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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
  • C07C45/518—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of sulfur-containing compounds to >C = O groups
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/01—Sulfonic acids
  • C07C309/25—Sulfonic acids having sulfo groups bound to carbon atoms of rings other than six-membered aromatic rings of a carbon skeleton
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
  • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
  • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
  • C07C321/22—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of rings other than six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
  • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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  • 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
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
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  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• This invention relates to materials and methods for preparing chiral ketones, and more particularly, to the stereoselective synthesis of optically active 3,4- disubstituted cyclopentanones.
• the substituted cyclopentanones can be used to make various optically-active cyclic amino acids, which are useful for treating pain and a variety of psychiatric and sleep disorders.
• United States Patent No. US 6,635,673 Bl to Bryans et al. (the '673 patent) describes a number of optically-active cyclic amino acids and their pharmaceutically acceptable salts, including (3S,4S)-(l-aminomethyl-3,4-dimethyl- cyclopentyl)-acetic acid. These compounds bind to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of a calcium channel. They are useful for treating a number of diseases including insomnia, epilepsy, faintness attacks, hypokinesia, depression, anxiety, panic, pain, irritable bowel syndrome, and arthritis, among others.
• diseases including insomnia, epilepsy, faintness attacks, hypokinesia, depression, anxiety, panic, pain, irritable bowel syndrome, and arthritis, among others.
• the '673 patent describes a number of methods for preparing the optically- active cyclic amino acids. Many of these methods employ, as chemical intermediates, optically active 3,4-disubstituted cyclopentanones, including (5,5)-3,4-dimethyl- cyclopentanone. Although methods exist for preparing cyclopentanones, many of the processes may be problematic for pilot- or full-scale production because of efficiency and cost concerns or because the processes use non-commercial starting materials. See, e.g., U.S. Patent No. 6,872,856 to Blakemore et al. Thus, improved methods for preparing 3,4-disubstituted cyclopentanones would be desirable.
• This invention provides a comparatively efficient and cost-effective method for preparing optically active 3,4-disubstituted cyclopentanones (Formula 1, below) from commercially available starting materials.
• (S,S)-3,4- dimethyl-cyclopentanone may be prepared from (R)-2-methyl-succinic acid 4-methyl ester in five steps.
• the 3,4-disubstituted cyclopentanones can be used to prepare optically-active cyclic amino acids (Formula 14, below), such as (35,4.S)-(I- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, which are thought to be useful for treating pain, as well as various psychiatric and sleep disorders.
• optically-active cyclic amino acids such as (35,4.S)-(I- aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid
• One aspect of the present invention provides a method of making a compound of Formula 1,
• R 1 and R 2 are each independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloalkyl-C 1-3 alkyl, C 3-6 cycloalkenyl-d- 3 alkyl, or aryl-Ci. 3 alkyl, wherein aryl may be optionally substituted with from one to three substituents selected from d- 6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, carboxy, hydroxy, halogeno, fluoro-d-6 alkyl, and nitro, the method comprising: hydrolyzing one or more compounds of Formula 13,
• R and R in Formula 13 are as defined above for Formula 1, and R 5 and R 6 are each independently hydrogen, methylsulfanyl, methylsulfinyl, oxysulfonyl anion, hydroxy, or absent, provided that R 5 and R 6 are different.
• Another aspect of the present invention provides a method of making the compound of Formula 1, above, or an opposite enantiomer thereof, and includes the step of removing an ester moiety from a compound of Formula 18,
• R 1 and R 2 in Formula 18 are as defined above for Formula 1, and R 7 is independently selected from the substituents that define R 1 and R 2 in Formula 1.
• Another aspect of the present invention provides a method of making a compound of Formula 14,
• the method comprises the steps of (a) hydrolyzing one or more compounds of Formula 13, above, their opposite enantiomers, or their salts, to give the compound of Formula 1 or its opposite enantiomer; and (b) converting the compound of Formula 1 or its opposite enantiomer to the compound of Formula 14 or its opposite enantiomer, or to a pharmaceutically acceptable salt of the compound of Formula 14 or its opposite enantiomer.
• Another aspect of the present invention provides a method of making the compound of Formula 14, above, or its opposite enantiomer, or a pharmaceutically acceptable salt of the compound of Formula 14 or its opposite enantiomer.
• the method includes the steps of (a) removing an ester moiety from a compound of Formula 18, above, or its opposite enantiomer, to give a compound of Formula 1, above, or its opposite enantiomer; and (b) converting the compound of Formula 1 or its opposite enantiomer, to the compound of Formula 14 or its opposite enantiomer, or to a pharmaceutically acceptable salt of the compound of Formula 14 or its opposite enantiomer.
• Another aspect of the present invention provides compounds of Formula 13, above, such as (35,45)-l-methanesulfinyl-3,4-dimethyl-l- methylsulfanyl-cyclopentane, (3i?,4,S)-3,4-dimethyl-l-methylsulfanyl-cyclopentene, and (35,45)-l-hydroxy-3,4-dimethyl-cyclopentanesulfonate sodium salt, including opposite enantiomers of the foregoing compounds.
• compounds of Formula 13, above such as (35,45)-l-methanesulfinyl-3,4-dimethyl-l- methylsulfanyl-cyclopentane, (3i?,4,S)-3,4-dimethyl-l-methylsulfanyl-cyclopentene, and (35,45)-l-hydroxy-3,4-dimethyl-cyclopentanesulfonate sodium salt, including opposite enantiomers of the foregoing compounds.
• Another aspect of the present invention provides compounds of Formula 19,
• R 1 and R 2 are as defined above for Formula 1 and R 10 is independently selected from hydrogen atom and the groups that define R 1 and R 2 .
• Compounds of Formula 19 include (2i?,3S)-2,3-dimethyl-5-oxo- cyclopentanecarboxylic acid methyl ester, (lS,2i?,3S)-2,3-dimethyl-5-oxo- cyclopentanecarboxylic acid methyl ester, and (li?,2jR,35)-2,3-dimethyl-5-oxo- cyclopentanecarboxylic acid methyl ester, including opposite enantiomers of the foregoing compounds.
• Other compounds of Formula 19 include (2i?,35)-2,3- dimethyl-5-oxo-cyclopentanecarboxylic acid, (15,2i?,35)-2,3-dimethyl-5-oxo- cyclopentanecarboxylic acid, (l/?,2i?,35)-2,3-dimethyl-5-oxo-cyclo ⁇ entanecarboxylic acid, opposite enantiomers of the foregoing compounds, and salts of the foregoing compounds.
• Another aspect of the present invention provides compounds selected from (5,5)-3,4-dimethyl-hexanedioic acid, (S,5')-3,4-diethyl-hexanedioic acid, (S,S)-3,4- dipropyl-hexanedioic acid, (R,i?)-3,4-diisopropyl-hexanedioic acid, (S,S)-3,4- dibenzyl-hexanedioic acid, opposite enantiomers of the foregoing compounds, and salts of the foregoing compounds.
• the present invention includes all salts, whether pharmaceutically acceptable or not, complexes, solvates, hydrates, and polymorphic forms of the above compounds, where possible.
• the wavy bonds indicate a Z- isomer, an E-isomer, or a mixture of Z and E isomers.
• Some formulae may include a dashed bond "zzzzz" to indicate a single or a double bond.
• 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, i-propyl, ra-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2- trimethyleth-1-yl, and n-hexyl.
• 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, and l,3-butadien-2-yl.
• 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 ethynyl, 1-propyn-l-yl, 2-propyn- 1-yl, 1-butyn-l-yl, 3-butyn-l-yl, 3-butyn-2-yl, and 2-butyn-l-yl. [0020] "Alkanoyl” refers to alkyl-C(O)-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon. Examples of alkanoyl groups include formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl.
• alkoxy and alkoxycarbonyl refer, respectively, to alkyl-O- and alkyl- OC(O)-, where alkyl is defined above.
• alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, rc-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s- pentoxy.
• alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, w-propoxycarbonyl, z-propoxycarbonyl, w-butoxycarbonyl, s- butoxycarbonyl, t-butoxycarbonyl, rc-pentoxycarbonyl, and s-pentoxycarbonyl.
• Halo “Halo,” “halogen” and “halogeno” may be used interchangeably, and refer to fluoro, chloro, bromo, and iodo.
• Haloalkyl refers to an alkyl group substituted with one or more halogen atoms, where alkyl is defined above.
• haloalkyl groups include trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
• 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 alkyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino.
• Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Examples of bicyclic cycloalkyl groups include bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0] ⁇ entyl, 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, ⁇ 006/002060
• 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 alkyl, alkenyl, alkynyl, 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, and 3- cyclohexenoyl.
• 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, and 3-cyclohexenoxy.
• cycloalkoxycarbonyl groups include cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, cyclohexoxycarbonyl, l-cyclobutenoxycarbonyl, 2- cyclobutenoxycarbonyl, l-cyclopentenoxycarbonyl, 2-cyclopentenoxycarbonyl, 3- cyclopentenoxycarbonyl, 1-cyclohexenoxycarbonyl, 2-cyclohexenoxycarbonyl, and S-cyclohexenoxycarbonyl.
• 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, and pyrimidinyl.
• Aryl and arylene groups also include bicyclic groups and tricyclic groups, 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, and indolizinyl.
• They aryl and arylene groups may be attached to another group at any ring atom, unless such attachment would violate valence requirements.
• the aryl and arylene groups may include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
• Useful substituents include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, and halo, as defined above, and hydroxy, mercapto, nitro, amino, and alkylamino.
• Heteroaryl and “heteroarylene” refer, respectively, to monovalent and divalent aryl and arylene groups, as defined above, which contain at least one heteroatom.
• 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.
• the monocyclic and bicyclic groups have ring members made up of carbon atoms and from 1 to 4 or from 1 to 6 heteroatoms, respectively, 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 another group 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, 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
• Arylalkyl and “heteroarylalkyl” refer, respectively, to aryl-alkyl and heteroaryl-alkyl, where aryl, heteroaryl, and alkyl are defined above. Examples include benzyl, fluorenylmethyl, and imidazol-2-yl-methyl.
• 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 a product having an excess of one stereoisomer, enantiomer, or diastereoisomer, which comprises at least about 90% of the product.
• a high level of enantioselectivity or diastereoselectivity would correspond to an ee or de of at least about 80%.
• Steps of the invention refer, respectively, to a sample of a compound that has more of one stereoisomer, enantiomer or diastereomer than another.
• the degree of enrichment may be measured by % of total product, or for a pair of enantiomers or diastereomers, by ee or de.
• substantially pure stereoisomer refers, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 95% of the sample.
• a substantially pure enantiomer or diastereomer would correspond to samples having an ee or de of about 90% or greater.
• a "pure stereoisomer,” “pure enantiomer,” “pure diastereomer,” and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, which comprises at least about 99.5% of the sample.
• a pure enantiomer or pure diastereomer would correspond to samples having an ee or de of about 99% or greater.
• Optesite enantiomer refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all of the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R 1 9 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 (ZfE) of the compound.
• ZfE 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 RJR,E configuration.
• solvent molecules e.g., EtOH, acetone, water.
• 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, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended 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, and aldehydes, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).
• 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 may be carried out at about RT, but particular reactions may require the use of higher (e.g., up to reflux) or lower temperatures (e.g., 0°C or less), depending on reaction kinetics, yields, and other considerations.
• polar protic solvents e.g., water, MeOH, EtOH, PrOH, i-PrOH, formic acid, HOAc, formamide
• polar aprotic solvents e.g., acetone, THF, MEK, EtOAc, ACN, DMF, DMSO
• non-polar solvents e.g., hexane, benzene, toluene, diethyl ether, MeCl 2 , MeCl 3 , CCl 4 ); or some combination of these.
• Any reference in the disclosure to a range, including a concentration range, a temperature range, and a pH range includes the indicated endpoints.
• R and R in Formula 1 may include C 1-6 alkyl, such as Me, Et, Pr, i-Pr, n-Bu, s-Bu, t-Bu, as well as aryl-C 1-3 alkyl, such as Bn.
• Representative 3,4-disubstituted cyclopentanones thus include (5,5)-3,4-dimethyl-cyclopentanone, (5,5)-3,4-diethyl-cyclopentanone, (5,5)-3,4-dipropyl-cyclopentanone, (R,R)-3,4- diisopropyl-cyclopentanone, and (S,,S)-3,4-dibenzyl-cyclo ⁇ entanone, including their opposite enantiomers, (jR,jR)-3,4-dimethyl-cyclopentanone, (i?,i?)-3,4-diethyl- cyclopentanone, (i?,/?)-3,4-dipropyl-cyclopentanone, (5,S)-3,4-diisopropyl- cyclopentanone, and (i?,/?)-3,4-dibenzyl-cyclopentanone.
• Scheme I shows a method for preparing the chiral cyclopentanones (Formula 1) and their opposite enantiomers.
• the method includes reacting an optically active, 2-substituted succinic acid monoester or succinamic acid (Formula 2) with an alkylating agent (Formula 3) to give a 2,3-disubstituted succinic acid monoester or succinamic acid (Formula 4). Reduction of the disubstituted monoester gives a diol (Formula 5), which is subsequently activated via reaction with, e.g., a sulfonylating agent (Formula 8).
• the resulting activated diol (Formula 9) is cyclized via bisalkylation with FAMSO. Hydrolysis of the resulting thioketal S-oxide (Formula 10) yields the desired cyclopentanone (Formula 1).
• R 1 and R 2 in Formula 2-5, 9, and 10 are as defined above for Formula 1;
• R 3 in Formula 2 and 4 is R 1 O- or amino;
• R 4 in Formula 8 and 9 is a C 1-6 alkylsulfonyl ⁇ e.g., mesyl), a fluoro- C 1-6 alkylsulfonyl (e.g., triflyl), or an arylsulfonyl (e.g., tosyl, brosyl, closyl, and nosyl);
• X 1 in Formula 3 and X 2 in Formula 8 are leaving groups (e.g., halogeno, R 4 O-).
• Representative R 1 and R 2 in Formula 2-5, 9, and 10 include C 1-6 alkyl and aryl-Ci- 3 alkyl, and representative R 3 in Formula 2 include amino, C 1-6 alkoxy, such as methoxy, ethoxy, n-propoxy, i-propoxy, and t-butoxy, and aryl-Ci -3 alkoxy, such as benzoxy.
• Useful starting materials thus include ( J R)-2-methyl-succinic acid 4-methyl ester, (i?)-2-methyl-succinic acid 4-ethyl ester, (jR)-2-methyl-succinic acid 4-propyl ester, (/?)-2-methyl-succinic acid 4-isopropyl ester, (i?)-2-methyl- succinic acid 4-tert-butyl ester, (/?)-2-methyl-succinamic acid, (i?)-2-ethyl-succinic acid 4-methyl ester, (2?)-2-ethyl-succinic acid 4-ethyl ester, (l?)-2-ethyl-succinic acid 4-propyl ester, (i?)-2-ethyl-succinic acid 4-isopropyl ester, (i?)-2-ethyl-succinic acid 4- tert-butyl ester, and (7?)-2-ethyl-succinamic acid
• representative 2,3-disubstituted succinic acid monoesters or succinamic acids thus include (i?,i?)-2,3-dimethyl-succinic acid 4-methyl ester, (/?,i?)-2,3-diethyl-succinic acid 4-methyl ester, (i?,i?)-2,3-dipropyl-succinic acid 4-methyl ester, (i?, J R)-2,3-diisopropyl-succinic acid 4-methyl ester, (R,R) ⁇ 2,3- dibenzyl-succinic acid 4-methyl ester, (2?,i?)-2,3-dimethyl-succinic acid 4-ethyl ester, (i?,/?)-2,3-diethyl-succinic acid 4-ethyl ester, (i?,i?)-2,3-dipropyl-succinic acid 4-ethyl ester, (i?,i?)
• Suitable bases include those that are capable of deprotonating the methylene group that is adjacent ( ⁇ ) to the ester or amide moiety (Formula 2). These include non- nucleophilic or hindered bases, including lithium amide bases, such as LDA, LHMDS, KHMDS, LICA, LTMP, LiNEt 2 , lithium dicyclohexylamide, and corresponding magnesium amide bases, such as (J-Pr) 2 NMgCl and Et 2 NMgCl.
• lithium amide bases such as LDA, LHMDS, KHMDS, LICA, LTMP, LiNEt 2 , lithium dicyclohexylamide, and corresponding magnesium amide bases, such as (J-Pr) 2 NMgCl and Et 2 NMgCl.
• the lithium and magnesium amide bases may be represented by LiNR 1 R 2 and R 1 R 2 NMgX 3 , respectively, where R 1 and R 2 are as defined above for Formula 1 and X 3 is halogeno.
• Compatible solvents include those whose conjugate acids have pKa's less than or equal to 9, typically less than or equal to 4, and often less than or equal to 1. Such solvents include, e.g., THF, Et 2 O, DMSO, ACN, DMF, and acetone, but do not include ammonia.
• the alkylating agent (Formula 3) includes a leaving group (X 1 ), which may include halo substituents, Cl, Br, and I, and sulfonate substituents, such as toluene-p-sulfonate, methylsulfonate, p-bromo-benzene-sulfonate, and triflate.
• X 1 a leaving group
• sulfonate substituents such as toluene-p-sulfonate, methylsulfonate, p-bromo-benzene-sulfonate, and triflate.
• Representative alkylating agents thus include Ci -S alkyl halides, such as MeCl, MeBr, MeI, EtCl, EtBr, EtI, n-PrCl, n-PrBr, rc-Prl, z-PrCl, HPrBr, and z-Prl, and C 1-6 alkylsulfonate esters, such as, MeOTs, MeOMs, MeOBs, MeOTf, EtOTs, EtOMs, EtOBs, EtOTf, n-PrOTs, n-PrOMs, n-PrOBs, n-PrOTf, /-PrTs, z-PrMs, i- PrBs, and J-PrTf.
• the alkylating agents may be obtained from commercial sources or may be prepared using known methods.
• the alkylation reaction may employ stoichiometric amounts of the reactants (i.e., molar ratio of the 2-substituted succinic acid monoester or succinamic acid to the alkylating agent of 1:1), but to improve conversion, minimize side- products, and so on, the alkylation step may employ an excess of one of the reactants (e.g., molar ratio of 1:1.1 to 1.1:1, 1:1.5 to 1.5:1, 2:1 to 1:2, 3:1 to 1:3).
• the reactants i.e., molar ratio of the 2-substituted succinic acid monoester or succinamic acid to the alkylating agent of 1:1
• the alkylation step may employ an excess of one of the reactants (e.g., molar ratio of 1:1.1 to 1.1:1, 1:1.5 to 1.5:1, 2:1 to 1:2, 3:1 to 1:3).
• the alkylation reaction may employ stoichiometric amounts of base (i.e., base to substrate molar ratio of 2: 1), but may also employ an excess of base (e.g., molar ratio of 2.1 : 1 , 2.5:1, 3:1).
• base i.e., base to substrate molar ratio of 2: 1
• excess of base e.g., molar ratio of 2.1 : 1 , 2.5:1, 3:1.
• the alkylation may be run at temperatures of about -30°C to reflux.
• the reaction is typically carried out at RT, but may benefit from higher or lower temperatures.
• the reaction mixture may be cooled to a temperature of about -30°C to about -25°C during addition of the starting material (Formula 2) to the base and subsequent addition of the alkylating agent (Formula 3).
• the resulting mixture may then be allowed to react at RT until complete.
• the contacting scheme may influence the yield.
• subsurface addition of the starting material (Formula 2) and the alkylating agent (Formula 3) may increase the de of the ⁇ ntz-diastereomer (Formula 3) when compared to above-surface reactant addition.
• the disubstituted succinic acid monoester (Formula 4) is reduced to a diol (Formula 5) via reaction with LAH in one or more ethereal (absolute) solvents, such as THF, MTBE, and Et 2 O.
• ethereal solvents such as THF, MTBE, and Et 2 O.
• Other useful reducing agents and solvents include NaBH 4 and AlCl 3 in diglyme; B 2 Hg in THF; 9-BBN in THF; LiAlH(OMe) 3 in THF; AlH 3 in THF; DIBAL-H in THF; and Red-Al in toluene or THF.
• the reaction normally employs a molar excess of the reducing agent (e.g., greater than 4 eq of LAH) and is run at a temperature ranging from about RT to reflux.
• the contacting scheme of the reduction workup may influence yield.
• a conventional (Fieser) workup following reduction using LAH — sequential addition of H 2 0, 15% NaOH aq, and H 2 O to the reaction mixture — may lead to processing difficulties when run at large (kg) scale.
• the initial water quench results in a rapid release of a large quantity of hydrogen gas and also traps a significant fraction of the product (Formula 5) in a solid byproduct.
• Some of the trapped product may be recovered by washing and filtering the solids, but the process is inefficient and time-consuming because much of the wash liquid flows around the filter cake rather than through it.
• the filter cake often cracks irreversibly. These cracks channel wash liquid away from the interior of the filter cake, which further reduces the effectiveness of the recovery process.
• the method optionally provides for conversion of the disubstituted succinic acid monoester or succinamic acid (Formula 4) into a diacid (Formula 6) or salt thereof, via acid or base hydrolysis of the ester or amide moieties.
• a diacid Formmula 6
• acid or base hydrolysis of the ester or amide moieties For example, treating the ester or amide with HCl or H 2 SO 4 and with excess H 2 O, 99 generates the diacid.
• succinic acid monoester or succinamic acid with an aqueous inorganic base, such as LiOH, KOH, NaOH, CsOH, Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 , in an optional polar solvent (e.g., THF, MeOH, EtOH, acetone, or ACN) gives a base addition salt of the diacid, which may be treated with an acid to generate the free diacid.
• an optional polar solvent e.g., THF, MeOH, EtOH, acetone, or ACN
• the resulting diacid (Formula 6) or a salt thereof is treated with acetic anhydride to give a cyclic anhydride (Formula 7).
• the reaction is ordinarily run in an aprotic polar solvent, such as THF, at a temperature ranging from about RT to reflux, though reaction temperatures ranging from about 50 0 C to about 75°C may be used.
• aprotic polar solvent such as THF
• Representative reaction substrates include(/?,/?)-2,3-dimethyl- succinic acid, (i?,/?)-2,3-diethyl ⁇ succinic acid, (i?,7?)-2,3-dipropyl-succinic acid, (R,R)- 2,3-diisopropyl-succinic acid, and (i?,7?)-2,3-dibenzyl-succinic acid, including salts thereof.
• Representative cyclic anhydrides include (/?,i?)-3,4-dimethyl- dihydro-furan-2,5-dione, (i?,i?)-3,4-diethyl-dihydro-furan-2,5-dione, (R,R)-3,4- dipropyl-dihydro-furan-2,5-dione, (R,R)-3 ,4-diisopropyl-dihydro-furan-2,5-dione, and (2?,i?)-3,4-dibenzyl-dihydro-furan-2,5-dione, including opposite enantiomers thereof.
• Preparation of the cyclic anhydride may provide advantages over direct reduction of the monoester or amide (Formula 4).
• the cyclic anhydride in contrast to the monoester, the cyclic anhydride is easily recrystallized and therefore can be isolated prior to reduction. Recrystallization of the cyclic anhydride appears to improve the efficiency of downstream isolation of the activated diol (Formula 9) by suppressing formation of mono-alkylated side-products and undesired diastereomers.
• the higher purity of crystalline cyclic anhydride should lead to improved throughput of the reduction step since the reducing agent (e.g., LAH) is not consumed by impurities or by the carboxylic acid moiety.
• the reducing agent e.g., LAH
• the diol (Formula 5) is activated via reaction with the compound of Formula 8.
• Useful diols include (jR,R) ⁇ 2,3-dimethyl-butan-l,4-diol, (i?,7?)-2,3-diethyl-butan-l ,4-diol, (i?,i?)-2,3-dipropyl-butan-l ,4-diol, (RJR)-2,3- diisopropyl-butan-l,4-diol, and (i?,R)-2,3-dibenzyl-butan-l,4-diol, including opposite enantiomers thereof.
• Useful compounds of Formula 8 include sulfonylating agents, such as TsCl, MsCl, BsCl, NsCl, and TfCl, and their corresponding anhydrides (e.g., p-toluenesulfonic acid anhydride).
• sulfonylating agents such as TsCl, MsCl, BsCl, NsCl, and TfCl
• anhydrides e.g., p-toluenesulfonic acid anhydride
• Compounds of Formula 5 may be reacted with TsCl or MsCl in the presence of pyridine or Et 3 N and an aprotic solvent, such as ethyl acetate, MeCl 2 , ACN, or THF, to give, e.g., (i?,/?)-2,3-dimethyl-l,4-bis-(toluene-4-sulfonyloxy)- butane, (2?,/?)-2,3-diethyl- 1 ,4-bis-(toluene-4-sulf onyloxy)-butane, (i?,i?)-2,3-dipropyl- 1 ,4-bis-(toluene-4-sulfonyloxy)-butane, (i?,i?)-2,3-diisopropyl-l ,4-bis-(toluene-4- sulfonyloxy)-butane, (i?,
• the reaction is carried out with an excess (e.g., 2.5 eq or more) of the sulfonylating agent (Formula 8) and with an excess of the base (e.g., 3 eq or more) and at a temperature of about RT or less (e.g., about 0°C).
• an excess e.g., 2.5 eq or more
• an excess of the base e.g., 3 eq or more
• a temperature of about RT or less e.g., about 0°C
• the resulting activated intermediate (Formula 9) is cyclized via bisalkylation with FAMSO and a base that is strong enough to deprotonate the methylene moiety (pKa of FAMSO is 29 in DMSO); hydrolysis of the resulting thioketal S -oxide (Formula 10) with aqueous acid yields the desired cyclopentanone (Formula 1).
• the reaction is typically carried out in excess base (i.e., more than two molar equivalents of base).
• the activated intermediate (Formula 9) and thioketal S-oxide (Formula 10) are susceptible to base-induced degradation, which may reduce the yield of the desired cyclopentanone.
• the thioketal S-oxide may undergo base- induced degradation to a vinyl sulfide (Formula 11) shown in Scheme I.
• Such contact may be minimized by pre-mixing the base (e.g., 2.0 eq to 2.5 eq) with a substantially equimolar amount of FAMSO, so that the base is consumed before addition of the substrate (Formula 9). However, this wastes one molar equivalent of FAMSO.
• One way to address this difficulty is to add the base (e.g., 2.0 eq to 2.5 eq) to a mixture of the substrate (Formula 9) and a slight excess of FAMSO (e.g., 1.1 eq to 1.4 eq) over an extended period of time and at a temperature high enough so that the base is substantially consumed as it is being added.
• Useful bases include lithium amides, such as LHMDS (in THF), which are added over, e.g., 1 h, 2 h, 3 h, 4 h, 5 h, or more and are reacted at temperatures of about 10°C, 15°C, 20°C, 25°C, 3O 0 C, 35°C, 40 0 C or higher.
• Another way to address the yield loss associated with the vinyl sulfide is to convert the thioketal S-oxide (Formula 10) to the cyclopentanone (Formula 1) without first isolating it. Since the vinyl sulfide is volatile, it is apparently lost during workup and isolation of the thioketal S-oxide, thereby lowering the yield of the cyclopentanone.
• the crude product of the FAMSO bisalkylation any vinyl sulfide formed during cyclization is converted to the cyclopentanone during subsequent acid hydrolysis of the thioketal S-oxide.
• Representative thioketal S-oxides include (35,45)- l-methanesulfinyl-3,4-dimethyl-l- methylsulfanyl-cyclopentane, (3S,4S)-l-methanesulfinyl-3,4-diethyl-l- methylsulfanyl-cyclopentane, (3S,4S)-l-methanesulfinyl-3,4-dipropyl-l- methylsulfanyl-cyclopentane, (3S,4S)-l-methanesulfinyl-3,4-diisopropyl-l- methylsulf anyl-cyclopentane, and (3 S, 4S)- 1 -methanesulf inyl-3 ,4-dibenzyl- 1 - methylsulfanyl-cyclopentane, including opposite enantiomers thereof.
• Representative vinyl sulfides include (37?,45)-3,4-dimethyl-l-methylsulfanyl-cyclopentene, (3R,4S)- 3,4-diethyl-l-methylsulfanyl-cyclopentene, (3i?,45)-3,4-dipropyl-l-methylsulfanyl- cyclopentene, (37?,4i?)-3,4-diisopro ⁇ yl-l-methylsulfanyl-cyclopentene, and (3R,4S)- 3,4-dibenzyl-l-methylsulfanyl-cyclopentene, including opposite enantiomers thereof.
• the method optionally includes conversion of the cyclopentanone (Formula 1) to a bisulfite adduct (Formula 12).
• the desired cyclopentanone (Formula 1) is a liquid, which is difficult to purify by distillation because of the presence of impurities having comparable boiling points.
• Reaction of the cyclopentanone (Formula 1) with a source of NaHSO 3 at a temperature of about O 0 C to about RT gives the bisulfite addition compound (Formula 12) as a crystalline solid.
• Representative bisulfite adducts include sodium salts of (S,,S)-1 -hydroxy-3, 4- dimethyl-cyclopentanesulfonate, (S 3 S)- l-hydroxy-3,4-diethyl-cyclopentanesulfonate, (S, S)- 1 -hydroxy-3 ,4-dipropyl-cyclopentanesulf onate, (S, S)- 1 -hydroxy-3 ,4- diisopropyl-cyclopentanesulf onate, and (S, S)- 1 -hydroxy-3 ,4-dibenzyl- cyclopentanesulfonate, including opposite enantiomers thereof.
• Scheme II shows an additional method for preparing the chiral cyclopentanones (Formula 1) and their opposite enantiomers.
• the method includes oxidizing a chiral 4,5-disubstituted cyclohexene (Formula 15) to give an optically active adipic acid derivative (Formula 16).
• the diacid (Formula 16) or its salt is reacted with an alcohol (R 7 OH) in the presence of an acid to give an optically active diester (Formula 17), which is subsequently treated with a base to provide a cyclopentanone carboxylic acid ester (Formula 18).
• the chiral cyclohexene (Formula 15) may be oxidized via treatment with aq H 2 O 2 in the presence of a catalyst at temperatures ranging from about 50°C to about 95°C or from about 75°C to about 9O 0 C.
• the hydrogen peroxide concentration of the aq H 2 O 2 solution may vary from about 30% to about 60%, based on weight, and the molar ratio of hydrogen peroxide to chiral cyclohexene may be about 4:1 or greater.
• Useful catalysts include sodium tungstate (Na 2 WO 4 ) together with a phase transfer catalyst, such as Me(W-OcIyI) S N + HSO 3 " , which may be present in molar ratios of about 1:1.
• Other useful catalysts include molecular sieves, such as those based on TAPO-5.
• the molar ratio of the chiral cyclohexene to each catalyst generally ranges from about 10:1 to about 1000:1 (e.g., about 100:1).
• oxidation catalysts see K. Sato et al., Science 281: 1646 (1998) and references cited therein; see also, S. Lee, Angew. Chem. Int. Ed. 42:1520 (2003) and references cited therein.
• Representative compounds of Formula 15 include (5,5)-4,5-dimethyl- cyclohexene, ( ⁇ S,S)-4,5-diethyl-cyclohexene, (5,5)-4,5-dipropyl-cyclohexene, (R,R)- 4,5-diisopropyl-cyclohexene, ( J R,i?)-4,5-dibenzyl-cyclohexene, and opposite enantiomers thereof.
• Representative compounds of Formula 16 thus include (S 5 S)- 3,4-dimethyl-hexanedioic acid, (S,S)-3,4-diethyl-hexanedioic acid, (S,S)-3,4-dipropyl- hexanedioic acid, (2?,/?)-3,4-diisopropyl-hexanedioic acid, (S,S)-3,4-dibenzyl- hexanedioic acid, and opposite enantiomers thereof.
• the resulting diacid (Formula 16) undergoes acid catalyzed esterification at temperatures ranging from about RT to reflux.
• the reaction generally employs excess alcohol (R 7 OH) since it may also serve as the solvent.
• the reaction also utilizes catalytic amounts (e.g., about 0.05 eq to about 0.5 eq) of the acid, based on the amount of the substrate (Formula 16).
• Useful acid catalysts include strong acids having a pKa of about 1 or less, including inorganic acids, such as H 2 SO 4 , HCl, HBr, HI, HNO 3 , and organic acids, such as TFA and TCA.
• Substituent R 7 of the alcohol, the diester (Formula 17), and the cyclopentanone carboxylic acid ester (Formula 18) is independently selected from the substituents that define R and R in Formula 1.
• Representative alcohols include MeOH, EtOH, PrOH, and BnOH.
• Representative compounds of Formula 17 thus include C 1-6 alkyl or aryl-C 1-3 alkyl diesters (e.g., dimethyl, diethyl, dipropyl, and dibenzyl esters) of (S,S)-3,4-dimethyl-hexanedioic acid dimethyl ester, (S,S)-3,4- diethyl-hexanedioic acid, (S,S)-3,4-dipropyl-hexanedioic acid, (i?,i?)-3,4-diisopropyl- hexanedioic acid, (S,S)-3,4-dibenzyl-hexanedioic acid, and opposite enantiomers thereof.
• C 1-6 alkyl or aryl-C 1-3 alkyl diesters e.g., dimethyl, diethyl, dipropyl, and dibenzyl esters
• the diester (Formula 17) is cyclized via treatment with a strong base to give a cyclopentanone carboxylic acid ester (Formula 18).
• the reaction is typically carried out in a polar aprotic solvent, such as THF, with a molar excess of base (e.g., about 1.1 to about 1.5 eq), and at a temperature which may range from about RT to reflux.
• Suitable bases include those which are strong enough to deprotonate a methylene group which is located adjacent ( ⁇ ) to one of the ester moieties (Formula 17), and include t-BuOK and t-BuONa.
• Representative compounds of Formula 18 include C 1-6 alkyl or 8TyI-C 1-3 alkyl esters (e.g., methyl, ethyl, propyl, and benzyl esters) of (lS/i?,2i?,3S)-2,3-dimethyl-5-oxo- cyclopentanecarboxylic acid, (15/i?,2 J R,3S')-2,3-diethyl-5-oxo-cyclopentanecarboxylic acid, (lS/i?,2R,3S)-2,3-di ⁇ ro ⁇ yl-5-oxo-cyclo ⁇ entanecarboxylic acid, (1S/R,2R,3R)- 2,3-diisopropyl-5-oxo-cyclopentanecarboxylic acid, (li?/5,2/?,3>S)-2,3-dibenzyl-5-oxo- cyclopentanecarboxylic acid, and
• the ester moiety of the cyclopentanone carboxylic acid ester (Formula 18) is removed to give the desired chiral cyclopentanone (Formula 1).
• the ester moiety may first be hydrolyzed via treatment with an aqueous base or acid to give a corresponding acid (Formula 19, above), which is subsequently decarboxylated under acidic conditions by heating (e.g., 45°C to reflux) to give the compound of Formula 1.
• Hydrolysis may be carried out using conditions described above in connection with the conversion of the succinic acid monoester (Formula 4) to the diacid (Formula 6).
• the ester moiety may be removed via Krapcho dealkoxycarbonylation, which involves heating the cyclopentanone carboxylic acid ester (Formula 18) in a dipolar aprotic solvent at a temperature of about 90°C to about 200°C or from about 120 0 C to about 160°C, in the presence of water or a salt or both.
• Useful dipolar aprotic solvents include DMSO and DMF; useful salts include LiCl, NaCl, LiI, NaCN, and KCN.
• Scheme m shows a method for converting the chiral cyclopentanone (Formula 1) to a compound of Formula 14.
• the method includes reacting the cyclopentanone (Formula 1) with a phosphono-acetic acid ester (Formula 20) to give an enoate ester (Formula 21). Addition of nitromethane yields a nitro ester (Formula 22), which upon reduction, cyclizes to furnish a lactam (Formula 23). Hydrolysis of the lactam gives the desired cyclic amino acid (Formula 14).
• Substituents R 1 and R 2 in Formula 14 and 21-23 are as defined above for Formula 1; substituent R 8 in Formula 20 and substituent R 9 in Formula 20-22 are each independently selected from the same groups as substituent R 1 and R 2 in Formula 1 and from C 1-6 haloalkyl.
• the Horner-Emmons reaction shown in Scheme IH may be carried out by reacting the phosphono-acetic acid ester (Formula 20) with a base at a temperature of about -10°C to about 25°C or about 10°C to about 22 0 C.
• the resulting enolate anion is subsequently contacted with the chiral cyclohexanone (Formula 14) at a temperature of about -2O 0 C to about 2O 0 C or about 0 0 C to about 15 0 C, and the reaction mixture is stirred at a temperature of about 10 0 C to about 30 0 C or about 1O 0 C to about 20 0 C.
• Useful bases include alkoxides (e.g., t-BuOK, t-BuOLi, t-BuONa), NaH, and LDA.
• Representative R 8 and R 9 in Formula 20-22 include C 1-6 alkyl and C 1-6 haloalkyl.
• Useful phosphono-acetic acid esters thus include di- C 1-6 alkylphosphono-acetic acid C 1-6 alkyl esters, such as trimethyl phosphonoacetate and triethyl phosphonoacetate, and di-Q- 6 haloalkylphosphono-acetic acid C 1-6 alkyl esters, such as bis(2,2,2-trifluoroethyl)phosphono-acetic acid methyl ester.
• representative enoate esters include (5,5)-(3,4-dimethyl- cyclopentylidene)-acetic acid methyl ester, (S,S)-(3,4-dimethyl-cyclopentylidene)- acetic acid ethyl ester, (5, ⁇ S)-(3,4-diethyl-cyclopentylidene)-acetic acid methyl ester, (S,5)-(3,4-diethyl-cyclopentylidene)-acetic acid ethyl ester, (5,S)-(3,4-dipropyl- cyclopentylidene)-acetic acid methyl ester, and (5,5)-(3,4-dibenzyl-cyclopentylidene)- acetic acid ethyl ester, including opposite enantiomers thereof.
• the enoate ester (Formula 21) is converted to the nitroester (Formula 22) via conjugate addition.
• the Michael addition is typically carried out at a temperature which may range from about RT to reflux.
• the reaction generally employs excess nitromethane and catalytic amounts of base (e.g., about 0.05 eq to about 0.5 eq) based on the amount of substrate (Formula 21).
• Useful catalysts include bases that are strong enough to deprotonate the methyl group of nitromethane, which may include inorganic bases, such as CS 2 CO 3 , K 2 CO 3 , and Na 2 CC> 3 , and organic bases, such as DBU and tetramethyl guanidine.
• inorganic bases such as CS 2 CO 3 , K 2 CO 3 , and Na 2 CC> 3
• organic bases such as DBU and tetramethyl guanidine.
• Representative nitroesters include (3S,4,S)-(3,4-dimethyl ⁇ l- nitromethyl-cyclopentyl)-acetic acid methyl ester, (35,4S)-(3,4-dimethyl-l- nitromethyl-cyclopentyl)-acetic acid ethyl ester, (35,45)-(3,4-diethyl-l-nitromethyl- cyclopentyl)-acetic acid methyl ester, (35,4!S)-(3,4-diethyl-l-nitromethyl- cyclopentyl)-acetic acid ethyl ester, (35,45)-(3,4-dipropyl-l-nitromethyl-cyclopentyl)- acetic acid ethyl ester, and (35,45)-(3,4-dibenzyl-l-nitromethyl-cyclopentyl)-acetic acid ethyl ester, including opposite enantiomers
• the nitroester (Formula 22) is reduced and cyclized in situ by treatment with a reducing agent to furnish the lactam (Formula 23).
• the reaction is typically performed in an alcoholic solvent, such as MeOH or z-PrOH, with a metal catalyst in the presence of hydrogen gas at pressures ranging from atmospheric to 250 psig, and at a temperature ranging from about RT to reflux.
• Useful metal catalysts include sponge nickel.
• the reaction can be ran in a conventional "batch mode" in which the catalyst and substantially all of the substrate (Formula 22) are first charged to a reaction vessel and hydrogen gas is subsequently added to effect conversion.
• the reaction may be carried out in a "semi- batch" mode to reduce side products and to increase yield.
• QI catalyst and hydrogen are present in the vessel at the beginning of the reaction, and the nitroester (Formula 22) is subsequently fed to the reactor at a rate comparable to the rate of reduction.
• hydrogen gas is also added to the reaction vessel during reduction of the nitro group. See Examples 53 and 54, below.
• the lactam (Formula 23) shown in Scheme HI may be hydrolyzed via treatment with acid at temperatures ranging from about RT to about reflux or from about 80°C to about 95 0 C to furnish the desired amino acid (Formula 14) or its salt.
• the acid concentration may vary from about 1% to about 50%, and the molar ratio may vary from about 1:1 to about 10:1.
• Useful acids include inorganic acids, such as HCl, H 2 SO 4 , HBr, HI, and HNO 3 , and organic acids, such as TFA and TCA.
• Representative lactams include (75,85)-7,8-dimethyl-2-aza- spiro[4.4]nonan-3-one, (75,8S)-7,8-diethyl-2-aza-spiro[4.4]nonan-3-one, (7S,8S)-7,8- dipropyl-2-aza-spiro[4.4]nonan-3-one, and (75,85)-7,8-dibenzyl-2-aza- spiro[4.4]nonan-3-one, including opposite enantiomers thereof.
• representative amino acids include (3S,4S)-(l-aminomethyl-3,4- dimethyl-cyclopentyl)-acetic acid, (3S,4S)-(l-aminomethyl-3,4-diethyl-cyclopentyl)- acetic acid, (3S,4S)-(l-aminomethyl-3,4-dipropyl-cyclopentyl)-acetic acid, and (3S,4S)-(l-aminomethyl-3,4-dibenzyl-cyclopentyl)-acetic acid, including opposite enantiomers thereof.
• Some of the compounds described in this disclosure are capable of forming pharmaceutically acceptable salts. These 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, and phosphorous, 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.
• 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, and methanesulfonate.
• 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+ ), and calcium cations (Ca 2+ ).
• suitable amines include N ⁇ /V'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, iV-methylglucamine, and procaine.
• S. M. Berge et al. "Pharmaceutical Salts," 66 J. ofPharm. ScL, 1-19 (1977); see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).
• Disclosed and claimed compounds may exist in both unsolvated and solvated forms and as other types of complexes besides salts.
• Useful complexes include clathrates orcompound-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 ⁇ -acetone, d 6 - DMSO.
• references to an unsolvated form of a compound also include the corresponding solvated or hydrated form of the compound.
• Some of the compounds disclosed in this specification may contain an asymmetric carbon, sulfur or phosphorus atom (a stereogenic center) and therefore may exist as an optically active stereoisomer (i.e., one enantiomer of a pair of enantiomers). Some of the compounds may also contain an alkenyl or cyclic group, so that cisltrans (or ZIE) stereoisomers (diastereoisomers) are possible. Still other compounds may contain two or more stereogenic centers so that diastereoisomers are possible, each of which may be optically active (i.e., comprise one enantiomer of a pair of enantiomers).
• some of the compounds may contain a keto or oxime group, so that tautomerism may occur.
• the scope of the present disclosure includes all tautomers and all stereoisomers, including enantiomers, diastereoisomers, and ZIE isomers, whether they are pure, substantially pure, or mixtures.
• Desired enantiomers of any of the compounds disclosed herein may be further enriched through classical resolution, chiral chromatography, or recrystallization.
• a mixture of enantiomers 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 may be further enriched by recrystallization in a suitable solvent when the enantiomer is 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).
• a suitable solvent e.g., typically not much less than about 85 % ee, and in some cases, not much less than about 90 % ee.
• 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.
• Use of isotopic variations e.g., deuterium, 2 H
• certain 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.
• the mixture was warmed to -10 0 C, stirred for 1 h, cooled back to -3O 0 C, and treated with a solution of methyl iodide (25.12 g, 0.1770 mol, 1.06 eq) in THF (25 mL) at a rate such that the temperature did not exceed -25°C (1.5 h).
• the aqueous layer was acidified with 6N HCl to pH 1.92 and extracted with MTBE (4 x 150 mL). The aqueous layer (about pH 3) was discarded. The organic extracts were combined and vacuum concentrated to a dark amber oil identified as the above-titled compound by 13 C-NMR and 1 H-NMR. The ratio of anti/syn/monomethyl was determined to be 88.5:7.8:3.7 by GC.
• the resulting thin slurry was treated drop wise with a solution of LHMDS in THF (Chemetall Foote Corp.; 205 mL of 1.28 M solution, 0.2624 mol, 2.27 eq) over 3.5 hours.
• HPLC analysis revealed that the ratio of thioketal monoxide to ditosylate was 69.2:30.8 (normalized wt%). Stirring was continued for another 18 h, at which time the ratio was 97.7:2.3.
• the reaction mixture was quenched with water (10 mL).
• the resulting greenish solution was transferred to a graduated cylinder. The volume was 358 mL.
• the yield of thioketal monoxide was determined to be 79.1 chem% by HPLC.
• the greenish solution was diluted with saturated brine (110 mL) and water (56 mL).
• the lower aqueous was separated.
• the upper organic layer was shaken with saturated brine (50 mL) and water (10 mL).
• the lower aqueous layer was separated.
• the two aqueous layers were combined, diluted with water (100 mL) and extracted with MeCl 2 (125 mL).
• the volume of the aqueous was 368 mL.
• the organic phases were combined and concentrated (200 Torr; final pot temp 5O 0 C) to a final volume of about 100 mL then diluted with water (25 mL).
• the reaction mixture (40 0 C) was treated over about 15 min with 37% HCl (35 mL, 42 g, containing 15.54 g or 3.69 eq HCl). Over the course of the addition, the temperature increased to 56°C.
• the reaction mixture was diluted with water (100 mL) and vacuum steam distilled (pot temp 74°Ct o 104°C/200 Torr) to give a two-phase distillate. To insure that the azeotrope is completely condensed, -10 0 C EtOH was put on the condenser.
• the lower aqueous phase (85 mL) was extracted with MTBE (20 mL), which was combined with the upper organic phrase (95 mL).
• the combined organic layers (111 mL) were analyzed by GC and found to contain the above-titled ketone (0.876 M, 0.09724 mol, 84.1 chem%), MeCl 2 (1.44 area%), Me 3 SiOH (12.70 area%), THF (28.96 area%), (Me 3 Si) 2 O (34.23 area%), MeSSMe (4.58 area%), thioketal (0.12 area% or less), and water (1.185 wt% KF).
• the precipitate was removed by vacuum filtration at 55 0 C (4 min filtration time) and washed twice with a 55°C mixture of MTBE (330 mL) and MeOH (28 mL) (15 min filtration for each wash). The combined filtrates were dried on MgSO 4 , clarified and concentrated in vacuo to a light oil (47.43 g). Branched octanes (100 g) were added and the biphasic mixture seeded at 20 0 C to afford a slurry after stirring for 5 min. Branched octanes (200 g) were added and the mixture was cooled to 3°C.
• MeI was rinsed in with THF (15 mL). The mixture was stirred at -30 0 C for 2 h, warmed to 0 0 C, and stirred for 1 h.
• GC showed a mixture of (i?,/?)-2,3-dimethyl- succinic acid monomethyl ester, 78.8 area%, (i?)-2-methyl-succinic acid 4-methyl ester, 15.0 area%, and meso isomer, (jR,S)-2,3-dimethyl-succinic acid, 6.2 area%.
• the solution was cooled to 30°C and branched octanes (200 mL) and t-amyl alcohol (200 mL) were added.
• the product was allowed to crystallize after seeding, and branched octanes (200 mL) were added.
• MeI (136 kg, 0.96 kg-mol, 1.05 eq) is mixed with a 2 volumes of THF and fed subsurface to the reaction mixture, while maintaining the temperature of the reaction mixture at -25°C or less. The temperature is adjusted over 8 h to RT.
• NH 4 Cl (136 kg) is dissolved in water (400 L) and is fed slowly to the reactor vessel to quench the reaction. More water (550 L) is added with stirring and then the agitator is stopped to allow the phases to separate. The organic phase is discarded.
• the aqueous phase is acidified with a mixture of 37% HCl (300 kg) and water (250 L), and is extracted with MTBE (4 x 400 L). The MTBE phases are combined and distilled to yield the above-titled compound as an oil.
• Table 2 shows the yields of the desired anti-diastereomer, (jR,i?)-2,3- dimethyl-succinic acid monomethyl ester, and the undesired syn-diastereomer, (R,S)- 2,3-dimethyl-succinic acid monomethyl ester, using subsurface reactant addition.
• Table 2 also shows the yields of the two diastereomers using a process similar to that described in the preceding paragraph except that the reactants are added via above-surface addition.
• the agitator is then shut off, the aluminum hydroxide is allowed to settle for 10 min to 15 min, and the product is removed by decanting.
• the solids are washed with MTBE (3 x 600 L) to extract additional product.
• the organic liquids are collected and distilled to yield the above- titled compound.
• Table 3 shows yields of (i?,i?)-2,3-dimethyl-butan-l,4-diol via LAH reduction of (7?,i?)-2,3-dimethyl-succinic acid monomethyl ester using the workup described in the preceding paragraph (i.e., addition to excess base, Examples 24-28).
• Table 3 also shows yields of (i?,jR)-2,3-dimethyl-butan-l,4- diol using a Fieser workup — sequential addition of H 2 0, 15% NaOH aq, and H 2 O following LAH reduction.
• TABLE 3 Yield of (i?,R)-2,3-dimethyl-butan-l,4-diol via LAH reduction and addition to excess base (Examples 24-28) or Fieser workup (Examples 29 and 30)
• a reactor vessel is dry-charged with p-toluenesulfonyl chloride (400 kg, 2.14 kg-mol, 2.5 eq).
• Acetonitrile (1000 L) is subsequently added and the resulting slurry is cooled to O 0 C. (i?,/?)-2,3-Dimethyl-butan-l,4-diol (100 kg, 0.85 kg-mol, 1 eq) is added to the reactor.
• Et 3 N 260 kg, 2.5 kg-mol, 3 eq
• EtOAc 660 L
• water 640 L
• EXAMPLE 33 Degradation of thioketal S-oxide, (3S,4,S)-l-methanesulfinyl-3,4- dimethyl-1-methylsulfanyl-cyclo ⁇ entane, to vinyl sulfide, (32?,4S)-3,4-dimethyl-l- methylsulfanyl-cyclopentene, by LHMDS
• a reactor was charged with (i?,i?)-2,3-dimethyl-l,4-bis-(toluene-4- sulfonyloxy)-butane (368.8 kg, 0.8646 kg-mol), THF (600 L), and FAMSO (127.8 kg, 1.0288 kg-mol, 1.19 eq).
• the mixture was cooled to -3°C and treated with a solution of LHMDS in THF (Chemetall Foote Corp.; 1432 kg of 20 wt% solution, 286.4 kg, 1.712 kg-mol, 1.98 eq).
• the mixture was stirred at O 0 C for 1 h, then at 20°C for 10 h.
• the mixture was quenched with water (480 L), extracted with EtOAc (3 x 370 kg), and washed with water (340 L).
• the organic phases were distilled under vacuum to a volume of 200 L, diluted with THF (100 L) and MTBE (150 L), treated with 6N HCl (160 L, 0.960 kg-mol, 1.11 eq), stirred at 10°C for 19 h, and diluted with water (100 L).
• the lower aqueous layer was separated and extracted with MTBE (160 L).
• the organic phase was vacuum concentrated to a volume of 150 L, treated with water (240 L), and steam distilled to a final volume of 150 L.
• the lower aqueous layer in the receiver was separated.
• the upper phase was identified as the above-titled compound (52.3 wt% pure) by GC. Weight: 109.2 kg (57.11 kg, 0.5092 kg-mol, 58.9%).
• Table 4 lists yields (mol%) of (5,5)-3,4-dimethyl-cyclopentanone as a function of the temperature at which LHMDS is added to a mixture of (R,R)-2,3- dimethyl-l,4-bis-(toluene-4-sulfonyloxy)-butane and FAMSO. Examples 38-40 were carried out using the general procedure of Example 37; Examples 41-45 were carried out using the general procedure of Example 4.
• the reaction mixture was stirred at 21 0 C for 16 h.
• the reaction mixture was cooled to 5°C and quenched with water (200 mL).
• the aqueous layer was extracted with heptane (3 x 50 mL).
• the organic extracts were combined, concentrated to approximately 50 mL, diluted with heptane (120 mL), washed with water (3 x 50 mL), and concentrated to an oil.
• the resulting thin slurry was treated dropwise with a solution of lithium bis(trimethylsilyl)amide in THF (205 mL of 1.28 M solution, 0.2624 mol, 2.27 eq) over 3.5 hours. Stirring was continued for another 18 h. The reaction mixture was quenched with water (10 mL). The greenish solution was diluted with brine (110 mL) and water (56 mL). The lower aqueous layer was separated. The upper organic layer was shaken with brine (50 mL) and water (10 mL). The two aqueous layers were combined, diluted with water (100 mL), and extracted with methylene chloride (125 mL).
• the organic phases were combined and concentrated to a final volume of about 100 mL, then diluted with water (25 mL).
• the reaction mixture (40°C) was treated over about a 15 min period with 37% hydrochloric acid (35 mL, 42 g, 0.426 mol HCl).
• the reaction mixture was diluted with water (100 mL) and vacuum distilled to give a two-phase distillate.
• the lower aqueous layer (85 mL) was extracted with MTBE (20 mL), and the resulting aqueous phase was combined with the upper organic layer (95 mL).
• the reaction mixture was stirred at 21°C for 16 h.
• the reaction mixture was cooled to 5°C and quenched with water (200 mL).
• the aqueous layer was extracted with heptane (3 x 50 mL).
• the organic extracts were combined, concentrated to a volume of about 50 mL, diluted with heptane (120 mL), washed with water (3 x 50 mL), and concentrated under vacuum to an oil containing a drop of water.
• the mixture was diluted with heptane (100 mL) and distilled atmospherically.
• the initial fraction of distillate (about 15 mL) contained the drop of water.
• a 250 mL round bottom flask was evacuated with nitrogen and charged with cesium carbonate (6.3 g, 0.019 mol, 0.2 eq), dimethyl sulfoxide (87 mL), nitromethane (7.4 mL, 8.4 g, 0.137 mol, 1.4 eq) and (5,5)-(3,4-dimethyl- cyclopentylidene)-acetic acid ethyl ester (17.6 g, 0.097 mmol, 1.0 eq).
• the mixture was evacuated with nitrogen and the slurry stirred at 8O 0 C for 10 h under nitrogen.
• the mixture was stirred at 1150 rpm and heated to about 80°C while maintaining a pressure of about 50 psig in the vessel with hydrogen. After hydrogen uptake had essentially ceased, the reactor temperature was increased to 90°C and its contents stirred for an additional 5 h. After cooling and holding overnight, the product mixture was carefully vacuum filtered and washed with MeOH (65% average yield upon isolation).
• the aqueous phases were washed in series with ethyl acetate (45 mL).
• the combined organic phases were charged to a 1-L four necked round bottom flask along with branched octanes (170 mL).
• the mixture was concentrated to 87 mL by vacuum distillation.
• the distillate was diluted with branched octanes (170 mL) and again concentrated to 87 mL by vacuum distillation. This dilution/distillation procedure was repeated two more times.
• the resulting 87 mL solution was cooled to ambient temperature over 1 h during which time crystals formed.
• the resulting slurry was cooled to about 0°C and stirred for 30 min before vacuum filtration.
• the resulting solution was cooled to a temperature of 50 to 60 0 C and was extracted with toluene (2 x 30 mL). The toluene washes were discarded.
• the aqueous phase was adjusted to pH 2.0 with 50% NaOH (approximately 19g, 0.23 mol, 2.0 eq).
• Activated carbon (4.Og), a filtering agent (4.Og), and water (1Og) were added to the flask and the contents stirred for 30 min at 50 0 C.
• the slurry was heated to 60 0 C and was filtered through a course frit and a 0.5 ⁇ m PTFE membrane, while maintaining the slurry at a temperature greater than 55 0 C.
• the filter cake was rinsed with water (25 mL) that had been heated to a temperature greater than 50 0 C.
• the combined aqueous layers were cooled to a temperature less than 40 0 C and vacuum distilled to a final volume of about 70 mL.
• the concentrated solution, which contained the product was adjusted to a pH of 6.5 to 7.5 with 50% NaOH (approximately 8.2g, 0.1 mol, 0.9 eq) to form a precipitate.
• the mixture was cooled with an ice bath to a temperature less than 5°C.
• the resulting slurry was stirred at a temperature less than 5°C for 60 min and then filtered to isolate the crude (solid) product.
• the cake was rinsed while still wet with water (20 g) and then allowed to dry on the filter for 24 to 48 h.
• An isopropanol/water (20 mL of a 40 wt% /-PrOH aq solution) was charged to the flask and heated to reflux.
• the rinse was transferred through the membrane and frit with nitrogen pressure and combined with the product solution filtrate.
• the combined filtrates were transferred to a pre-marked (at 102 mL) 500 mL 4 neck RBF equipped with overhead agitation, distillation condenser, and thermocouple, under a nitrogen blanket.
• the solution was cooled to less than 40 0 C.
• the slurry was vacuum distilled at 40 to 50 0 C to a total volume of 102 mL.
• the isopropanol content was adjusted to 24 to 27 wt% z-PrOH.
• the slurry was re-heated to reflux (about 87°C) and held until all solids were in solution.
• the solution was slowly cooled at a rate of 20°C/h to 5°C and was held for 60 min to precipitate the product.
• the final (solid) product was isolated by vacuum filtration and washed with isopropanol (30 mL, cooled to less than 5°C).
• the filter cake was dried at 40°C under vacuum for 24 hours to provide (3 ⁇ S,45)-(l-aminomethyl-3,4-dimethyl-cyclopentyl)- acetic acid (21.0 g, 95%).

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