include 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 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. Examples include phenoxycarbonyl, imidazol-2-yloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, imidazol-2-yl-methyloxycarbonyl, and the like.
  • 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 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 ofisomerically enriched 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, including geometrical isomers (Z/E) of the compound.
  • Z/E geometrical isomers
  • the specified compound has S,R,Z stereochemical configuration
  • its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, as well as 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.
  • (+)-CAMP (i?)-(+)-cyclohexyl(2-anisyl)methylphosphine; a monophosphine
  • reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO 2 from the decarboxylation of a diacid, etc.).
  • reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).
  • 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 and ambient pressure, but depending on reaction kinetics, yields, and the like, some reactions may be run at elevated pressures or employ higher (e.g., reflux conditions) or lower (e.g., -70 0 C to 0°C) temperatures. Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield.
  • the one or more solvents may be polar protic solvents (including water), 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., whether or not expressly using the word "range,” also includes the indicated endpoints.
  • R 1 , R 2 , R 3 , etc. when used in a subsequent formula, will have the same definition as in the earlier formula.
  • R 20 in a first formula is hydrogen atom, halogeno, or C 1-6 alkyl
  • R 20 in a second formula is also hydrogen, halogeno, or C 1-6 alkyl.
  • This disclosure concerns materials and methods for preparing precursors of the optically active ⁇ -amino acids represented by Formula 1, above, including opposite enantiomers thereof and 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 and R 2 , which are defined above.
  • Compounds of Formula 1 include those in which R 1 is selected from hydrogen atom and C 1-6 alkyl, and R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-Ci.
  • each alkyl or cycloalkyl moiety is optionally substituted with from one to five fluorine atoms
  • each phenyl and pyridyl moiety 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 from one to three fluorine atoms, and C 1-3 alkoxy optionally substituted with from one to three fluorine atoms.
  • Compounds of Formula 1 therefore include those in which R 1 is hydrogen and R 2 is C 2-6 alkyl (e.g., Et, n-Pr, and n-Bu), phenyl, benzyl, or phenyl-ethyl, and those in which R 1 is C 1-6 alkyl (e.g., Me) and R 2 is C 1-6 alkyl (e.g., Me, Et, rc-Pr, and n-Bu), phenyl, benzyl, or phenyl-ethyl.
  • Representative compounds of Formula 1 thus include (3S,5R)-3- amino-5-methyl-heptanoic acid, (35',5i?)-3-amino-5-methyl-octanoic acid, (3S,5R)-3- amino-5-methyl-nonanoic acid, (2?,2?,i?)-3-amino-4,5-dimethyl-hexanoic acid, (2?,/?,i?)-3-amino-4,5-dimethyl-heptanoic acid, (/?,/?,7?)-3-amino-4,5-dimethyl- octanoic acid, and (2?,/?, J R)-3-amino-4,5-dimethyl-nonanoic acid, as well as their opposite enantiomers and their diastereomers.
  • Scheme I shows a method of preparing various precursors (Formula 4 and Formula 5) of the optically active ⁇ -amino acids represented by Formula 1.
  • Substituents R and R in Formula 2, 3, 4, and 5, are as defined for Formula 1, above, and substituents R and R 4 in Formula 4 and 5 are independently selected from 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, and aryl-C 2-6 alkynyl, provided that R 3 and R 4 are not both hydrogen atoms.
  • the malonic acid derivative (Formula 2) and the terminal alkyne (Formula 3) may be reacted in about stoichiometric amounts, though the method often employs a slight excess (e.g., about 1.2 eq to about 1.5 eq) of the alkyne.
  • malonic acid derivatives and terminal alkynes include mono- and di- C 1-6 alkyl esters of ⁇ -substituted and unsubstituted malonic acid, such as malonic acid diethyl ester and 2-methyl-malonic acid diethyl ester, and C 1-6 alkyl-substituted terminal alkynes, such as prop-1-yne, but-1-yne, pent-1-yne, and hex-1-yne, respectively.
  • representative addition (Formula 4) and condensation (Formula 5) products include mono- and di-Q.e alkyl esters of ⁇ -monosubstituted and disubstituted malonic acid, such as 2-isopropenyl-2-methyl-malonic acid diethyl ester, 2 ⁇ methyl-2-(l-methylene-propyl)-malonic acid diethyl ester, 2-methyl-2-(l- methylene-butyl)-malonic acid diethyl ester, and 2-methyl-2-(l-methylene-pentyl)- malonic acid diethyl ester, and 2-isopropylidene-malonic acid diethyl ester, 2-sec- butylidene-malonic acid diethyl ester, 2-(l-methyl-butylidene)-malonic acid diethyl ester, and 2-(l-methyl-pentylidene)-malonic acid diethyl ester, respectively.
  • the reaction shown in Scheme I is carried out in the presence of an In(III) catalyst.
  • useful catalysts include indium salts such as InCl 3 , InBr 3 , In(OTf) 3 , and the like.
  • Indium (III) is present in catalytic amounts with s/c ratios generally ranging from about 1000:1 to about 10:1, from about 100:1 to about 10:1, and from about 100:1 to about 20:1.
  • the reaction shown in Scheme I may be carried out neat or in a compatible solvent at a temperature of about 50 0 C to about 150 0 C, or more typically, at a temperature of about 100 0 C to about 140 0 C.
  • Useful solvents include aromatic solvents, such as o- xylene, toluene, and the like.
  • Schemes II to Scheme V show various methods for converting the Markovnikov addition products (Formula 4) and Knoevenagel condensation products (Formula 5) to the desired ⁇ -amino acids (Formula 1).
  • Scheme II illustrates a method for converting the Markovnikov addition products (Formula 4) to optically active ⁇ -ketoesters (Formula 13), which may be used to prepare the desired ⁇ -amino acids (Formula 1) via processes shown in Scheme IV and Scheme V.
  • the method shown in Scheme II includes reacting the addition product (Formula 4) with hydrogen in the presence of a chiral catalyst to give an optically-active diester (Formula 6) which is subsequently hydrolyzed by treatment with an acid or base to give a chiral diacid (Formula 7).
  • the diacid (Formula 7) is decarboxylated by treatment with an acid to give a mixture of stereoisomers (Formula 8), which are resolved to provide a desired diastereoisomer (Formula 9).
  • the carboxylic acid (Formula 9) is activated through, e.g., reaction with a coupling agent such as CDI.
  • the activated acid is reacted with a malonic acid ester or salt (Formula 11) in the presence of a base to give an ⁇ -substituted malonic acid intermediate (Formula 12), which is subsequently decarboxylated by treatment with an acid to provide the optically-active ⁇ -ketoester (Formula 13).
  • Substituents R 1 , R 2 , R 3 , and R 4 in Formula 6 to 13 are as defined for Formula 1 and 2; substituent R 5 in Formula 10 is a leaving group; and substituent R 6 in Formula 11 is a hydrogen atom 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 shown in Scheme II includes reacting the addition product (Formula 4) with hydrogen in the presence of a chiral catalyst to give an optically-active diester (Formula 6).
  • a chiral catalyst Depending on which stereoisomer of the chiral catalyst is used, the asymmetric hydrogenation generates an excess (de) of a stereoisomer of Formula 6.
  • Useful chiral catalysts, solvents, and reaction conditions, including temperature, pressure, and s/c ratios, include those described in Scheme IV, below, in connection with the asymmetric hydrogenation of an enamine (Formula 21) and enamide (Formula 23).
  • Scheme III illustrates a method for converting the Knoevenagel condensation products (Formula 5) to optically active ⁇ -ketoesters (Formula 20), which may be used to prepare the desired ⁇ -amino acids (Formula 1) via processes shown in Scheme IV and Scheme V.
  • the method shown in Scheme III includes reacting the condensation product (Formula 5) with hydrogen in the presence of a catalyst to give a diester (Formula 14), which is subsequently hydrolyzed by treatment with an acid or base to give a diacid (Formula 15).
  • the diacid (Formula 15) is decarboxylated by treatment with an acid to give a mixture of enantiomers (Formula 16), which are resolved to provide a desired enantiomer (Formula 17).
  • the carboxylic acid (Formula 17) is activated through, e.g., reaction with a coupling agent such as CDI. As in Scheme ⁇ , the activated acid is reacted with a malonic acid ester or salt (Formula 11) in the presence of a base to give an ⁇ -substituted malonic acid intermediate (Formula 19), which is subsequently decarboxylated by treatment with an acid to provide the optically-active ⁇ -ketoester (Formula 20).
  • Substituents R 1 , R 2 , R 3 , and R 4 in Formula 14 to 20 are as defined for Formula 1 and 2, and substituent R in Formula 18 is a leaving group.
  • the method shown in Scheme III includes reacting the Knoevenagel condensation product (Formula 5) with hydrogen in the presence of a catalyst to give the diester of Formula 14. Hydrogenation is carried out in the presence of a catalyst and one or more polar solvents, including alcohols, ethers, esters and acids, such as MeOH, EtOH, EPA, 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.
  • Potentially useful catalysts include 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 , and
  • Useful catalysts thus include palladium catalysts such as Pd/C, PdZSrCO 3 , Pd/Al 2 O 3 , PdMgO, 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 , RhIC, RuO 2 , and the like.
  • Scheme IV illustrates a method of preparing a desired stereoisomer of the. compound of Formula 1 from the optically active ⁇ -ketoesters (Formula 13 or Formula 20).
  • the stereoselective synthesis includes reacting the optically active ⁇ dicarbonyl (Formula 13) with a source of ammonia to give an optically active enamine (Formula 21) that is optionally reacted with an acylating agent (Formula 22) to give an optically active enamide (Formula 23).
  • the enamine (Formula 21) or the enamide (Formula 23) is reacted with hydrogen in the presence of a chiral catalyst to yield the compound of Formula 24, 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 13, 21, 23,, and 24 are as defined for Formula 1 and Formula 2; substituent R 7 in Formula 22 and Formula 23 and substituent R 8 in Formula 24 are each independently selected from 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, and aryl-C 1-6 alkoxycarbon
  • the ⁇ -ketoesters (Formula 13 or Formula 20) are converted to the enamine (Formula 21) through treatment with an ammonia source.
  • Representative ⁇ -ketoesters (Formula 13) include various C 1-6 alkyl esters of (7?)-5-methyl-3-oxo-heptanoic acid, (7?)-5-methyl-3-oxo-octanoic acid, (i?)-5-methyl-3-oxo-nonanoic acid, (R,R)-4,5- dimethyl-3-oxo-heptanoic acid, (i?,i?)-4,5-dimethyl-3-oxo-octanoic acid, (R,R)-4,5- dimethyl-3-oxo-nonanoic acid, and their stereoisomers.
  • ammonia and ammonium acetate are useful sources of ammonia.
  • 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., 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 21) is optionally converted to the enamide (Formula 23) via contact with an acylating agent (Formula 22).
  • 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, (R)-3- amino-5-methyl-non-2-enoic acid, (i?,i?)-3-amino-4,5-dimethyl-hept-2-enoic acid, (2?,7?)-3-amino-4,5-dimethyl-oct-2-enoic acid, (i?,2?)-3-amino-4,5-dimethyl-non-2- enoic acid, their opposite enantiomers and their diastereomers.
  • Examples of enamines thus include the Z- and E-isomers of (2?)-3-amino-5-methyl-hept-2-enoic acid ethyl ester, (i?)-3-amino-5-methyl-oct-2-enoic acid ethyl ester, (i?)-3-amino-5-methyl-non- 2-enoic acid ethyl ester, (7?,i?)-3-amino-4,5-dimethyl-hept-2-enoic acid ethyl ester, (i?,/?)-3-amino-4,5-dimethyl-oct-2-enoic acid ethyl ester, (i?,/?)-3-amino-4,5-dimethyl- non-2-enoic acid ethyl ester, their opposite enantiomers and their diastereomers.
  • Useful acylating agents include carboxylic acids, which have been activated either prior to contacting the enamine (Formula 21) 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.
  • R 9 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-Ci. 6 alkyl, heterocyclyl, heteroaryl, or heteroaryl-C 1-6 alkyl.
  • 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 DCC, DMT-MM, FDPP, TATU, BOP, PyBOP, ⁇ DCI, diisopropyl carbodiimide, isopropenyl chloroformate, isobutyl chloroformate, N,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 21) or the enamide (Formula 23) undergoes asymmetric hydrogenation in the presence of a chiral catalyst to give the compound of Formula 24.
  • useful enamide hydrogenation substrates (Formula 23) 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 (i?)-3-acetylamino-5- methyl-hept-2-enoic acid, (i?)-3-acetylamino-5-methyl-oct-2-enoic acid, (R)-3- acetylamino-5-methyl-non-2-enoic acid, (i?,7?)-3-acetylamino-4,5-dimethyl-hept-2- enoic acid, (7?,7?)-3-acetylamino-4,5-dimethyl-oct-2-enoic acid
  • Examples of useful enamides thus include the Z- and E- isomers of (R)-3- acetylamino-5-methyl-hept-2-enoic acid ethyl ester, ( J R)-3-acetylamino-5-methyl-oct- 2-enoic acid ethyl ester, (i?)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester, (i?,i?)-3-acetylamino-4,5-dimethyl-hept-2-enoic acid ethyl ester, (i?,/?)-3-acetylamino- 4,5-dimethyl-oct-2-enoic acid ethyl ester, (i?,i?)-3-acetylamino-4,5-dimethyl-non-2- enoic acid ethyl ester, their opposite enantiomers and their diastereomers.
  • 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 enamine (Formula 21) or enamide (Formula 23) 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 24.
  • 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 about 90 % or greater.
  • the asymmetric hydrogenation of the enamine (Formula 21) or enamide (Formula 23) employs a chiral catalyst having the requisite stereochemistry.
  • Useful chiral catalysts include 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.
  • chiral phosphine ligands e.g., monophosphines, bisphosphines, bisphospholanes, etc.
  • 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 BisP*; (K)-BINAPINE; (S)-Me-ferrocene-Ketalphos, (K 5 K)-DIOP; (R,R)-OJPAMP; (/J)-(S)-BPPFA; (S-S)-BPPM; (+)-CAMP; (S 5 S)-CHIRAPHOS; (K)-PROPHOS; (R,R)- NORPHOS; (K)-BINAP; (K)-CYCPHOS; (/2,K)-BDPP; (K 5 K)-DEGUPHOS; (RjK)- Me-DUPHOS; (K 5 K)-Et-DUPHOS; (K 5 KH-Pr-DUPHOS; (K 5 K)-Me-BPE; (K 5 K)-Et- BPE (/J)-PNNP; (/J)-BICHEP; (K 5 S 5 K 5 S)-Me-PENNPHOS; (
  • Other useful chiral ligands include (K)-(-)-l-[(S)-2-(di(3,5- bistrifluoromethylphenyl)phosphino)ferrocenyl]ethyldicyclohexyl-phosphine; (K)-(-)- l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi(3,5- dimethylphenyl)phosphine; (K)-(-)-l-[(S)-2-(di-t-butylphosphino)ferro- cenyl]ethyldi(3,5-dimethylphenyl)phosphine; (K)-(-)-l-[(S)-2-(dicyclohexylphosphi- no)ferrocenyl]ethyldi-t-butylphosphine
  • 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)-PHANEPHOS; (5,S)-Me-DUPHOS; (S 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, Ix or Pd complexed with the phosphine ligand and either a diene (e.g., NBD, 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., NBD, 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 enamine (Formula 21) or the enamide (Formula 23), which undergoes enantioselective hydrogenation to the desired chiral compound (Formula 24).
  • Examples of chiral catalysts or catalyst precursors include (+)- TMBTP-ruthenium(II) chloride acetone complex; (S)-Cl-MeO-BIPHEP-ruthenium(II) chloride Et 3 N complex; (S)-BINAP-ruthenium(JI) Br 2 complex; (S)-tol-BINAP- ruthenium(II) Br 2 complex; [((3i?,42?)-3,4-bis(diphenylphosphino)-l- methylpyrrolidine)-rhodium-( 1 ,5 -cyclooctadiene)] -tetrafluoroborate complex ; [((2?,i?,S,S)-TANGPhos)-rhodium(I)-bis(l,5-cyclooctadiene)]-trifluoromethane sulfonate complex; [(i?)-BINAPINE-rhodium-(l ,5-cycloo
  • 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 IdPa 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 21 or 23) within about 24 h. With many of the chiral catalysts, decreasing the H 2 pressure increases the enantioselectivity.
  • a variety of organic solvents may be used in the asymmetric hydrogenation, including protic solvents, such as MeOH, EtOH, and i-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 MeOH and THF.
  • the method may provide for reacting the enamide 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 enamide with hydrogen in the presence of a chiral catalyst comprised of (i?)-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 24) 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 24 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 24 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 8 in Formula 24 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 24 include ⁇ -amino and ⁇ - amido C 1-6 alkyl esters in which R 1 is hydrogen or C 1-3 alkyl and R 2 is C 1-6 alkyl.
  • Useful compounds of Formula 24 also include those in which R 1 is hydrogen and R 2 is ethyl, n-propyl or /z-butyl, i.e., C 1-6 alkyl esters of (3S,5i?)-3-amino-5-methyl- heptanoic acid, (3S,5i?)-3-amino-5-methyl-octanoic acid, (35,5i?)-3-amino-5-methyl- nonanoic acid, (35,52?)-3-acetylamino-5-methyl-heptanoic acid, (3S,5R)-3- acetylamino-5-methyl-octanoic acid, (3S,5i?)-3-acetylamino-5-methyl-nonanoic acid, and
  • Examples of useful ⁇ -amino C 1-6 alkyl esters thus include (35',52?)-3-amino-5-methyl-heptanoic acid ethyl ester, (3S,5i?)-3-amino-5-methyl- octanoic acid ethyl ester, (3S,5i?)-3-amino-5-methyl-nonanoic acid ethyl ester, and their stereoisomers.
  • useful ⁇ -amido C 1-6 alkyl esters include (3S,5R)-3- acetylamino-5-methyl-heptanoic acid ethyl ester, (3S,5i?)-3-acetylamino-5-methyl- octanoic acid ethyl ester, (3S,5i?)-3-acetylamino-5-methyl-nonanoic acid ethyl ester, and their stereoisomers.
  • R 1 is methyl and R 2 is ethyl, n-propyl or ⁇ -butyl, i.e., C 1-6 alkyl esters of (R,R,R)-3-amno- 4,5-dimethyl-heptanoic acid, (2?,7?,/?)-3-amino-4,5-dimethyl-octanoic acid, (R,R,R)-3- amino-4,5-dimethyl-nonanoic acid, (i?,7?,7?)-3-acetylamino-4,5-dimethyl-heptanoic acid, (2?,/?,2?)-3-acetylamino ⁇ 4,5-diniethyl-octanoic acid, (i?,/?,2?)-3-acetylammo-4,5- dimethyl-nonanoic acid, and their stereoisomers.
  • Examples of useful ⁇ -amino C 1-6 alkyl esters thus include (7?,i?,i?)-3-amino-4,5-dimethyl-heptanoic acid ethyl ester, (/?,/?,/?)-3-amino ⁇ 4,5-dimethyl-octanoic acid ethyl ester, (R, J R, J R)-3 ⁇ amino ⁇ 4,5- dimethyl-nonanoic acid ethyl ester, (i?,/?,i?)-3-acetylamino-4,5-dimethyl-heptanoic acid ethyl ester, (i?,/?,i?)-3-acetylamino-4,5-dimethyl-octanoic acid ethyl ester, (7?,i?,/?)-3-acetylamino-4,5-dimethyl-nonanoic acid ethyl ester, and their stereoisomers.
  • Compounds of Formula 24 include ⁇ -amido acids in which R 1 is hydrogen or C 1-3 alkyl and R 2 is C 1-6 alkyl.
  • Useful ⁇ -amido acids of Formula 24 also include those in which R is hydrogen and R is ethyl, n-propyl or 7i-butyl, such as (3S,5R)-3- acetylamino-5-methyl-heptanoic acid, (3S,52?)-3-acetylamino-5-methyl-octanoic acid, (3S,5i?)-3-acetylamino-5-methyl-nonanoic acid, and their stereoisomers.
  • R 1 is methyl and R 2 is ethyl, n- propyl or n-butyl, such as (i?,i?,i?)-3-acetylamino-4,5-dimethyl-heptanoic acid, (i?,i?,i?)-3-acetylamino-4,5-dimethyl-octanoic acid, (i?,i?,/?)-3-acetylamino-4,5- dimethyl-nonanoic acid, and their stereoisomers.
  • the compound of Formula 1, or its opposite enantiomer or diastereoisomers may be further enriched through, e.g., fractional recrystallization or chromatography or by recrystallization in a suitable solvent.
  • compounds of Formula 1 or Formula 24 may be enriched through treatment with an enzyme such as a lipase or amidase.
  • Scheme V illustrates an additional method for preparing the desired stereoisomer of the compound of Formula 1.
  • the stereoselective synthesis includes reducing an optically active ⁇ -ketoester (Formula 13) by, e.g., reacting it with hydrogen in the presence of a metal catalyst, to give an optically active ⁇ -hydroxy carboxylic acid derivative (Formula 25).
  • Activating the ⁇ -hydroxy moiety via, e.g., reaction with a compound of Formula 26 gives an intermediate (Formula 27), which undergoes elimination via treatment with a base.
  • substituent R 10 in Formula 27 is a leaving group (e.g., R 11 O-);
  • substituent R 11 in Formula 26 is tosyl, mesyl, brosyl, closyl (p-chloro-benzenesulfonyl), nosyl, or triflyl; and
  • substituent X 2 in Formula 26 is halogeno or R ⁇ -O-.
  • Representative optically active secondary or tertiary amines include ⁇ - amino C 1-6 alkyl esters of (l ⁇ S,3S,5i?)-3 ⁇ [benzyl-(l-phenyl-ethyl)-amino]-5-methyl- heptanoic acid, (15 r ,3iS',5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid, (l>S,3S,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid, and their stereoisomers.
  • Examples of ⁇ -amino C 1-6 alkyl esters thus include (lS,3S,5R)-3- [benzyl-(l-phenyl-ethyl)-amino]-5-methyl-heptanoic acid ethyl ester, (lS,3S,5R)-3- [benzyl-(l-phenyl-ethyl)-amino]-5-methyl-octanoic acid ethyl ester, (lS,3S,5R)-3- [benzyl-(l-phenyl-ethyl)-amino]-5-methyl-nonanoic acid ethyl ester, and their stereoisomers.
  • optically active secondary or tertiary amines include ⁇ -amino C 1-6 alkyl esters of (15,3 J R,4i?,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-4,5- dimethyl-heptanoic acid, (lS,3i?,4R,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-4,5- dimethyl-octanoic acid, (15,3i?,42?,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-4,5- dimethyl-nonanoic acid, and their stereoisomers.
  • Examples of ⁇ -amino C 1-6 alkyl esters thus include (l,S',3i?,4i?,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-4,5-dimethyl- heptanoic acid ethyl ester, (lS,32?,4i?,5i?)-3-[benzyl-(l-phenyl-ethyl)-arnino]-4,5- dimethyl-octanoic acid ethyl ester, (15',3i?,4i?,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]- 4,5-dimethyl-nonanoic acid ethyl ester, and their stereoisomers.
  • ⁇ -hydroxy carboxylic acid derivatives include C 1-6 alkyl esters of (5R)-3- hydroxy-5-methyl-heptanoic acid, (5i?)-3-hydroxy-5-methyl-octanoic acid, (52?)-3- hydroxy-5-methyl-nonanoic acid, (4i?,52?)-3-hydroxy-4,5-dimethyl-heptanoic acid, (4i?,52?)-3-hydroxy-4,5-dimethyl-octanoic acid, (42?,52?)-3-hydroxy-4,5-dimethyl- nonanoic acid, and their stereoisomers.
  • 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, (5i?)-3-hydroxy-5-methyl-nonanoic acid ethyl ester, (4/?,5i?)-3-hydroxy-4,5-dimethyl-heptanoic acid ethyl ester, (4/?,5i?)-3-hydroxy-4,5- dimethyl-octanoic acid ethyl ester, (4i?,5i?)-3-hydroxyr4,5-dimethyl-nonanoic acid ethyl ester, and their stereoisomers.
  • Useful compounds of Formula 26 include sulfonylating agents, such as TsCl, MsCl, BsCl, NsCl, TfCl, and the like, and their corresponding anhydrides (e.g., p-toluenesulfonic acid anhydride).
  • sulfonylating agents such as TsCl, MsCl, BsCl, NsCl, TfCl, and the like, and their corresponding anhydrides (e.g., p-toluenesulfonic acid anhydride).
  • compounds of Formula 25 or stereoisomers thereof 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 (5i?)-5-methyl-3-(toluene-4-sulfonyloxy)-heptanoic acid, (5i?)-5- methyl-3-(toluene-4-sulfonyloxy)-octanoic acid, (5i?)-5-methyl-3-(toluene-4- sulfonyloxy)-nonanoic acid, (4i?,5i?)-4,5-dimethyl-3-(toluene-4-sulfonyloxy)- heptanoic acid, (4i?,5i?)-4,5-dimethyl-3-(toluene-4-sulfonyloxy)-octanoic acid, (4i
  • compounds of Formula 25 or stereoisomers thereof may be reacted with MsCl in the presence of a an aprotic solvent and a hindered base, such as Et 3 N, to give C 1-6 alkyl esters of (5i?)-3-methanesulfonyloxy-5-methyl-heptanoic acid, (5R)- 3-methanesulfonyloxy-5-methyl-octanoic acid, (5R)-3-methanesulfonyloxy-5-methyl- nonanoic acid, (4i?,5 J R)-3-methanesulfonyloxy-4,5-dimethyl-heptanoic acid, (4R,5R)- 3-methanesulfonyloxy-4,5-dimethyl-octanoic acid, (4i?,57?)-3-methanesulfonyloxy- 4,5-dimethyl-nonanoic acid, or stereoisomers thereof.
  • a hindered base such as Et 3
  • the resulting intermediate (Formula 27) is reacted with a base to give an unsaturated carboxylic acid derivative (Formula 28).
  • 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 t-BuOK, DBN, DBU, Et 3 N, 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 28) and include C 1-6 alkyl esters of the Z- and E-isomers of (R)S- methyl-hept-2-enoic acid, (i?)-5-methyl-oct-2-enoic acid, (i?)-5-methyl-non-2-enoic acid, (i?,/?)-4,5-dimethyl-hept ⁇ 2-enoic acid, (i?,/?)-4,5-dimethyl-oct-2-enoic acid, (7?,i?)-4,5-dimethyl-non-2-enoic acid, and their stereoisomers.
  • Examples include the Z- and E-isomers of (i?)-5-methyl-hept-2-enoic acid ethyl ester, (i?)-5-methyl-oct-2- enoic acid ethyl ester, (i?)-5-methyl-non-2-enoic acid ethyl ester, (i?,i?)-4,5-dimethyl- hept-2-enoic acid ethyl ester, (i?,i?)-4,5-dimethyl-oct-2-enoic acid ethyl ester, (R,R) ⁇ 4,5-dimethyl-non-2-enoic acid ethyl ester, and their stereoisomers.
  • Chiral amines include (i?)-(+)-N-benzyl- ⁇ -methylbenzylamine, (S)-(-)-iV-benzyl-oc- 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 29) 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 28) to give the optically active secondary or tertiary amine (Formula 30) having the desired stereochemical configuration.
  • Desired enantiomers of any of the compounds disclosed herein may be enriched through classical resolution, chiral chromatography, or recrystallization.
  • the compounds of Formula 8 or Formula 16 may be reacted with an enantiomerically-pure compound (e.g., acid or base) to yield a pair of diastereoisomers, each composed of a single enantiomer, which are separated via, say, fractional recrystallization or chromatography.
  • the desired enantiomer is subsequently regenerated from the appropriate diastereoisomer.
  • the desired enantiomer often may be further enriched by recrystallization in a suitable solvent when it is it available in sufficient quantity (e.g., typically not much less than about 85 % ee, and in some cases, not much less than about 90 % ee).
  • salts include 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 sodium cations (Na + ), potassium cations (K + ), magnesium cations (Mg 2+ ), calcium cations (Ca 2+ ), and the like.
  • suitable amines include N, ⁇ P-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N- methylglucamine, and procaine.
  • 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).
  • 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.
  • 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 isotopes of hydrogen, such as 2 H and 3 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 18 F; and isotopes of chlorine, such as 36 Cl.
  • isotopic variations e.g., deuterium, H
  • isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • a radioactive isotope e.g., tritium, 3 H, or 14 C
  • Example 1 to Example 39 were carried out under nitrogen atmosphere unless otherwise noted.
  • the solvents and reagents used were from commercial sources and no further purification was performed. Reactions were monitored by mass spectrometry (MS) on a Micromass Platform LC and by thin-layer chromatography on 0.25 mm
  • MS mass spectrometry
  • E. Merck silica gel 60 plates F 254 ) using UV light and aqueous potassium permanganate-sodium bicarbonate as visualizing agents.
  • E. Merck silica gel 60 (0.040-0.063 mm and 0.063-0.200 mm particle sizes) was used for column chromatography.
  • Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded at 400 MHz on a Varian UNITY INOVA AS400.
  • a malonate (Formula 2, 10.0 mmol) was combined with an alkyne (Formula 3, 1.2 eq) and an indium (III) catalyst (0.5-2 mol%) in toluene or o-xylene (10 mL) in accordance with Scheme I.
  • the resulting mixture was heated at 110°C to 140°C in a sealed tube for 10 h to 20 h to give a Markovnikov addition product (Formula 4) or a Knoevenagel condensation product (Formula 5).
  • the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/heptane).
  • EXAMPLE 20 2-(l-Methylene-butyl)-malonic acid diethyl ester.
  • a malonate derivative (Formula 2, 10.0 mmol) was combined with an alkyne (Formula 3, 1.2-1.5 equiv.) and an indium (III) catalyst (1-5 mol%) in toluene, o-xylene (10 mL) or neat in accordance with Scheme I.
  • the resulting mixture was heated at 110°C to 140°C for 16 to 24 h to give a Markovnikov addition product (Formula 4) or a Knoevenagel condensation product (Formula 5) or both.
  • the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/heptane).
  • TABLE 5 lists substituents (R 1 , R 2 , R 3 , and R 4 ) for the reactants (Formula 2 and 3) and products (Formula 4 and 5) as well as reaction temperature, catalyst, and yield.
  • EXAMPLE 30 2-Methoxy-2-(l -phenyl- vinyl)-malonic acid dimethyl ester. Orange oil: 1 H NMR (CDCl 3 ): ⁇ 3.49 (s, 3H), 3.73 (s, 6H), 5.52 (s, IH), 5.76 (s, IH), 7.28 (m, 3H), 7.42 (m, 2H). 13 C NMR (CDCl 3 ): ⁇ 53.1, 54.3, 87.8, 121.6, 127.2, 128.1, 128.4, 138.7, 142.4, 168.2. Anal. Calc'd for C 14 H 16 O 5 : C, 63.63; H, 6.10. Found: C, 64.01; H, 6.12.
  • EXAMPLE 33-34 2-(l-Phenyl-vinyl)-malonic acid diethyl ester.
  • a ⁇ -ketoester (Formula 32, 10.0 mmol) was combined with an alkyne (Formula 3, 1.2-1.5 equiv.) and InCl 3 (1-5 mol%) in toluene, ⁇ -xylene (10 mL) or neat in accordance with Scheme VI.
  • the resulting mixture was heated at 130°C to 140°C for 16 h to 24 h to give a Markovnikov addition product (Formula 33) or a Knoevenagel condensation product (Formula 34) or both.
  • the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/heptane).
  • 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 50°C to 60°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°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 60 0 C for at least 12 hours, then cooled to 0°C to 1O 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.
  • EXAMPLE 49 Preparation of (lS,3S,5i?)-3-[benzyl-(l-phenyl-ethyl)-amino]-5- methyl-octanoic acid ethyl ester from (2?)-5-methyl-oct-2-eneoic acid ethyl ester [0142] To a cooled solution of (5)-benzyl-(l-phenyl-ethyl)-amine (21.3 kg) in THF (77 L) was added 24% n-BuLi (27 kg) at -20°C to -3O 0 C.
  • the resulting solution was heated to 80 0 C to 100 0 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).
  • EXAMPLE 51 Preparation of (/?,E)-5-methyl-non-2-eneoic acid ethyl ester from (i?)-5-methyl-3-oxo-nonanoic acid ethyl ester [0144] To a reactor containing (2?)-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+5 0 C under 50 psig of hydrogen for 20 hours.
  • 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 -20°C and Et 3 N (23 kg) was slowly added while maintaining the temperature below 2O 0 C.
  • the solution was warmed to about 50 0 C for at least 12 hours, cooled to 0 0 C to 10 0 C, and quenched with' aq HCl..
  • 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 56 Preparation of (3S,5i?)-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,>S)-TangPhos-Rh catalyst
  • the vials were opened and their contents were charged to the flask.
  • 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 ran 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 57 Preparation of (3>S r ,5i?)-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 CR)-BINAPINE-Rh catalyst
  • EXAMPLE 60 Preparation of (i?,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester from (i?)-5-methyl-3-oxo-nonanoic acid ethyl ester via (7?,Z)-3-amino-5-methyl- non-2-enoic acid ethyl ester
  • 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 0 C to 20 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 (2?)-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 63 Preparation of (35',52?)-3-acetylamino-5-methyl-nonanoic acid ethyl ester via asymmetric hydrogenation of (i?,Z)-3-acetylamino-5-methyl-non-2-enoic acid ethyl ester using (i?)-BINAPINE-Rh catalyst and (R)-mTCFP-Rh catalyst [0158] A pressure vessel was charged with (i?,Z)-3-acetylamino-5-methyl-non-2- enoic acid ethyl ester (100 kg) and MeOH (320 kg) and was purged with nitrogen.
  • (2?)-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°C under 25 psig H 2 for 2 to 5 days. (7?)-mTCFP- Rh(COD)BF 4 (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 H 2 . Following completion of the reaction, the mixture was concentrated by vacuum distillation to give the titled compound as an oil.
  • EXAMPLE 65 Preparation of (35,5i?)-3-amino-5-methyl-nonanoic acid (zwitterion) from (3S,5i?)-3-amino-5-methyl-nonanoic acid HCl salt [0160] (35',52?)-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 25°C to 35°C and slowly cooled to 0°C to 10°C to form a solid precipitate.
  • 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 (i?)-(S)-JOSIPHOS-Rh(COD)BF 4 (50 mg).
  • the vessel contents are purged with hydrogen and are reacted at 50 0 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.
  • EXAMPLE 68 Preparation of (3S,52?)-3-amino-5 ⁇ methyl-nonanoic acid from (3S,5i?)-3-amino-5-methyl-nonanoic acid ethyl ester
  • reaction mixture was stirred for 1 h. Then this solution was added to the malonate/MgCl 2 slurry over 10 minutes. The reaction mixture was then was heated at 45°C to 50°C for 6 h and at RT for 16 h. The reaction mixture was then added to 1.0 M aq HCl (300 mL) while maintaining the temperature at 20°C to 25°C (15 min). The reaction mixture pH was 3. The mixture was stirred at RT for an additional 30 min. EtOAc (400 mL) was added to the reaction mixture and the phases were separated. The aqueous layer was extracted with EtOAc (300 mL) and the combined organic layers were washed with brine (100 mL).

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Abstract

L'invention concerne des matériaux et des procédés pour la préparation de précurseurs de ß-aminoacides optiquement actifs, qui se lient à la sous-unité alpha-2-delta (a2d) d'un canal calcique et qui sont utiles pour le traitement de la douleur, de la fibromyalgie, et de divers troubles psychiatriques ou du sommeil. Le procédé de l'invention consiste à faire réagir un dérivé de malonate avec un alcyne terminal en présence d'un catalyseur In(III).
PCT/IB2006/001126 2005-03-24 2006-03-13 Preparation de precurseurs de beta-aminoacide par addition de markovnikov et condensation de knoevenagel a mediation assuree par de l'indium (iii) WO2006100606A2 (fr)

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CN109692708A (zh) * 2017-10-24 2019-04-30 沈阳中化农药化工研发有限公司 一种不对称环丙化催化剂及其应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008004067A2 (fr) * 2006-06-30 2008-01-10 Pfizer Products Inc. Méthodes de traitement faisant appel à des composés à sélectivité alpha-2-delta-1
WO2008004067A3 (fr) * 2006-06-30 2009-01-29 Pfizer Prod Inc Méthodes de traitement faisant appel à des composés à sélectivité alpha-2-delta-1

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