US20050283023A1 - Preparation of pregabalin and related compounds - Google Patents

Preparation of pregabalin and related compounds Download PDF

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US20050283023A1
US20050283023A1 US11/157,585 US15758505A US2005283023A1 US 20050283023 A1 US20050283023 A1 US 20050283023A1 US 15758505 A US15758505 A US 15758505A US 2005283023 A1 US2005283023 A1 US 2005283023A1
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compound
salt
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cyano
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Shanghui Hu
Carlos Martinez
Junhua Tao
William Tully
Patrick Kelleher
Yves Dumond
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Priority to US12/951,429 priority patent/US8044227B2/en
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    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/12—Formation of amino and carboxyl groups
    • A—HUMAN NECESSITIES
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
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    • 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
    • C07C227/20—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 by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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    • 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
    • C07C229/24—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 more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C12P13/001—Amines; Imines
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    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/002—Nitriles (-CN)
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    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/42—Hydroxy-carboxylic acids

Definitions

  • This invention relates to methods and materials for preparing enantiomerically-enriched ⁇ -amino acids via enzymatic kinetic resolution, and is particularly useful for preparing ⁇ -amino acids that exhibit binding affinity to the human ⁇ 2 ⁇ calcium channel subunit, including pregabalin and related compounds.
  • Pregabalin (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, is related to the endogenous inhibitory neurotransmitter ⁇ -aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity.
  • GABA ⁇ -aminobutyric acid
  • Pregabalin exhibits anti-seizure activity, as discussed in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., and is thought to be useful for treating, among other conditions, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including mania and bipolar disorder. See, respectively, U.S. Pat. No. 6,242,488 to L.
  • Pregabalin has been prepared in various ways. Typically, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid is synthesized and subsequently resolved into its R- and S-enantiomers. Such methods may employ an azide intermediate, a malonate intermediate, or Hofman synthesis. See, respectively, U.S. Pat. No. 5,563,175 to R. B. Silverman et al.; U.S. Pat. Nos. 6,046,353, 5,840,956, and 5,637,767 to T. M. Grote et al.; and U.S. Pat. Nos. 5,629,447 and 5,616,793 to B. K. Huckabee & D. M.
  • Pregabalin has also been synthesized directly using a chiral auxiliary, (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone. See, e.g., U.S. Pat. Nos. 6,359,169, 6,028,214, 5,847,151, 5,710,304, 5,684,189, 5,608,090, and 5,599,973, all to R. B. Silverman et al, which are herein incorporated by reference in their entirety and for all purposes.
  • a recently published U.S. patent application discusses a method of making pregabalin via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methylhexanoic acid. See commonly assigned U.S. Patent Application No. 2003/0212290 A1 to Burk et al., published Nov. 13, 2003, which is herein incorporated by reference in its entirety for all purposes.
  • the cyano precursor is subsequently reduced to give pregabalin.
  • the asymmetric hydrogenation employs a chiral catalyst that is comprised of a transition metal bound to a bisphosphine ligand, such as (R,R)-Me-DUPHOS.
  • the method results in substantial enrichment of pregabalin over (R)-3-(aminomethyl)-5-methylhexanoic acid.
  • the present invention provides materials and methods for preparing enantiomerically enriched ⁇ -amino acids (Formula 1) such as pregabalin (Formula 9).
  • the method of the present invention involves a kinetic resolution of a racemic cyano diester intermediate (Formula 4 or Formula 12) using an enzyme that is adapted to enantioselectively hydrolyze an ester moiety of the intermediate.
  • the resulting dicarboxylic acid monoester (Formula 3 or Formula 11), which is substantially enantiopure, undergoes further reaction to yield the desired enantiomerically-enriched ⁇ -amino acids (Formula 1 or Formula 9).
  • the unreacted enantiomer (Formula 5 or Formula 13) from the kinetic resolution can be reused in the enzymatic resolution following racemization, thereby improving overall yield.
  • the claimed method offers significant advantages over existing processes for preparing enantiomerically-enriched ⁇ -amino acids (Formula 1 and Formula 9).
  • the optically-active ⁇ -amino acids can be prepared without using chiral auxiliaries or proprietary hydrogenation catalysts, which should lead to lower unit costs. Since enzymatic processes can be carried out at room temperature and at atmospheric pressure, the claimed methods should help minimize scheduling conflicts arising from the use of specialized equipment capable of handling high pressures and low temperatures.
  • the present invention can be used to prepare pregabalin starting from a racemic cyano-substituted diester (Formula 12) in good yield (26% to 31%) after a single batch recycle of the unreacted enantiomer (Formula 13). This translates into about a 50% savings in cost of goods over the malonate method described above.
  • One aspect of the present invention provides a method of making a compound of or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, in which
  • Another aspect of the present invention provides a method of making a compound of Formula 1, above, the method comprising:
  • the compound of Formula 6, above may be prepared by hydrolyzing a compound of Formula 3, or a salt thereof, wherein R 1 and R 2 in Formula 3 are as defined above in Formula 1, and R 3 is C 1-12 alkyl, C 3-12 cycloalkyl, or aryl-C 1-6 alkyl.
  • An additional aspect of the present invention provides method of making a compound of Formula 1, above, the method comprising:
  • the compound of Formula 8 may be prepared by decarboxylating a compound of Formula 3, above, or a salt thereof, or by hydrolyzing and decarboxylating the compound of Formula 3 or a salt thereof, to yield the compound of Formula 8 or a salt thereof.
  • a further aspect of the present invention provides a method of making the compound of Formula 3, above, or a salt thereof, the method comprising:
  • Any number of enzymes may be used to enantioselectively hydrolyze the compound of Formula 4 to the compound of Formula 3 or a salt thereof.
  • Useful enzymes include lipases, such as those derived from Thermomyces lanuginosus.
  • Another aspect of the present invention provides compounds represented by Formula 2, above, including complexes, salts, solvates or hydrates thereof, provided that when one of the substituents represented by R 1 or R 2 in Formula 2 is hydrogen, the other substituent is not C 1-3 alkyl or C 5 alkyl.
  • An additional aspect of the present invention provides compounds of Formula 27, including complexes, salts, solvates or hydrates thereof, wherein
  • Compounds of Formula 27 include those represented by Formula 3, Formula 4, Formula 5, Formula 6, and Formula 7, above, including their complexes, salts, solvates or hydrates.
  • Useful compounds of Formula 2-7 and 27 include those in which R 1 is a hydrogen atom and R is isobutyl.
  • a further aspect of the present invention provides a method of making a compound of Formula 9, or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, the method comprising:
  • the compound of Formula 10 or a salt thereof may be prepared by reducing a cyano moiety of a compound of Formula 11, or a salt thereof, wherein R 3 is as defined above in Formula 3.
  • Another aspect of the present invention provides a method of making a compound of Formula 9, above, or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, the method comprising:
  • the compound of Formula 14, above may be prepared by hydrolyzing a compound of Formula 11, or salt thereof, wherein R 3 in Formula 11 is as defined above in Formula 3.
  • An additional aspect of the present invention provides a method of making a compound of Formula 9, above, or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, the method comprising:
  • the compound of Formula 16 may be prepared by decarboxylating (e.g., by heating) the compound of Formula 11, above, or a salt thereof, or by hydrolyzing and decarboxylating the compound of Formula 11 or a salt thereof.
  • a further aspect of the present invention provides a method of making the compound of Formula 11, above, or a salt thereof, the method comprising:
  • the corresponding salts of the compound of Formula 11 include those selected from alkali metal salts, such as potassium salt; primary amine salts, such as a t-butyl amine salt; and secondary amine salts.
  • useful enzymes include lipases, such as those derived from Thermomyces lanuginosus.
  • Another aspect of the present invention provides a compound selected from:
  • 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 Z/E) stereoisomers are possible, or may contain a keto or oxime group, so that tautomerism may occur.
  • the present invention generally includes all Z/E isomers and tautomeric forms, whether they are pure, substantially pure, or mixtures.
  • FIG. 1 depicts a scheme for preparing enantiomerically-enriched ⁇ -amino acids (Formula 1).
  • FIG. 2 depicts a scheme for preparing cyano-substituted diesters (Formula 4).
  • ⁇ a dash (“ ⁇ ”) to indicate a bond between atoms or a point of attachment to a named or unnamed atom or group of atoms.
  • 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.
  • “Substituted” groups are those in which one or more hydrogen atoms have been replaced with one or more non-hydrogen 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 and C 1-12 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms).
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-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-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-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. Examples of alkynyl groups include, without limitation, ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.
  • alkanoyl and alkanoylamino refer, respectively, to alkyl-C(O)— and alkyl-C(O)—NH—, 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. 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.
  • alkynoyl groups include, without limitation, propynoyl, 2-butynoyl, 3-butynoyl, 2-pentynoyl, 3-pentynoyl, 4-pentynoyl, and the like.
  • Alkoxy refers, respectively, to alkyl-O—, alkenyl-O, and alkynyl-O; to alkyl-O—C(O)—, alkenyl-O—C(O)—, alkynyl-O—C(O)—; and to alkyl-O—C(O)—NH—, alkenyl-O—C(O)—NH—, and alkynyl-O—C(O)—NH—, where alkyl, alkenyl, and alkynyl are defined above.
  • alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, i-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.
  • Alkylamino refers, respectively, to alkyl-NH—, alkyl-NH—C(O)—, alkyl 2 -N—C(O)—, alkyl-S(O 2 )—, HS(O 2 )—NH-alkyl-, and alkyl-S(O)—NH—C(O)— where alkyl is defined above.
  • Aminoalkyl and cyanoalkyl refer, respectively, to NH 2 -alkyl and N ⁇ C-alkyl, where alkyl is defined above.
  • 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.
  • Examples of hydroxyalkyl and oxoalkyl groups include, without limitation, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, oxomethyl, oxoethyl, 3-oxopropyl, 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[1.1.1]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,
  • 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-O 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, 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, 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 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-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indoli
  • Heteroaryl and heteroarylene refer, respectively, to monovalent and divalent heterocycles or heterocyclyl groups, as defined above, which are aromatic. Heteroaryl 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, 1-(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, 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,” “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-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 ⁇ (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 ⁇ (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., ester hydrolysis, hydrogenation, hydroformylation, ⁇ -allyl palladium coupling, hydrosilation, hydrocyanation, olefin metathesis, hydroacylation, allylamine isomerization, etc.) that yields more of one stereoisomer, enantiomer, or diastereoisomer than of another, respectively.
  • a given process e.g., ester hydrolysis, hydrogenation, hydroformylation, ⁇ -allyl palladium coupling, hydrosilation, hydrocyanation, olefin metathesis, hydroacylation, allylamine isomerization, etc.
  • “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.
  • a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.
  • Stepoisomerically enriched refers, 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.
  • Opte 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 (ZiE) of the compound.
  • ZiE 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.
  • “Lipase Unit” or “LU” refers to the amount of enzyme (in g) that liberates 1 ⁇ mol of titratable butyric acid/min when contacted with tributyrin and an emulsifier (gum arabic) at 30° C. and pH 7.
  • 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, including the enantioselective hydrolysis of the racemic diester (Formula 4) described in detail below, may be carried out at about RT, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rate and yield.
  • the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or some combination. Any references in the disclosure to a concentration range, a temperature range, a pH range, a catalyst loading range, and so on, whether expressly using the word “range” or not, include the indicated endpoints.
  • the present invention provides materials and methods for preparing optically active ⁇ -amino acids (Formula 1) including pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
  • the compounds of Formula 1 include substituents R 1 and R 2 , which are defined above.
  • Useful compounds of Formula 1 thus include those in which R 1 is a hydrogen atom and R 2 is C 1-12 alkyl, C 3-12 cycloalkyl, or substituted C 3-12 cycloalkyl, or those in which R 2 is a hydrogen atom and R 1 is C 1-12 alkyl, C 3-1 2 cycloalkyl, or substituted C 3-12 cycloalkyl.
  • Particularly useful compounds of Formula 1 include those in which R 1 is a hydrogen atom and R 2 is C 1-6 alkyl or C 3-7 cycloalkyl, or those in which R 2 is a hydrogen atom and R 1 is C 1-6 alkyl or C 3-7 cycloalkyl.
  • Particular useful compounds of Formula 1 include those in which R 1 is a hydrogen atom and R 2 is C 1-4 alkyl, such as pregabalin (Formula 9).
  • FIG. 1 shows a process for preparing optically active ⁇ -amino acids (Formula 1).
  • the process includes the step of contacting or combining a reaction mixture, which is comprised of a cyano-substituted diester (Formula 4) and water, with an enzyme to yield a product mixture that includes an optically active dicarboxylic acid monoester (Formula 3) and an optically-active diester (Formula 5).
  • the cyano-substituted diester (Formula 4) has a stereogenic center, which is denoted by an asterisk (“*”), and as described below, may be prepared in accordance with a reaction scheme shown in FIG. 2 .
  • the cyano-substituted diester Prior to contacting the enzyme, typically comprises a racemic (equimolar) mixture of the diester of Formula 5 and its opposite enantiomer.
  • Substituents R 1 , R 2 , and R 3 in Formula 3, Formula 4, and Formula 5, and substituent R 4 in Formula 4 and Formula 5 are as defined above in connection with Formula 1.
  • substituent identifier R 1 , R 2 , R 3 , etc.
  • the enzyme may be any protein that, while having little or no effect on the compound of Formula 5, will catalyze the hydrolysis of its opposite enantiomer to yield the dicarboxylic acid monoester (Formula 3).
  • Useful enzymes for enantioselectively hydrolyzing the compound of Formula 4 to Formula 3 may thus include hydrolases, including lipases, certain proteases, and other enantioselective esterases.
  • Such enzymes may be obtained from a variety of natural sources, including animal organs and microorganisms. See, e.g., Table 2 for a non-limiting list of commercially available hydrolases.
  • Protease BioCatalytics101 Pseudomonas sp. Lipase BioCatalytics103 Fungal Lipase BioCatalytics105 Microbial, lyophilized Lipase BioCatalytics108 CAL-B, lyophilized BioCatalytics110 Candida sp., lyophilized BioCatalytics111 CAL-A, lyophilized BioCatalytics112 Thermomyces sp.
  • useful enzymes for the enantioselective conversion of the cyano-substituted diester (Formula 4 and Formula 12) to the desired optically active dicarboxylic acid monoester (Formula 3 and Formula 11) include lipases.
  • Particularly useful lipases include enzymes derived from the microorganism Thermomyces lanuginosus , such as those available from Novo-Nordisk A/S under the trade name LIPOLASE® (CAS no. 9001-62-1).
  • LIPOLASE® enzymes are obtained by submerged fermentation of an Aspergillus oryzae microorganism genetically modified with DNA from Thermomyces lanuginosus DSM 4109 that encodes the amino acid sequence of the lipase.
  • LIPOLASE® 100L and LIPOLASE® 100T are available as a liquid solution and a granular solid, respectively, each having a nominal activity of 100 kLU/g.
  • Other forms of LIPOLASE® include LIPOLASE® 50L, which has half the activity of LIPOLASE® 100L, and LIPOZYME® 100L, which has the same activity of LIPOLASE® 100L, but is food grade.
  • Suitable enzymes For example, large numbers of commercially available enzymes may be screened using high throughput screening techniques described in the Example section below. Other enzymes (or microbial sources of enzymes) may be screened using enrichment isolation techniques. Such techniques typically involve the use of carbon-limited or nitrogen-limited media supplemented with an enrichment substrate, which may be the racemic substrate (Formula 4) or a structurally similar compound. Potentially useful microorganisms are selected for further investigation based on their ability to grow in media containing the enrichment substrate.
  • an enrichment substrate which may be the racemic substrate (Formula 4) or a structurally similar compound.
  • microorganisms are subsequently evaluated for their ability to enantioselectively catalyze ester hydrolysis by contacting suspensions of the microbial cells with the racemic substrate and testing for the presence of the desired optically-active dicarboxylic acid monoester (Formula 3) using analytical methods such as chiral HPLC, gas-liquid chromatography, LC/MS, and the like.
  • enzyme engineering may be employed to improve the properties of the enzyme it produces.
  • enzyme engineering may be used to increase the yield and the enantioselectivity of the ester hydrolysis, to broaden the temperature and pH operating ranges of the enzyme, and to improve the enzyme's tolerance to organic solvents.
  • Useful enzyme engineering techniques include rational design methods, such as site-directed mutagenesis, and in vitro-directed evolution techniques that utilize successive rounds of random mutagenesis, gene expression, and high throughput screening to optimize desired properties. See, e.g., K. M. Koeller & C.-H. Wong, “Enzymes for chemical synthesis,” Nature 409:232-240 (11 Jan. 2001), and references cited therein, the complete disclosures of which are herein incorporated by reference.
  • the enzyme may be in the form of whole microbial cells, permeabilized microbial cells, extracts of microbial cells, partially purified enzymes, purified enzymes, and the like.
  • the enzyme may comprise a dispersion of particles having an average particle size, based on volume, of less than about 0.1 mm (fine dispersion) or of about 0.1 mm or greater (coarse dispersion).
  • coarse enzyme particles may be used repeatedly in batch processes, or in semi-continuous or continuous processes, and may usually be separated (e.g., by filtration) from other components of the bioconversion more easily than fine dispersions of enzymes.
  • Useful coarse enzyme dispersions include cross-linked enzyme crystals (CLECs) and cross-linked enzyme aggregates (CLEAs), which are comprised primarily of the enzyme. Other coarse dispersions may include enzymes immobilized on or within an insoluble support.
  • Useful solid supports include polymer matrices comprised of calcium alginate, polyacrylamide, EUPERGIT®, and other polymeric materials, as well as inorganic matrices, such as CELITE®.
  • CLECs and other enzyme immobilization techniques see U.S. Pat. No. 5,618,710 to M. A. Navia & N. L. St. Clair.
  • CLEAs including their preparation and use, see U.S. Patent Application No.
  • the reaction mixture may comprise a single phase or may comprise multiple phases (e.g., a two- or a three-phase system).
  • the enantioselective hydrolysis shown in FIG. 1 may take place in a single aqueous phase, which contains the enzyme, the initially racemic substrate (Formula 4), the undesired optically-active diester (Formula 5), and the desired optically-active dicarboxylic acid monoester (Formula 3).
  • the reaction mixture may comprise a multi-phase system that includes an aqueous phase in contact with a solid phase (e.g., enzyme or product), an aqueous phase in contact with an organic phase, or an aqueous phase in contact with an organic phase and a solid phase.
  • the enantioselective hydrolysis may be carried out in a two-phase system comprised of a solid phase, which contains the enzyme, and an aqueous phase, which contains the initially racemic substrate, the undesired optically-active diester, and the desired optically-active dicarboxylic acid monoester.
  • the enantioselective hydrolysis may be carried out in a three-phase system comprised of a solid phase, which contains the enzyme, an organic phase that initially contains the racemic substrate (Formula 4), and an aqueous phase that initially contains a small fraction of the racemic substrate.
  • a solid phase which contains the enzyme
  • an organic phase that initially contains the racemic substrate (Formula 4)
  • an aqueous phase that initially contains a small fraction of the racemic substrate.
  • the desired optically-active dicarboxylic acid monoester has a lower pKa than the unreacted optically-active diester (Formula 5) and therefore exhibits greater aqueous solubility
  • the organic phase becomes enriched in the unreacted diester while the aqueous phase becomes enriched in the desired dicarboxylic acid monoester as the reaction proceeds.
  • the amounts of the racemic substrate (Formula 4) and the biocatalyst used in the enantioselective hydrolysis will depend on, among other things, the properties of the particular cyano-substituted diester and enzyme. Generally, however, the reaction may employ a substrate having an initial concentration of about 0.1 M to about 3.0 M, and in many cases, having an initial concentration of about 1.5 M to about 3.0 M. Additionally, the reaction may generally employ an enzyme loading of about 1% to about 10%, and in many cases, may employ an enzyme loading of about 3% to about 4% (v/v).
  • the enantioselective hydrolysis may be carried out over wide ranges of temperature and pH.
  • the reaction may be carried out at a temperature of about 10° C. to a temperature of about 50° C., but is typically carried out at about RT.
  • Such temperatures generally permit substantially full conversion (e.g., about 42% to about 50%) of the racemate (Formula 4) in a reasonable amount of time (about 2 h to about 24 h) without deactivating the enzyme.
  • the enantioselective hydrolysis may be carried out at a pH of about 5 to a pH of about 10, more typically at a pH of about 6 to a pH of about 9, and often at a pH of about 6.5 to a pH of about 7.5.
  • the hydrolysis reaction may be run with internal pH control (i.e., in the presence of a suitable buffer) or may be run with external pH control through the addition of a base.
  • suitable buffers include potassium phosphate, sodium phosphate, sodium acetate, ammonium acetate, calcium acetate, BES, BICINE, HEPES, MES, MOPS, PIPES, TAPS, TES, TRICINE, Tris, TRIZMA®, or other buffers having a pKa of about 6 to a pKa of about 9.
  • the buffer concentration generally ranges from about 5 mM to about 1 mM, and typically ranges from about 50 mM to about 200 mM.
  • Suitable bases include aqueous solutions comprised of KOH, NaOH, NH 4 OH, etc., having concentrations ranging from about 0.5 M to about 15 M, or more typically, ranging from about 5 M to about 10 M.
  • Other inorganic additives such as calcium acetate may also be used.
  • the desired optically active dicarboxylic acid monoester (Formula 3) is isolated from the product mixture using standard techniques.
  • the product mixture may be extracted one or more times with a nonpolar organic solvent, such as hexane or heptane, which separates the desired dicarboxylic monoester (Formula 2) and the unreacted diester (Formula 5) in aqueous and organic phases, respectively.
  • the monoester and diester may be separated batch-wise following reaction, or may be separated semi-continuously or continuously during the enantioselective hydrolysis.
  • the unreacted diester (Formula 5) may be isolated from the organic phase and racemized to yield the racemic substrate (Formula 4).
  • the resulting racemate (Formula 4) may be recycled or combined with unconverted racemic substrate, which subsequently undergoes enzymatic conversion to Formula 3 as described above. Recycling the unreacted diester (Formula 5) increases the overall yield of the enantioselective hydrolysis above 50%, thereby increasing the atom economy of the method and lowering costs associated with disposal of the undesired enantiomers.
  • the treatment of the diester (Formula 5) with a base that is strong enough to abstract an acidic ⁇ -proton of the malonate moiety generally results in inversion of the stereogenic center and generation of the racemic substrate (Formula 4).
  • Useful bases include organic bases, such as alkoxides (e.g., sodium ethoxide), linear aliphatic amines, and cyclic amines, and inorganic bases, such as KOH, NaOH, NH 4 OH, and the like.
  • the reaction is carried out in a compatible solvent, including polar protic solvents, such as EtOH or aprotic polar solvents, such as MTBE. Reaction temperatures above RT typically improve the yield of the racemization process.
  • the substantially enantiopure dicarboxylic acid monoester (Formula 3) may be converted to an optically active ⁇ -amino acid (Formula 1) using at least three different methods.
  • the monoester (Formula 3) is hydrolyzed in the presence of an acid catalyst or a base catalyst to yield an optically-active cyano-substituted dicarboxylic acid (Formula 6) or corresponding salt.
  • the cyano moiety of the resulting dicarboxylic acid (or its salt) is reduced to yield an optically-active ⁇ -amino dicarboxylic acid (Formula 7) or a corresponding salt, which is subsequently decarboxylated by treatment with an acid, by heating, or both, to yield the desired optically active ⁇ -amino acid (Formula 1).
  • the cyano moiety may be reduced via reaction with H 2 in the presence of catalytic amounts of Raney nickel, palladium, platinum, and the like, or through reaction with a reducing agent, such as LiAlH 4 , BH 3 —Me 2 S, and the like.
  • Useful acids for the hydrolysis and decarboxylation reactions include mineral acids, such as HClO 4 , H 1 , H 2 SO 4 , HBr, HCl, and the like.
  • Useful base catalysts for the hydrolysis reaction include various alkali and alkaline earth metal hydroxides and oxides, including LiOH, NaOH, KOH, and the like.
  • the dicarboxylic acid monoester (Formula 3) undergoes reductive cyclization to form an optically-active cyclic 3-carboxy-pyrrolidin-2-one (Formula 2), which is subsequently treated with an acid to yield the desired enantiomerically-enriched ⁇ -amino acid (Formula 1).
  • the reductive cyclization may be carried out by reacting the monoester (Formula 3) with H 2 in the presence of catalytic amounts of Raney nickel, palladium, platinum and the like.
  • One or more acids may be used to hydrolyze and decarboxylate the resulting lactam acid (Formula 2), including mineral acids such as HClO 4 , H 1 , H 2 SO 4 , HBr, and HCl, and organic acids such as HOAc, TFA, p-TSA, and the like.
  • the concentration of the acids may range from about 1N to about 12 N, and the amount of the acids may range from about 1 eq to about 7 eq.
  • the hydrolysis and decarboxylation reactions may be carried out at a temperature of about RT or higher, or at a temperature of about 60° C. or higher, or at temperature in a range of about 60° C. to about 130° C.
  • the ester moiety of the dicarboxylic acid monoester (Formula 3) is first hydrolyzed to give the cyano-substituted dicarboxylic acid (Formula 6 or its salt) as described above.
  • the resulting dicarboxylic acid (or its salt) is subsequently decarboxylated to give an optically-active cyano-substituted carboxylic acid or its salt (Formula 8 in which R 5 is a hydrogen atom, though R 5 can also be C 1-12 alkyl, C 3-12 cycloalkyl, or aryl-C 1-6 alkyl as noted below).
  • the dicarboxylic acid monoester (Formula 3) may be first decarboxylated directly to a cyano substituted monoester (Formula 8) by heating the aqueous solution of the dicarboxylic acid monoester (as a salt) to a temperature of from about 50° C. to reflux.
  • Krapcho conditions DMSO/NaCl/water
  • the cyano moiety of the compound of formula 8 is subsequently reduced to give the optically active ⁇ -amino acid (Formula 1).
  • a number of other catalysts may be used to reduce the cyano moiety of the compounds of Formula 3, 6 and 8.
  • These 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.
  • Useful catalysts thus include palladium catalysts such as Pd/C, Pd/SrCO 3 , Pd/Al 2 O 3 , Pd/MgO, Pd/CaCO 3 , Pd/BaSO 4 , PdO, Pd black, PdCl 2 , and the like, containing from about 1% to about 5% Pd, based on weight.
  • Other useful catalysts include Rh/C, Ru/C, Re/C, PtO 2 , Rh/C, RuO 2 , and the like.
  • the catalytic reduction of the cyano moiety is typically carried out in the presence of one or more polar solvents, including without limitation, water, 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° 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.
  • Isolation of the lactam acid reduces the carryover of water-soluble impurities into the final product mixture and permits higher reactant concentration (e.g., about 1 M to about 2 M) during hydrolysis and decarboxylation, thereby increasing process throughput.
  • reactant concentration e.g., about 1 M to about 2 M
  • direct decarboxylation by heating the aqueous solution of the dicarboxylic acid monoester (Formula 3) affords the cyanomonoester (Formula 8) in high enantiomeric purity.
  • This compound can be separated from the reaction medium by extraction in an organic solvent or by direct phase separation, ensuring efficient removal of inorganic impurities by the water phase. High reaction throughput and the avoidance of strongly acidic conditions are two advantages of this approach.
  • FIG. 2 illustrates a process for preparing cyano-substituted diesters (Formula 4), which may serve as substrates for the enzymatic enantioselective hydrolysis shown in FIG. 1 .
  • the process includes a crossed aldol condensation, which comprises reacting an unsymmetrical ketone or an aldehyde (Formula 17) with a malonic acid diester (Formula 18) in the presence of catalytic amounts of a base to yield an ⁇ , ⁇ -unsaturated malonic acid diester (Formula 19) in which R 1 , R 2 , R 3 , and R 4 are as defined above in connection with Formula 1.
  • any base capable of generating an enolate ion from the malonic acid diester may be used, including secondary amines, such as di-n-propylamine, di-1-propylamine, pyrrolidine, etc., and their salts.
  • the reaction may include a carboxylic acid, such as HOAc, to neutralize the product and to minimize enolization of the unsymmetrical ketone or aldehyde (Formula 17).
  • Reactions involving unsymmetrical ketones may also employ Lewis acids, such as titanium tetrachloride, zinc chloride, zinc acetate, and the like to facilitate reaction.
  • the reaction is typically run in a hydrocarbon solvent under reflux conditions.
  • Useful solvents include hexane, heptane, cyclohexane, toluene, methyl t-butyl ether, and the like, with azeotropic removal of water.
  • a cyanide source such as HCN, acetone cyanohydrin, an alkali metal cyanide (NaCN, KCN, etc.), or an alkaline earth metal cyanide (magnesium cyanide, etc.
  • a cyanide source undergoes conjugate addition to the ⁇ -carbon of the ⁇ , ⁇ -unsaturated malonic acid diester (Formula 19).
  • the reaction is typically carried out in one or more polar protic solvents, including EtOH, MeOH, n-propanol, isopropanol, or polar aprotic solvents, such as DMSO, and the like.
  • polar protic solvents including EtOH, MeOH, n-propanol, isopropanol, or polar aprotic solvents, such as DMSO, and the like.
  • polar protic solvents such as EtOH, MeOH, n-propanol, isopropanol, or polar aprotic solvents, such
  • the desired (S)- or (R)-enantiomers of any of the compounds disclosed herein may be further enriched through classical resolution, chiral chromatography, or recrystallization.
  • the optically active ⁇ -amino acids (Formula 1 or Formula 9) 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).
  • stereoisomers As described throughout the specification, many of the disclosed compounds have stereoisomers. Some of these compounds may exist as single enantiomers (enantiopure compounds) or mixtures of enantiomers (enriched and racemic samples), which depending on the relative excess of one enantiomer over another in a sample, may exhibit optical activity. Such stereoisomers, which are non-superimposable mirror images, possess a stereogenic axis or one or more stereogenic centers (i.e., chirality). Other disclosed compounds may be stereoisomers that are not mirror images. Such stereoisomers, which are known as diastereoisomers, may be chiral or achiral (contain no stereogenic centers).
  • the scope of the present invention generally includes the reference compound and its stereoisomers, whether they are each pure (e.g., enantiopure) or mixtures (e.g., enantiomerically enriched or racemic).
  • the compounds may also contain a keto or oxime group, so that tautomerism may occur.
  • the present invention generally includes tautomeric forms, whether they are each pure or mixtures.
  • salts include, without limitation, acid addition salts (including diacids) 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, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, procaine, and t-butyl amine.
  • 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, d6-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 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, 2H
  • 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
  • Enzyme screening was carried out using a 96-well plate, which is described in D. Yazbeck et al., Synth. Catal. 345:524-32 (2003), the complete disclosure of which is herein incorporated by reference for all purposes. All enzymes used in the screening plate (see Table 2) were obtained from commercial enzyme suppliers including Amano (Nagoya, Japan), Roche (Basel, Switzerland), Novo Nordisk (Bagsvaerd, Denmark), Altus Biologics Inc. (Cambridge, Mass.), Biocatalytics (Pasadena, Calif.), Toyobo (Osaka, Japan), Sigma-Aldrich (St. Louis, Mo.) and Fluka (Buchs, Switzerland).
  • Regular 13 C NMR spectra were acquired using 30-degree tip angle pulses, 2.0 s recycle delay, and 2048 scans at a resolution of 1 Hz/point.
  • Spectral width was typically 25 KHz from +235 to ⁇ 15 ppm (Reference TMS at 0 ppm).
  • Proton decoupling was applied continuously and 1 Hz line broadening was applied during processing. Typical acquisition time was 102 min.
  • Mass Spectrometry was performed on a HEWLETT PACKARD 1100MSD using HP Chemstation Plus Software.
  • the LC was equipped with an Agilent 1100 quaternary LC system and an Agilent liquid handler as an autosampler. Data were acquired under electron spray ionization with ACN/water (containing 0.1% formic acid) as the solvent (10% ACN to 90%, 7 min). Temperatures: probe was 350° C., source was 150° C. Corona discharge was 3000 V for positive ion and 3000 V for negative ion.
  • HPLC High Performance Liquid Chromatography
  • GC Gas Chromatography
  • Enzyme screening was carried out using a screening kit comprised of individual enzymes deposited in separate wells of a 96-well plate, which was prepared in advance in accordance with a method described in D. Yazbeck et al., Synth. Catal. 345:524-32 (2003). Each of the wells had an empty volume of 0.3 ml (shallow well plate).
  • One well of the 96-well plate contained only phosphate buffer (10 ⁇ L, 0.1 M, pH 7.2), another well contained only ACN (10 ⁇ L), and each of the remaining wells contained one of the 94 enzymes listed in Table 2 (10 ⁇ L, 100 mg/mL). Prior to use, the screening kit was removed from storage at ⁇ 80° C.
  • Potassium phosphate buffer (85 ⁇ L, 0.1 M, pH 7.2) was dispensed into each of the wells using a multi-channel pipette.
  • Concentrated substrate (Formula 20, 5 ⁇ L) was subsequently added to each well via a multi-channel pipette and the 96 reaction mixtures were incubated at 30° C. and 750 rpm. The reactions were quenched and sampled after 24 h by transferring each of the reaction mixtures into separate wells of a second 96-well plate. Each of the wells had an empty volume of 2 mL (deep well plate) and contained EtOAc (1 mL) and HCl (1N, 100 ⁇ L).
  • each well was mixed by aspirating the well contents with a pipette.
  • the second plate was centrifuged and 100 ⁇ L of the organic supernatant was transferred from each well into separate wells of a third 96-well plate (shallow plate).
  • the wells of the third plate were subsequently sealed using a penetrable mat cover. Once the wells were sealed, the third plate was transferred to a GC system for determination of optical purity (ee).
  • Table 3 lists enzyme, trade name, supplier, and E value for some of the enzymes that were screened.
  • the E value may be interpreted as the relative reactivity of a pair of enantiomers (substrates).
  • the E values listed in Table 3 were calculated from HPLC data (fractional conversion, ⁇ , and ee) using a computer program called Ee2, which is available from the University of Graz.
  • Ee2 which is available from the University of Graz.
  • enzymes exhibiting S-selectivity and an E value of about 35 or greater are suitable for scale-up.
  • the reaction mixture Upon reaching a conversion of about 40-45% (e.g., after about 24 h) the reaction mixture was transferred to a separatory funnel. The aqueous mixture was extracted with heptane (205 L). EtOH (absolute) was added (up to about 5% v/v) to disrupt a light emulsion that formed, and the aqueous and organic layers were separated. The extraction step was repeated twice, and the aqueous layer containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23) may be further concentrated under vacuum (e.g., 25-50% of its original volume).
  • a reactor (3.92 L) equipped with overhead stirring is charged with calcium acetate buffer (1.47 L, 100 mM, pH 7.0) and (R/S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20, 1 kg).
  • the mixture is stirred at 1100 RPM for 5 min and KOH (5 M) is added to adjust the pH to 7.0.
  • LIPOLASE® 100L, type EX (75 mL) is added and the resulting mixture is titrated with KOH (5 M) during hydrolysis to maintain a pH of 7.0.
  • the extent of reaction is monitored by HPLC (C 18 column, 4.6 mm ⁇ 150 mm, detection at 200 nm).
  • the reaction mixture Upon reaching a conversion of about 42% to 45% (e.g., after about 20-25 h) the reaction mixture is transferred to a separatory funnel.
  • the aqueous mixture is extracted with hexane (100% v/v).
  • EtOH absolute
  • EtOH absolute
  • the extraction step is repeated twice to obtain an aqueous layer containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23), which may be used in subsequent transformations without isolation.
  • a vessel was charged with an aqueous solution containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid potassium salt (Formula 23, 411 L from Example 2).
  • Raney Nickel (50% aq solution, Sigma-Aldrich) was added to the mixture, and hydrogen gas was introduced into the vessel over a 20 h period to maintain a pressure of 50 psig in the vessel headspace throughout reaction.
  • the hydrogenation reaction was monitored by H 2 uptake and HPLC analysis (C 18 column, 4.6 mm ⁇ 150 mm, detection at 200 nm) of the vessel contents.
  • the aqueous mixture was filtered to remove the Raney Ni catalyst.
  • the pH of the concentrated solution was adjusted to 3.0 using 37% HCl (about 14 L).
  • optical purity of (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid was determined via a derivatization method.
  • a sample of (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid was esterified with EtOH in the presence of a catalytic amount of dry HCl in dioxane at 70° C.
  • the resulting lactam ester was analyzed by HPLC (CHIRALPAK AD-H, 4.6 mm ⁇ 250 mm) using a mobile phase of hexane and EtOH (95:5), a flow rate of 1.0 mL/min, injection volume of 10 ⁇ L, column temperature of 35° C., and detection at 200 nm.
  • pregabalin The optical purity of pregabalin was analyzed via a derivatization method.
  • a sample of pregabalin was derivatized with Marfey's reagent (1-fluoro-24-dinitrophenyl-5-L-alanine amide) and then analyzed by HPLC (LUNA C 18 (2) column, 0.46 mm ⁇ 150 mm, 3 ⁇ m) using a mobile phase of aqueous NaPO 4 (20 nM, pH 2.0) and ACN (90:10 for 10 min, 10:90 for 3 min, 90:10 for 5 min), a flow rate of 1.2 mL/min, an injection volume of 10 ⁇ L, column temperature of 35° C., and detection at 200 nm.
  • a reactor (16000 L) equipped with overhead stirring is charged with calcium acetate (254 kg), deionized water (1892.7 kg) and LIPOZYME® TL 100 L (food grade LIPOLASE®, 983.7 kg).
  • (R/S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (Formula 20, 9000 kg, 85% purity assay) is charged and the mixture is stirred for 24 h.
  • NaOH (2068 kg of a 30% solution) is added over the course of the reaction to maintain the pH at 7.0.
  • the extent of reaction is monitored by HPLC (C 18 column, 4.6 mm ⁇ 150 mm, detection at 200 nm).
  • a reactor (16000 L) equipped with overhead stirring is charged with the final aqueous solution from Example 10 (9698.6 L, containing (3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid sodium salt, Formula 23), NaCl (630 kg) and toluene (900 L).
  • the mixture is stirred for 2 h under refluxing conditions (75-85° C.).
  • the stirring is stopped; the organic phase is immediately separated and the aqueous phase is washed twice with toluene (900 L).
  • the organic layers, which contain (S)-3-cyano-5-methyl-hexanoic acid ethyl ester (Formula 24) are combined and concentrated.
  • the ethyl ester (Formula 24) is subsequently hydrolyzed in accordance with Example 12.
  • a hydrogenator (12000 L) is charged with water (942.1 L) and with the reaction mixture from Example 12, which contains (S)-3-cyano-5-methyl-hexanoic acid potassium salt (Formula 26,4122.9 L).
  • a Raney nickel suspension (219.6 kg, 50% w/w in H 2 O) is added. The hydrogenation is conducted under 50 psig at 35° C. After 6 h, the Raney nickel is filtered and the resulting filtrate is transferred to a reactor (16000 L) for crystallization. After adding H 2 O (1098 L), the pH of the solution is adjusted to 7.0-7.5 using HOAc (864.7 kg). The resulting precipitate is filtered and washed once with H 2 O (549 L) and twice with IPA (2,586 L each).
  • the solid is recrystallized with IPA (12296 L) and H 2 O (6148 L). The mixture is heated to 70° C. and subsequently cooled to 4° C. After 5-10 h, the crystalline solid is filtered, washed with IPA (5724 L), and dried in a vacuum oven at 45° C. for 24 h to give pregabalin as a white crystalline solid (1431 kg, 30.0% overall yield, 99.5% purity and 99.75% ee).
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