[go: up one dir, main page]

US20050215816A1 - Cyclic ketones, their preparation and their use in the synthesis of amino acids - Google Patents

Cyclic ketones, their preparation and their use in the synthesis of amino acids Download PDF

Info

Publication number
US20050215816A1
US20050215816A1 US11/074,250 US7425005A US2005215816A1 US 20050215816 A1 US20050215816 A1 US 20050215816A1 US 7425005 A US7425005 A US 7425005A US 2005215816 A1 US2005215816 A1 US 2005215816A1
Authority
US
United States
Prior art keywords
formula
compound
cyclopentanone
methyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/074,250
Inventor
David Blakemore
Justin Bryans
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US11/074,250 priority Critical patent/US20050215816A1/en
Publication of US20050215816A1 publication Critical patent/US20050215816A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—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 saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/395—Saturated compounds containing a keto group being part of a ring of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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

  • the present invention relates to methods for the synthesis of alkyl- and alkenyl- and cycloalkyl-substituted cyclopentanones that are useful inter alia as intermediates for the synthesis of analogues of gabapentin (Neurontin®). It also relates to methods for the synthesis of gabapentin analogues using these intermediates, and also to certain novel intermediates per se.
  • Gabapentin is an anti-convulsant agent that is useful in the treatment of epilepsy and that has recently been shown to be a potential treatment for neurogenic pain. It is 1-(aminomethyl)-cyclohexaneacetic acid of structural formula:
  • Gabapentin is one of a series of compounds of formula in which R 1 is hydrogen or a lower alkyl radical and n is 4, 5, or 6. These compounds are described U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Their disclosed uses are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The disclosures of the above two patents are hereby incorporated by reference.
  • WO 99/21824 discloses further cyclic amino acids that are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammation, especially arthritis.
  • the compounds disclosed include those of the formula: and salts thereof, in which:
  • R is hydrogen or a lower alkyl
  • R 1 to R 8 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, —CO 2 H, —CO 2 R 15 , —CH 2 CO 2 H, —CH 2 CO 2 R 15 , —OR 15 wherein R 15 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and R 1 to R 8 are not simultaneously hydrogen.
  • a method for preparing a compound of formula (1) in the following reaction scheme and pharmaceutically acceptable salts thereof comprises:
  • This invention is concerned with the problem that the cyclopentanones available up to now have been limited in their range of stereoisomers and substituents because they have been derived from natural sources, or have been complex.
  • (R)-3-methyl-cyclopentanone is a compound that is readily available commercially from natural sources, whereas (S)-3-methyl-cyclopentanone is not.
  • the enantiomeric purity of the resulting compounds of formula (I) and (II) can be tested by reacting them with an asymmetric diol such as (2R,3R)-2,3-butanediol to give an acetal having an additional asymmetric centre in the molecule, e.g and obtaining the NMR spectrum of the resulting chiral acetal.
  • an asymmetric diol such as (2R,3R)-2,3-butanediol
  • a compound of formula (I) and (II) may be converted in manner known per se to a gabapentin analogue of one of the formulae shown below: in which the substituents R and R′ and the wedges have the meanings indicated above, and may be further converted into a pharmaceutically acceptable salt thereof.
  • Conversion to a compound of formula (XI)-(XIV) may, for example, follow one of the general schemes disclosed in WO 99/21824, or it may follow the Knoevenagel addition route disclosed in USSN 60/169602. In the latter case, there may be produced the key intermediates (XV)-(XVIII) shown below: in which the substituents R and R′ and the wedges have the meanings indicated above. Thereafter, the intermediate of formula (XV)-(XVIII) may be converted to a compound of formula (I) or (II) by one of the three principal strategies disclosed in USSN 60/169602, i.e.
  • the invention provides enantiomerically pure compounds of the formula: wherein R and R′ represent C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 3 -C 10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents being trans, and at least one of R and R′ not being methyl.
  • the compounds of the invention can be prepared in chirally pure form from (R)-4-acetoxycyclopent-2-en-1-one (1) or (S)-4-acetoxycyclopent-2-en-1-one (2).
  • leaving groups may be present in the starting materials employed in the above process in place of the acetoxy compounds, and in general any compound that is available in optically pure form and that has a 4-substituent that permits stereospecific addition to the en-one conjugated system and can then undergo elimination can be used.
  • leaving groups are halides and sulfonic acid ester groups.
  • alternative starting materials include:
  • n-Propylmagnesium chloride (15.7 ml of a 2M solution in ether, 31.4 mmol) was added slowly to a stirred solution of dimethylzinc (15.7 ml of a 2M solution in toluene, 31.4 mmol) in THF (80 ml) under argon at 0° C. After 30 minutes, the mixture was cooled to ⁇ 78° C. and (R)-4-acetoxycyclopent-2-enone (4.0 g, 28.5 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml).
  • acetoxy cyclopentanone 1 (approx. 28.5 mmol) in ether (40 ml) was added dropwise over 1 hr to a stirred solution of DBU (4.27 ml, 28.5 mmol) in ether (50 ml) at ⁇ 40° C. under argon. The mixture was allowed to warm to ⁇ 30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2 ⁇ 100 ml).
  • ketone 3 (0.12 g, 0.95 mmol), (2R,3R)-(-)-2,3-butanediol (0.087 ml, 0.96 mmol) and p-toluenesulphonic acid (0.018 g, 0.095 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo to give a single diastereoisomeric acetal 7 (0.12 g, 65%).
  • Methylmagnesium chloride (7.1 ml of a 3M solution in ether, 21.3 mmol) was added slowly to a stirred solution of dimethylzinc (5.3 ml of a 2M solution in toluene, 10.6 mmol) in TBF (80 ml) under argon at 0° C. After 30 minutes the mixture was cooled to ⁇ 78° C. and 2 (1.2 g, 9.7 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated amnmonium chloride solution (20 ml).
  • ketone 4 (0.12 g, 0.86 mmol), (2R,3R)-(-)-2,3-butanediol (0.086 ml, 0.94 mmol) and p-toluenesulphonic acid (0.0163 g, 0.086 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo to give 8 (0.08 g, 44%).
  • Ketones 5 and 6 were made using the same procedures as in the preceding examples, but starting from (S)-4-acetoxycyclopent-2-enone.
  • Methylmagnesium chloride (11.3 ml of a 3M solution in THF, 33.9 mmol) was added slowly to a stirred solution of dimethylzinc (17.0 ml of a 2M solution in toluene, 34.0 mmol) in THF (80 ml) at 0° C. under argon. After 20 minutes, the mixture was cooled to ⁇ 78° C. and (S)-4-acetoxycyclopent-2-enone (4.33 g, 30.9 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml).
  • Acetoxy cyclopentanone 11 (approx. 30.9 mmol) in dichloromethane (40 ml) was added dropwise over 1 hour to a stirring solution of DBU (4.6 ml, 30.9 mmol) in dichloromethane (50 ml) at ⁇ 40° C. under argon. The mixture was allowed to warm to ⁇ 30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2 ⁇ 100 ml).
  • Methylmagnesium chloride (5.2 ml of a 3M solution in ether, 15.6 mmol) was added slowly to a stirred solution of dimethylzinc (3.9 ml of a 2M solution in toluene, 7.8 mmol) in THF (20 ml) under argon at 0° C. After 30 minutes the mixture was cooled to ⁇ 78° C. and 12 (0.67 g, 7.0 mmol) in THF (10 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (10 ml).
  • reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (40 ml) and extracted with ether (3 ⁇ 50 ml). The organic layer was washed with brine (50 ml), dried (MgSO 4 ) and the solvent was removed under reduced pressure to yield 13 as a solution in toluene which was purified by column chromatography (SiO 2 , pentane-ether, 95:5) to give the dimethylcyclopentanone 13 (0.45 g, 52%).
  • the ketone 13 (0.25 g, 2.23 mmol), (2R,3R)-(-)-2,3-butanediol (0.23 ml, 2.45 mmol) and p-toluenesulphonic acid (0.042 g, 0.22 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (gSO 4 ) and concentrated in vacuo to give 14 (0.21 g, 51%).
  • Compound 15 was prepared using the same method as 12.
  • the ketone 16 (0.25 g, 2.55 mmol), (2R,3R)-(-)-2,3-butanediol (0.26 ml, 2.80 mmol) and p-toluenesulphonic acid (0.05 g, 0.255 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo to give the acetal 17 (0.20 g, 47%).
  • Acetoxy cyclopentanone 18 (approx. 35.7 mmol) in dichloromethane (45 ml) was added dropwise over 1 hr to a stirring solution of DBU (5.34 ml, 35.7 mmol) in dichloromethane (100 ml) at ⁇ 40° C. under argon. The mixture was allowed to warm to ⁇ 30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (30 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2 ⁇ 100 ml).
  • Methylmagnesium chloride (22.5 ml of a 3M solution in ether, 67.5 mmol) was added slowly to a stirred solution of dimethylzinc (16.9 ml of a 2M solution in toluene, 33.8 mmol) in THF (100 ml) under argon at 0° C. After 30 minutes the mixture was cooled to ⁇ 78° C. and 19 (3.37 g, 30.6 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (25 ml).
  • the ketone 20 (0.22 g, 1.74 mmol), (2R,3R)-(-)-2,3-butanediol (0.18 ml, 1.91 mmol) and p-toluenesulphonic acid (0.033 g, 0.174 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction nixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (gSO 4 ) and concentrated in vacuo to give 24 (0.19 g, 55%).
  • the ketone 21 (0.098 g, 0.874 mmol), (2R,3R)-(-)-2,3-butanediol (0.088 ml, 0.96 mmol) and p-toluenesulphonic acid (0.017 g, 0.087 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap.
  • the reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo to give 25 (0.12 g, 73%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A method is provided for making an enantiomerically pure compound of the formula:
Figure US20050215816A1-20050929-C00001
in which R and R′ represent C1-C10 alkyl, C2-C10 alkenyl or C3-C10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans. Conjugate addition is carried out between an organometallic nucleophile that provides a group R as defined above and (R)-4-acetoxycyclopent-2-en-1-one, (S)-4-acetoxycyclopent-2-en-1-one or a similar compound in which acetoxy is replaced by another leaving group to give, e.g. in the case of the acetoxy compound, a trans 3,4-disubstituted addition product of formula III or IV;
Figure US20050215816A1-20050929-C00002

Description

    FIELD OF THE INVENTION
  • The present invention relates to methods for the synthesis of alkyl- and alkenyl- and cycloalkyl-substituted cyclopentanones that are useful inter alia as intermediates for the synthesis of analogues of gabapentin (Neurontin®). It also relates to methods for the synthesis of gabapentin analogues using these intermediates, and also to certain novel intermediates per se.
    • BACKGROUND TO THE INVENTION
  • Gabapentin (Neurontin®) is an anti-convulsant agent that is useful in the treatment of epilepsy and that has recently been shown to be a potential treatment for neurogenic pain. It is 1-(aminomethyl)-cyclohexaneacetic acid of structural formula:
    Figure US20050215816A1-20050929-C00003
  • Gabapentin is one of a series of compounds of formula
    Figure US20050215816A1-20050929-C00004
    in which R1 is hydrogen or a lower alkyl radical and n is 4, 5, or 6. These compounds are described U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Their disclosed uses are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The disclosures of the above two patents are hereby incorporated by reference.
  • WO 99/21824, whose disclosure is also incorporated by reference, discloses further cyclic amino acids that are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammation, especially arthritis. The compounds disclosed include those of the formula:
    Figure US20050215816A1-20050929-C00005
    and salts thereof, in which:
  • R is hydrogen or a lower alkyl;
  • R1 to R8 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, —CO2H, —CO2R15, —CH2CO2H, —CH2CO2R15, —OR15 wherein R15 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and R1 to R8 are not simultaneously hydrogen.
  • The compounds of WO 99/21824 may be synthesized:
    • using a general strategy (General Scheme 1) outlined by G. Griffiths et al., Helv. Chim. Acta, 1991; 74:309;
    • analogously to the published procedure for the synthesis of 3-oxo-2,8-diazaspiro[4,5]decane-8carboxylic acid tert-butyl ester, see P. W. Smith et al., J. Med. Chem., 1995; 38:3772 (General Scheme 2);
    • by the methods outlined by G. Satzinger et al., (Ger Offen 2,460,891; U.S. Pat. No. 4,024,175, and Ger Offen 2,611,690; U.S. Pat. No. 4,152,326) (General Schemes 3 and 4);
    • by a route outlined by G. Griffiths et al., Helv. Chim. Acta, 1991; 74:309 (General Scheme 5).
      Figure US20050215816A1-20050929-C00006
      Figure US20050215816A1-20050929-C00007
      Figure US20050215816A1-20050929-C00008
      Figure US20050215816A1-20050929-C00009
      Figure US20050215816A1-20050929-C00010
  • Intermediates disclosed in WO 99/21824 include the following:
    Figure US20050215816A1-20050929-C00011
    Figure US20050215816A1-20050929-C00012
  • Our U.S. Patent Application 60/169,602, the disclosure of which is also incorporated herein by reference, describes and claims methods for the stereocontrolled synthesis of five-member ring Gabapentin analogues that are pure stereoisomers of compounds of formulae shown below and to salts thereof.
    Figure US20050215816A1-20050929-C00013
    wherein R represents C1-C10 alkyl and C3-C10 cycloalkyl. The synthesis starts with the Knoevenagel condensation of a 3-substituted cyclopentanone of the kind described above with ethyl cyanoacetate and proceeds via the key intermediates
    Figure US20050215816A1-20050929-C00014
  • A method for preparing a compound of formula (1) in the following reaction scheme and pharmaceutically acceptable salts thereof comprises:
    • a) adding ethyl cyanoacetate to a mixture of a chiral cyclopentanone of formula (1) in a solvent to which a C1-C6 carboxylic acid and an amphoteric catalyst were added, and stirring the mixture to produce the alkene of formula (2);
    • b) adding the product of Step a) above to a mixture of benzylmagnesium chloride in a dry solvent to produce the addition product of formula (3);
    • c) adding the product of Step b) above to a mixture of a base in a solvent and stirring the mixture to produce the carboxylic acid of formula (4);
    • d) contacting the product of Step c) above with (S)-α-methyl-benzylamine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the (S)-α-methyl-benzylamine salt;
    • e) adding the product of Step d) to an inorganic acid dissolved in a solvent and stirring to produce the carboxylic acid of formula (6);
    • f) adding the product of Step e) to a mixture of iodomethane in a solvent to which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added, and stirring to produce the ester of formula (7);
    • g) adding the product of Step f) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(III) chloride were added, and stirring to produce the carboxylic acid of formula (8);
    • h) adding the product of Step g) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (9);
    • i) adding the product of Step h) to a solvent to which methanol was added, and stirring to produce the carbamate of formula (10);
    • j) adding the product of Step i) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula Ia;
    • k) converting the product of Step j) to a compound of Formula I, and further converting, if desired, to a pharmaceutically acceptable salt by known means:
      Figure US20050215816A1-20050929-C00015
  • Preparation of a compound of formula II can proceed by a method which involves following the above-described sequence of steps (a) to (e) to produce the intermediate of step (6), and thereafter following the further steps indicated below:
    • f) adding the product of Step e) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (11);
    • g) adding the product of Step f) to a solvent to which methanol was added and stirring to produce the carbamate of formula (12);
    • h) adding the product of Step g) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(III) chloride were added, and stirring to produce the carboxylic acid of formula (13);
    • i) adding the product of Step h) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula IIa;
    • k) converting the product of Step i) to a compound of Formula I, and further converting, if desired, to a pharmaceutically acceptable salt by known means:
      Figure US20050215816A1-20050929-C00016
  • An alternative route to the compounds of formula (II), also proceeding from compound (6) above involves the further steps of:
    • f) adding oxalyl chloride to a mixture of the product of Step e) and a solvent to which N,N-dimethylformamide (DMAF) was added, and stirring to produce the acid chloride of formula (14);
    • g) adding the product of Step f) to a mixture of tert-butyl alcohol in a solvent to which an amine base was added, and stirring to produce the ester of formula (15);
    • h) adding the product of Step g) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(III) chloride were added, and stirring to produce the carboxylic acid of formula (16);
    • i) adding the product of Step h) to a solvent to which methanol and (trimethylsilyl)diazomethane were added, and stirring to produce the bis ester of formula (17);
    • j) adding an acid to a mixture of the product from Step i) and a solvent and stirring to produce the carboxylic acid of formula (18);
    • k) adding the product of Step j) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (19);
    • l) adding the product of Step k) to a solvent to which methanol was added and stirring to produce the carbamate of formula (20);
    • m) adding the product of Step 1) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula IIa;
    • n) converting the product of Step m) to a compound of Formula II, and further converting, if desired, to a pharmaceutically acceptable salt by known means:
      Figure US20050215816A1-20050929-C00017
  • Compounds of formula (III) can be prepared by processes that involve the same steps as those for the compounds of formula (I), for example by following the sequence of reactions set out below:
    Figure US20050215816A1-20050929-C00018
  • Similarly, compounds of formula (IV) may be made by a sequence of reactions analogous to those described above:
    Figure US20050215816A1-20050929-C00019
  • It will be noted that the synthetic methods disclosed in both WO 99/21824 and USSN 60/169602 rely on 3- or 3,4-substituted cyclopentanones.
    • SUMMARY OF THE INVENTION
  • This invention is concerned with the problem that the cyclopentanones available up to now have been limited in their range of stereoisomers and substituents because they have been derived from natural sources, or have been complex. For example, (R)-3-methyl-cyclopentanone is a compound that is readily available commercially from natural sources, whereas (S)-3-methyl-cyclopentanone is not. It is an object of the invention to provide a simple stereospecific synthetic route to 3-substituted or 3,4-disubstituted cyclopentanones that permits a range of desired substituents to be introduced and a range of desired stereoisomers to be made.
  • That problem is solved, according to the invention, by a process method of making an enantiomerically pure compound of the formula (I) or (II):
    Figure US20050215816A1-20050929-C00020
    wherein R and R′ represent C1-C10 alkyl, C2-C10 alkenyl or C3-C10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans, which method comprises:
      • conjugate addition of an organometallic nucleophile that provides a group R as defined above to a compound of the formula (III) or (IV):
        Figure US20050215816A1-20050929-C00021
        wherein X represents a leaving group (e.g. an acetoxy group as in (R)-4-acetoxycyclopent-2-en-1-one or (S)-4-acetoxycyclopent-2-en-1-one) to give a trans 3,4-disubstituted addition product of formula (V) or (VI) in which R and X are as previously defined;
        Figure US20050215816A1-20050929-C00022
        eliminating the leaving-group from the addition product of formula (V) or (VI) to give an (R)- or (S)-4-alkyl or 4-alkenyl cyclopent-2-en-1-one of formula (VII) or (VIII)
        Figure US20050215816A1-20050929-C00023
        and either
  • (i) hydrogenation of the compound of formula (VII) or (VII) to give a cyclopentanone of formula (I) or
  • (ii) conjugate addition of a second organometallic nucleophile that provides a group R′ as defined above to the compound of formula (VII) or (VIII) to give a trans 3,4-disubstituted addition product of formula (II).
  • While conjugate addition to conjugated cyclopentenones is known for soft nucleophiles such as enolates, sulfides and bromides, such reactions have not been carried out with carbon-based nucleophiles with a view to producing chirally pure ketones. The group AcO— in the starting material brings about stereospecific addition of the group R during the first Michael addition, and where a second Michael addition is carried out, the group R that is already present in the compound of formula (VII) or (VIII) brings about stereospecific addition of the group R′. The enantiomeric purity of the resulting compounds of formula (I) and (II) can be tested by reacting them with an asymmetric diol such as (2R,3R)-2,3-butanediol to give an acetal having an additional asymmetric centre in the molecule, e.g
    Figure US20050215816A1-20050929-C00024
    and obtaining the NMR spectrum of the resulting chiral acetal. If the starting material is an enantiomeric mixture, then the two resulting cyclic acetals will be diastereomeric and give distinguishable peaks in the NMR spectrum provided that the enantiomeric impurity is present in an amount of 2% or above. No such peaks have been observed in the materials that we have made, and we therefore believe that the method of the invention gives desired enantiomers with a purity of at least 98%.
  • According to a furrer aspect of the invention, a compound of formula (I) and (II) may be converted in manner known per se to a gabapentin analogue of one of the formulae shown below:
    Figure US20050215816A1-20050929-C00025
    in which the substituents R and R′ and the wedges have the meanings indicated above, and may be further converted into a pharmaceutically acceptable salt thereof.
  • Conversion to a compound of formula (XI)-(XIV) may, for example, follow one of the general schemes disclosed in WO 99/21824, or it may follow the Knoevenagel addition route disclosed in USSN 60/169602. In the latter case, there may be produced the key intermediates (XV)-(XVIII) shown below:
    Figure US20050215816A1-20050929-C00026
    in which the substituents R and R′ and the wedges have the meanings indicated above. Thereafter, the intermediate of formula (XV)-(XVIII) may be converted to a compound of formula (I) or (II) by one of the three principal strategies disclosed in USSN 60/169602, i.e. (i) transforming the phenyl ring to a carboxylic acid and then to an amine; (ii) transforming the carboxylic acid group into an amine and oxidizing the phenyl group to an acid, or (iii) protecting the carboxylic acid group, oxidizing the phenyl ring to a second carboxylic acid group, protecting the second carboxylic acid group, selectively de-protecting the first carboxylic acid group, transforming the first carboxylic acid group to an amine, and de-protecting the second carboxylic acid group.
  • Certain of the present intermediates are believed to be new. In a further aspect, therefore, the invention provides enantiomerically pure compounds of the formula:
    Figure US20050215816A1-20050929-C00027
    wherein R and R′ represent C1-C10 alkyl, C2-C10 alkenyl or C3-C10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents being trans, and at least one of R and R′ not being methyl.
    • DESCRIPTION OF PREFERRED FEATURES
  • As previously stated, the compounds of the invention can be prepared in chirally pure form from (R)-4-acetoxycyclopent-2-en-1-one (1) or (S)-4-acetoxycyclopent-2-en-1-one (2).
    Figure US20050215816A1-20050929-C00028
  • The reactions of 4-Oxo-2-cyclopentenyl Acetate (4-Acetoxy-2-cyclopenten-1-one) have been reviewed by M. Harre, P. Raddatz, R. Walenta and E. Winterfeldt, Angew. Chem. Int. Ed. Engl., 1982, 21, 480. It has been synthesised in enantiomerically pure form using two main approaches:
    • Acetylation of chirally pure 4-hydroxy-2-cyclopenten-1-one, see K. Ogura, M. Yamashita and G. Tsuchihashi, Tetrahedron Letters, 1976, 759. For examples of approaches to chiral 4-hydroxy-2-cyclopenten-1-one see the following and references therein: S. R. Ghorpade, K. B. Bastawade, D. V. Gokhale, P. D. Shinde, V. A. Mahajan, U. R. Kalkote and T. Ravindranathan, Tetrahedron Asymmetry, 1999, 10, 4115; S. P. Khanapure, N. Najafi, S. Manna, J-J. Yang and J. Rokach, J. Org. Chem., 1995, 60, 7548; E. Mezzina, D. Savoia, E. Tagliavini, C. Trombini and A. Umani-Ronchi, J. Chem. Soc. Perkin Trans. 1, 1989, 845; M. Kitamura, K. Manabe and R. Noyori, Tetrahedron Letters, 1987, 28, 4719; R. Noyori, I. Tomino, M. Yamada and M. Nishizawa, J. Am. Chem. Soc., 1984, 106, 6717; M. Suzuki, T. Kawagishi, T. Suzuki and R. Noyori, Tetrahedron letters, 1982, 23, 4057; R. Noyori, Pure & Appl. Chem., 1981, 53, 2315; T. J. N. Watson, T. T. Curran, D. A. Hay, R. S. Shah, D. L. Wenstrup and M. E. Webster, Organic Process Research & Development, 1998, 2, 357; S. R. Ghorpade, K. B. Bastawade, D. V. Gokhale, P. D. Shinde, V. A. Mahajan, U. R. Kalkote and T. Ravindranathan, Tetrahedron: Asymmetry, 1999, 10, 4115-4122).
    • Oxidation of 3-acetoxy-5-hydroxycyclopent-1-enes, for example see: M. Korach, D. R. Nielsen and W. H. Rideout, Org. Synth, Collect. Vol. 5, 1973, 414; D. R. Deardoff and D. C. Myles, Org. Synth., 1989, 67, 114; D. R. Deardorff, C. Q. Windham and C. L. Craney, Org. Synth., 1995, 73, 25; C. R. Johnson and S. J. Bis, Tetrahedron Letters, 1992, 33, 7287.
  • The following reactions may be used to make compounds according to the invention:
    • A) Conjugate addition to a cyclopent-2-en-1-one (1) or (2) can be carried out using an organo-Grignard reagent in the presence of dimethylzinc giving a trans 3,4-disubstituted intermediate e.g. an addition product of formula (3) or (4). In particular, the chiral cyclopentenone of formula (1) or (2) may be added to the organo-Grignard reagent or to an organo-lithium reagent in the presence of a dialkylzinc or zinc chloride or a copper (I) salt or a trialkylaluminium in a solvent, for example, tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether or tert-butyl methyl ether at a temperature from −100° C. to 0° C. to produce said addition product.
    • B) Adding the product of step A) above to a mixture of base, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethyl guanidine (TMG), lithium hydride or sodium hydride in a solvent, for example, dichloromethane, diethyl ether, tetrahydrofliran, tert-butyl methyl ether or 1,4-dioxane to produce an elimination product of formula (5) or (6).
    • C) Adding the product of step B) above to a mixture of organo-Grignard reagent or organo-lithium reagent in the presence of a dialkylzinc or zinc chloride or a copper (I) salt or a trialkylaluminium salt in a solvent, for example, tetrahydroflran, 1,4-dioxane, n-heptane, toluene, diethyl ether or tert-butyl methyl ether at a temperature from −100° C. to 0° C. can be used to produce an addition product of formula (7) or (8).
    • D) Adding the product of step B) above to a hydrogenation catalyst, for example, palladium on charcoal, platinum oxide, Raney nickel, Rhodium on alumina in a solvent, for example, ethyl acetate or methanol under a hydrogen atmosphere at 1 to 30 atmospheres pressure and at a temperature in the range 0-60° C., can be used to make a product of formula (9) or (10).
  • The above described reactions are illustrated in the following schemes:
    Figure US20050215816A1-20050929-C00029
    Figure US20050215816A1-20050929-C00030
  • An example of the utility of the above reaction scheme is shown below:
    Figure US20050215816A1-20050929-C00031
  • Compounds that can be made by the present process are shown below, and the following are believed to be new:
      • (3S,4S)-3,4-diethyl-cyclopentanone;
      • (3R,4R)-3,4-diethyl-cyclopentanone;
      • (3S,4S)-3-ethyl-4-methyl-cyclopentanone;
      • (3R,4R)-3-ethyl-4-methyl-cyclopentanone;
      • (3S,4S)-3-methyl-4-propyl-cyclopentanone;
      • (3R,4R)-3-methyl-4-propyl-cyclopentanone;
      • (3S,4S)-3-ethyl-4-propyl-cyclopentanone; and
      • (3R,4R)-3-ethyl-4-propyl-cyclopentanone.
        Figure US20050215816A1-20050929-C00032
  • Other leaving groups may be present in the starting materials employed in the above process in place of the acetoxy compounds, and in general any compound that is available in optically pure form and that has a 4-substituent that permits stereospecific addition to the en-one conjugated system and can then undergo elimination can be used. Examples of such leaving groups are halides and sulfonic acid ester groups. Examples of alternative starting materials include:
    Figure US20050215816A1-20050929-C00033
  • For preparation see T. Hirao, S. Mikami, M. Mori, Y. Ohshiro, Tet. lett., 1991, 32(14), 1741-4. For stereospecific preparation of R and S enantiomers see R. Gerdil, H. Liu, G. Bernardinelli, Helv. Chim. Acta., 1999, 82(3), 418-34.
    Figure US20050215816A1-20050929-C00034
  • For preparation see: F. Gavina, A. Costero, A. Gonzalez, S. Luis, J. Org. Chem., 1987, 52(14), 2997-9; C. H. DePuy, M. Isaks, K. L. Eilers, G. F. Morris, J. Org. Chem., 1964, 29, 3503-10; J. A. Bloodworth, H. J. Eggelte, J. Chem. Soc. Perkin Trans. 1, 1981, 12, 3272-8.
    Figure US20050215816A1-20050929-C00035
  • For preparation of the above two compounds or the class of compounds of the third formula, in which R=straight or branched alkyl of C1-C6, see M. Minamii, Y. Ueda, JP 62116537 (JP 85-262204), JP 85-167970 and M. Minamii, Y. Ueda, EP-A-0170506.
  • The invention will now be further described in the following Examples.
    • EXAMPLE 1 Enantiomerically Pure (S)-3-n-propyl-cyclopentanone (3)
  • Figure US20050215816A1-20050929-C00036
    • (3R,4R)-3-acetoxy-4-n-propyl-cyclopentanone (1)
  • n-Propylmagnesium chloride (15.7 ml of a 2M solution in ether, 31.4 mmol) was added slowly to a stirred solution of dimethylzinc (15.7 ml of a 2M solution in toluene, 31.4 mmol) in THF (80 ml) under argon at 0° C. After 30 minutes, the mixture was cooled to −78° C. and (R)-4-acetoxycyclopent-2-enone (4.0 g, 28.5 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield the acetoxy cyclopentanone 1 as a solution in toluene which was used without further purification in the next step.
    υmax(film)/cm−1 1740 (C═O).
  • δH(400 MHz; CDCl3) 5.08 (1H, m, CHOAc), 2.70 (1H, dd, J 19.2, 5.9), 2.59 (1H, dd, J 8.1, 1.2), 2.34 (1H, m), 2.23 (1H, dd, J 19.1, 4.6), 2.07 (3H, s, OCOMe), 1.98 (1H, dd, J 18.4, 6.4), 1.54 (1H, m), 1.46-1.21 (3H, m), 0.94 (3H, t, J 7.1, Me).
    • (R)-4-n-propyl-cyclopent-2-enone (2)
  • The acetoxy cyclopentanone 1 (approx. 28.5 mmol) in ether (40 ml) was added dropwise over 1 hr to a stirred solution of DBU (4.27 ml, 28.5 mmol) in ether (50 ml) at −40° C. under argon. The mixture was allowed to warm to −30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×100 ml). The combined ether layers were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 8:2) to give the propylcyclopentenone 2 (2.4 g, 68% from (R)-4-acetoxycyclopent-2-enone).
    υmax(film)/cm−1 1708 (C═O).
  • δH(400 MHz; CDCl3) 7.64 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.14 (1H, dd, J 5.6, 2.0, CH═CHC═O), 2.75 (1H, m), 2.53 (1H, dd, J 18.8, 6.4, CHAHBC═O), 2.00 (1H, dd, J 18.8, 2.0, CHAHBC═O) 1.60-1.20 (4H, m), 0.96 (3H, t, J 6.8, Me).
    • (S)-3-n-propylcyclopentanone (3)
  • A mixture of 2 (1.2 g, 9.7 mmol) and 10% palladium on charcoal (catalytic quantity) in ethyl acetate (30 ml) was shaken in hydrogen at 55 psi and at 30° C. for 6 hours. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 9:1) to give the 3-propylcyclopentanone 3 (1.07 g, 88%).
    υmax(film)/cm−1 1744 (C═O).
  • δH(400 MHz; CDCl3) 2.29 (1H, dd, J 16.0, 8.4), 2.38 (1H, dd, J 18.8, 7.6), 2.21-2.09 (2H, m), 1.79 (1H, dd, J 18.0, 9.6), 1.56-1.34 (6H, m), 0.93 (3H, t, J 7.2, Me).
    • Enantiomeric Purity By Conversion To Acetal (7)
  • Figure US20050215816A1-20050929-C00037
  • The ketone 3 (0.12 g, 0.95 mmol), (2R,3R)-(-)-2,3-butanediol (0.087 ml, 0.96 mmol) and p-toluenesulphonic acid (0.018 g, 0.095 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution, brine, dried (MgSO4) and concentrated in vacuo to give a single diastereoisomeric acetal 7 (0.12 g, 65%).
  • δH(400 MHz; CDCl3) 3.61-3.57 (2H, m), 2.1-1.76 (5H, m), 1.47-1.40 (2H, m), 1.35-1.20 (10H, m), 0.88 (3H, t, J 6.8, Me); δC(CDCl3) 117.2, 78.3, 78.1, 44.6, 38.4, 37.6, 37.2, 30.1, 21.3, 17.2, 17.1, 14.2.
    • EXAMPLE 2 (3R,4R)-3-methyl-4-n-propyl-cyclopentanone (4)
  • Figure US20050215816A1-20050929-C00038
  • Methylmagnesium chloride (7.1 ml of a 3M solution in ether, 21.3 mmol) was added slowly to a stirred solution of dimethylzinc (5.3 ml of a 2M solution in toluene, 10.6 mmol) in TBF (80 ml) under argon at 0° C. After 30 minutes the mixture was cooled to −78° C. and 2 (1.2 g, 9.7 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated amnmonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield 4 as a solution in toluene which was purified by column chromatography (SiO2, pentane-ether, 1:0 to 9:1 to give the cyclopentanone 4 (0.86 g, 63%).
    υmax(CDCl3)/cm−1 1733 (C═O).
  • δH(400 MHz; CDCl3) 2.49-2.42 (2H, m), 1.87-1.80 (3H, m), 1.79-1.61 (2H, m), 1.80-1.43 (3H, m), 1.12 (3H, d, J 6.1, Me), 0.93 (3H, t, J 7.3, Me); δC(CDCl3) 220.0, 48.1, 46.2, 45.5, 38.4, 37.0, 232.1, 19.6, 15.8.
    • Enantiomeric Purity By Conversion To Acetal 8
  • Figure US20050215816A1-20050929-C00039
  • The ketone 4 (0.12 g, 0.86 mmol), (2R,3R)-(-)-2,3-butanediol (0.086 ml, 0.94 mmol) and p-toluenesulphonic acid (0.0163 g, 0.086 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO4) and concentrated in vacuo to give 8 (0.08 g, 44%).
  • δH(400 MHz; CDCl3) 3.61-3.58 (2H, m), 2.51-2.39, 2.27, 2.19-2.06, 1.90-1.60 (6H, m), 1.60-1.04 (10H, m), 0.98 (3H, d, J 6.6, Me), 0.89 (3H, t, J 7.3, Me); δC(400 MHz; CDCl3) 115.8, 78.2, 78.1, 47.2, 45.1, 45.0, 38.4, 36.5, 21.4, 18.8, 17.3 (×2), 14.4.
    • EXAMPLES 3 & 4 (R)-3-n-propyl-cyclopentanone (5) And (3S,4S)-3-methyl4-n-propyl-cyclopentanone (6)
  • Figure US20050215816A1-20050929-C00040
  • Ketones 5 and 6 were made using the same procedures as in the preceding examples, but starting from (S)-4-acetoxycyclopent-2-enone.
    • Enantiomeric Purity By Conversion To Chiral Acetals 9, 10.
  • Figure US20050215816A1-20050929-C00041
  • The enantiomeric purity of ketone 5 was confirmed by making acetal 9 using the procedure of the foregoing examples.
  • δH(400 MHz; CDCl3) 3.60-3.48 (2H, m), 2.45-1.76 (5H, m), 1.44-1.41 (2H, m), 1.38-1.14 (10H, m), 0.88 (3H, t, J 7.1, mE); δC(CDCl3) 117.2, 78.2, 78.1, 44.9, 38.2, 38.0, 37.7, 30.5, 21.3, 17.0, 16.9, 14.2.
    Figure US20050215816A1-20050929-C00042
  • The enantiomeric purity of ketone 6 was confirmed by making acetal 10 using the procedure of the above examples.
  • δH(400 MHz; CDCl3) 3.56-3.49 (2H, m), 2.49-2.22, 2.13-2.04, 1.90-1.62 (6H, m), 1.60-1.02 (10H, m), 0.97 (3H, d, J 6.1, Me), 0.89 (3H, t, J 7.3, Me); δC(CDCl3) 115.7, 78.1, 47.6, 45.5, 45.2, 38.6, 36.0, 21.4, 18.2, 16.9 (×2), 14.4.
    • EXAMPLE 5 Enantiomerically Pure (3S,4S)-3,4-dimethylcyclopentanone (13)
  • Figure US20050215816A1-20050929-C00043
    • The Acetoxy Cyclopentanone 11
  • Methylmagnesium chloride (11.3 ml of a 3M solution in THF, 33.9 mmol) was added slowly to a stirred solution of dimethylzinc (17.0 ml of a 2M solution in toluene, 34.0 mmol) in THF (80 ml) at 0° C. under argon. After 20 minutes, the mixture was cooled to −78° C. and (S)-4-acetoxycyclopent-2-enone (4.33 g, 30.9 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield the acetoxy cyclopentanone 11 as a solution in toluene which was used without further purification in the next step.
    υmax(film)/cm−1 1737 (C═O).
  • δH(400 MHz; CDCl3) 5.01 (1H, m, CHOAc), 2.72 (1H, dd, J 19.0, 6.6), 2.59 (1H, m), 2.46 (1H, m), 2.24 (1H, dd, J 19.0, 4.6), 2.07 (3H, s, OCOMe), 1.95 (1H, dd, J 18.6, 5.7), 1.13 (3H, d, J 7.1, CHMe).
    • The Methylcyclopentanone 12
  • Acetoxy cyclopentanone 11 (approx. 30.9 mmol) in dichloromethane (40 ml) was added dropwise over 1 hour to a stirring solution of DBU (4.6 ml, 30.9 mmol) in dichloromethane (50 ml) at −40° C. under argon. The mixture was allowed to warm to −30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×100 ml). The combined ether layers were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 7:3) to give methylcyclopentenone 12 (1.51 g, 51% from (S)-4-acetoxycyclopent-2-enone).
    υmax(film)/cm−1 1715 (C═O).
  • δH(400 MHz; CDCl3) 7.59 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.14 (1H, dd, J 5.6, 2.0, CH═CHC═O), 3.02 (1H, m), 2.60 (1H, dd, J 18.8, 6.3, CHAHBC═O), 1.95 (1H, dd, J 18.8, 2.2, CHAHBC═O) 1.21 (3H, d, J 7.1, CHMe).
    • The Dimethylcyclopentanone 13
  • Methylmagnesium chloride (5.2 ml of a 3M solution in ether, 15.6 mmol) was added slowly to a stirred solution of dimethylzinc (3.9 ml of a 2M solution in toluene, 7.8 mmol) in THF (20 ml) under argon at 0° C. After 30 minutes the mixture was cooled to −78° C. and 12 (0.67 g, 7.0 mmol) in THF (10 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (10 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (40 ml) and extracted with ether (3×50 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield 13 as a solution in toluene which was purified by column chromatography (SiO2, pentane-ether, 95:5) to give the dimethylcyclopentanone 13 (0.45 g, 52%).
  • ti υmax(filmn)/cm−1 1732 (C═O).
  • δH(400 MHz; CDCl3) 2.50-2.39 (2H, m), 1.89-1.72 (4H, m), 1.12 (6H, d, J 5.6, 2×Me).
    • Enantiomeric Purity of 13 Was Established By Conversion To Acetal 14
  • Figure US20050215816A1-20050929-C00044
  • The ketone 13 (0.25 g, 2.23 mmol), (2R,3R)-(-)-2,3-butanediol (0.23 ml, 2.45 mmol) and p-toluenesulphonic acid (0.042 g, 0.22 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (gSO4) and concentrated in vacuo to give 14 (0.21 g, 51%).
  • δC(CDCl3) 115.5, 78.0, 47.8, 40.1, 17.7, 16.9.
  • m/z (CI+) 185 (M+H, 70%)
  • The acetal made from racemic (3RS,4RS)-3,4dimethylketone has signals as shown below:
  • δC(CDCl3) 115.6, 115.5, 78.2, 78.1, 47.8, 47.5, 40.2, 40.0, 18.1, 17.7, 17.3, 16.9
    • EXAMPLE 6 Enantiomerically Pure (S)-3-methylcyclopentanone (16)
  • Figure US20050215816A1-20050929-C00045
    • The Methylcyclopentenone 15
  • Compound 15 was prepared using the same method as 12.
    • The Methylcyclopentanone 16
  • A mixture of 15 (1.17 g, 12.2 mmol) and 10% palladium on charcoal (catalytic quantity) in ethyl acetate (30 ml) was shaken at 55 psi Hydrogen at 30° C. for 6 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 9:1) to give the 3-methylcyclopentanone 16 (1.09 g, 91%).
    υmax(film)/cm−1 (C═O) 1731.
  • δH(400 MHz; CDCl3) 2.42-2.08 (5H, m), 1.78 (1H, ddd, J 16.8, 9.3, 0.7), 1.51 (1H, m), 1.13 (3H, d, J 6.8).
    • The Acetal 17
  • The ketone 16 (0.25 g, 2.55 mmol), (2R,3R)-(-)-2,3-butanediol (0.26 ml, 2.80 mmol) and p-toluenesulphonic acid (0.05 g, 0.255 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO4) and concentrated in vacuo to give the acetal 17 (0.20 g, 47%).
  • δH(400 MHz; CDCl3) 3.59 (2H, m), 2.08-1.17 (13H, m), 1.01 (3H, d, J 6.8, Me); δC(CDCl3) 117.4, 78.3, 78.0, 46.4, 38.0, 32.1, 20.6, 17.2, 17.1
  • The acetal of the racemic 3-methylcyclopentanone has signals as shown below:
  • δC(CDCl3) 117.4, 78.3, 78.1 (×2), 78.0, 46.7, 46.4, 38.5, 38.0, 32.5, 32.1, 20.6, 20.2, 17.2, 17.1, 16.9 (×2).
    • EXAMPLE 7 Enantiomerically Pure (3S,4S)-3-ethyl-4-methyl-cyclopentanone (20)
  • Figure US20050215816A1-20050929-C00046
    • The Acetoxy Cyclopentanone 18
  • Ethylmagnesium chloride (19.6 ml of a 2M solution in THF, 39.2 mmol) was added slowly to a stirred solution of dimethylzinc (19.6 ml of a 2M solution in toluene, 39.2 mmol) in THF (80 ml) at 0° C. under argon. After 20 minutes, the mixture was cooled to −78° C. and (S)-4-acetoxycyclopent-2-enone (5.0 g, 35.7 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with IN hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield the acetoxy cyclopentanone 18 as a solution in toluene which was used without further purification in the next step.
    υmax(film)/cm−1 1741 (C═O).
  • δH(400 MHz; CDCl3) 5.10 (1H, m, CHOAc), 2.70 (1H, dd, J 19.3, 6.7), 2.57 (1H, ddd, J 18.5, 8.3, 1.2), 2.32-2.20 (2H, m), 2.07 (3H, s, OCOMe), 2.00 (1H, m), 1.62 (2H, m), 0.98 (3H, t, J 7.2, Me).
    • The Ethylcyclopentenone 19
  • Acetoxy cyclopentanone 18 (approx. 35.7 mmol) in dichloromethane (45 ml) was added dropwise over 1 hr to a stirring solution of DBU (5.34 ml, 35.7 mmol) in dichloromethane (100 ml) at −40° C. under argon. The mixture was allowed to warm to −30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (30 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×100 ml). The combined ether layers were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 8:2) to give ethylcyclopentenone 19 (3.4 g, 86% from (S)-4-acetoxycyclopent-2-enone).
    υmax(film)/cm−1 1713 (C═O).
  • δH(400 MHz; CDCl3) 7.65 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.16 (1H, dd, J 5.6, 2.0, CH═CHC═O), 2.88 (1H, m), 2.54 (1H, dd, J 19.0, 6.3, CHAHBC═O), 2.02 (1H, dd, J 18.8, 2.2, CHAHBC═O) 1.63 (1H, m), 1.47 (1H, m), 0.99 (3H, t, J 7.6, Me).
    • The Cyclopentanone 20
  • Methylmagnesium chloride (22.5 ml of a 3M solution in ether, 67.5 mmol) was added slowly to a stirred solution of dimethylzinc (16.9 ml of a 2M solution in toluene, 33.8 mmol) in THF (100 ml) under argon at 0° C. After 30 minutes the mixture was cooled to −78° C. and 19 (3.37 g, 30.6 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for 20 minutes and then quenched by the addition of saturated ammonium chloride solution (25 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield 20 as a solution in toluene which was purified by column chromatography (SiO2, pentane-ether, 95:5) to give the cyclopentanone 20 (2.4 g, 62%).
    υmax(film)/cm−1 1738 (C═O).
  • δH(400 MHz; CDCl3) 2.50-2.40 (2H, m), 1.92-1.60 (6H, m), 1.12 (3H, d, J 6.1, Me), 0.93 (3H, t, J 6.5, Me).
    • Conversion To An Acetal
  • Figure US20050215816A1-20050929-C00047
  • The ketone 20 (0.22 g, 1.74 mmol), (2R,3R)-(-)-2,3-butanediol (0.18 ml, 1.91 mmol) and p-toluenesulphonic acid (0.033 g, 0.174 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction nixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (gSO4) and concentrated in vacuo to give 24 (0.19 g, 55%).
  • δC(CDCl3) 115.6, 78.1 (×2), 47.6, 47.1, 44.9, 38.2, 26.2, 19.3, 18.2, 16.9, 14.2; m/z (CI+) 199 (+H, 82%).
    • EXAMPLE 8 Enantiomerically Pure (R)-3-ethylcyclopentanone (21)
  • Figure US20050215816A1-20050929-C00048
  • A mixture of 19 (3.4 g, 30.9 mmol) and 10% palladium on charcoal (catalytic quantity) in ethyl acetate (50 ml) was shaken at 55 psi in hydrogen at 30° C. for 6 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 9:1) to give the 3-ethylcyclopentanone 21 (3.4 g, 98%).
    υmax(film)/cm−1 1737 (C═O).
  • δH(400 MHz; CDCl3) 2.38 (1H, dd, J 18.1, 7.3), 2.29 (1H, dd, J 16.1, 8.8), 2.21-2.04 (4H, m), 1.79 (1H, ddd, J 18.1, 9.8, 1.1), 1.47 (2H, m), 0.95 (3H, t, J 7.6, Me).
    • Conversion To Acetal 25
  • Figure US20050215816A1-20050929-C00049
  • The ketone 21 (0.098 g, 0.874 mmol), (2R,3R)-(-)-2,3-butanediol (0.088 ml, 0.96 mmol) and p-toluenesulphonic acid (0.017 g, 0.087 mmol) were refluxed together in benzene (10 ml) for 3 hours using a Dean-Stark trap. The reaction mixture was allowed to cool, taken up in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution, brine, dried (MgSO4) and concentrated in vacuo to give 25 (0.12 g, 73%).
  • δC(CDCl3) 117.2, 78.2, 78.1, 44.5, 39.8, 38.0, 30.1, 28.6, 17.0, 16.9, 12.5; m/z (CI+) 185 (M+H, 75%)
    • EXAMPLES 10 & 11 (3R,4R)-3 ethyl4-methyl-cyclopentanone (22) And (S)-3-ethyl-cyclopentanone (23)
  • Figure US20050215816A1-20050929-C00050
  • Compounds 22 and 23 were made using the procedure of the previous examples.
    • Conversion To Acetals 26, 27
  • Figure US20050215816A1-20050929-C00051
  • The enantiomeric purity of ketone 22 was confirmed by making acetal 26 using the previously described procedure.
  • δC(CDCl3) 115.7, 78.2, 78.1, 47.3, 46.9, 44.6, 38.0, 26.6, 19.3, 18.8, 17.3, 17.2, 14.2; m/z (CI+) 199 (M+H, 80%)
  • The enantiomeric purity of ketone 23 was also confirmed by making acetal 26 using the previously described procedure.
  • δC(CDCl3) 117.2, 78.3, 78.1, 44.2, 39.3, 37.6, 29.7, 28.8, 17.2, 12.5; m/z (CI+) 185 (M+H,78%).

Claims (25)

1-29. (canceled)
30. A method of making an enantiomerically pure compound of the formula (I) or (II):
Figure US20050215816A1-20050929-C00052
wherein R and R′ represent C1-C10 alkyl, C2-C10 alkenyl or C3 -C10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans, which method comprises:
conjugate addition of an organometallic nucleophile that provides a group R as defined above to a compound of the formula (III) or (IV):
Figure US20050215816A1-20050929-C00053
wherein X represents a leaving group to give a trans 3,4-disubstituted addition product of formula (V) or (VI) in which R and X are as previously defined;
Figure US20050215816A1-20050929-C00054
eliminating the leaving-group X from the addition product of formula (V) or (VI) to give an (R)- or (S)-4-alkyl or 4-alkenyl cyclopent-2-en-1-one of formula (VII) or (VIII)
Figure US20050215816A1-20050929-C00055
and either
(i) hydrogenation of the compound of formula (VII) or (VIII) to give a cyclopentanone of formula (I) or
(ii) conjugate addition of a second organometallic nucleophile that provides a group R′ as defined above to the compound of formula (VII) or (VIII) to give a trans 3,4-disubstituted addition product of formula (II).
31. The method of claim 30, when used to make an (S)-compound of formula (I).
32. The method of claim 30, when used to make an (R)-compound of formula (I).
33. The method of claim 30, when used to make a (3S,4S)-compound of formula (II).
34. The method of claim 30, when used to make a (3R,4R)-compound of formula (II).
35. The method of claim 30, when used to make a compound in which R and R′ (if present) represent methyl, ethyl or n-propyl.
36. The method of claim 30, when used to make any of the following compounds:
(S)-3-methylcyclopentanone;
(R)-3-methylcyclopentanone;
(S)-3-ethylcyclopentanone;
(R)-3-ethylcyclopentanone;
(S)-3-n-propylcyclopentanone;
(R)-3-n-propylcyclopentanone;
(3S,4S)-3,4-dimethyl-cyclopentanone;
(3R,4R)-3,4-dimethyl-cyclopentanone;
(3S,4S)-3,4-diethyl-cyclopentanone;
(3R,4R)-3,4-diethyl-cyclopentanone;
(3S,4S)-3-ethyl-4-methyl-cyclopentanone;
(3R,4R)-3-ethyl-4-methyl-cyclopentanone;
(3S,4S)-3-methyl-4-propyl-cyclopentanone;
(3R,4R)-3-methyl-4-propyl-cyclopentanone;
(3S,4S)-3-ethyl-4-propyl-cyclopentanone;
(3R,4R)-3-ethyl-4-propyl-cyclopentanone.
37. The method of claim 30, wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I).
38. The method of claim 30 wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I); and wherein
the hydrogenation catalyst is selected from palladium on charcoal, platinum oxide, Raney nickel, and rhodium on alumina.
39. The method of claim 30, wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I); and wherein
the solvent is ethyl acetate or methanol.
40. The method of claim 30, wherein the conjugate addition is carried out by treating the elimination product of formula (VII) or (VIII) with a second organo-Grignard reagent or with a second an organo-lithium reagent in the presence of a dialkylzinc or zinc chloride or a copper (I) salt or a trialkylaluminium in a solvent at a temperature from −100° C. to 0° C. to produce a compound of formula (II).
41. The method of claim 40, wherein the solvent is selected from tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether and t-butyl methyl ether.
42. The method of claim 30, wherein the leaving group X in the compound of formula (III) or (IV) is acetoxy.
43. The method of claim 30, wherein the leaving group X in the compound of formula (III) or (IV) is halogen or sulfonic acid ester group.
44. An enantiomerically pure compound made by the method of claim 30.
45. The compound of claim 44, whose enantiomeric purity is 98% or above.
46. A method of producing a compound of one of the formulae shown below:
Figure US20050215816A1-20050929-C00056
in which the substituents R and R′ and the wedges have the meanings indicated in claim 30, which comprises providing a compound of formula (I) or (II) produced by the method of claim 30, converting said compound to a compound of formula (XI), (XII), (XIII) or (XIV), and optionally further converting said compound into a pharmaceutically acceptable salt.
47. The method of claim 46, wherein said conversion is via an intermediate (XV)-(XVIII) shown below:
Figure US20050215816A1-20050929-C00057
in which the substituents R and R′ and the wedges have the meanings indicated above.
48. The method of claim 47, wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by transforming the phenyl ring to a carboxylic acid and then to an amine.
49. The method of claim 47, wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by transforming the carboxylic acid group into an amine and oxidizing the phenyl group to an acid.
50. The method of claim 47, wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by protecting the carboxylic acid group, oxidizing the phenyl ring to a second carboxylic acid group, protecting the second carboxylic acid group, selectively de-protecting the first carboxylic acid group, transforming the first carboxylic acid group to an amine, and de-protecting the second carboxylic acid group.
51. A method of producing a compound of the formula (XV)-(XVIII) shown below:
Figure US20050215816A1-20050929-C00058
in which the substituents R and R′ and the wedges have the meanings indicated in claim 30, which comprises providing a compound of formula (I) or (II) produced by the method of claim 30, and converting said compound to a compound of formula (XV)-(XVIII).
52. An enantiomerically pure compound of the formula:
Figure US20050215816A1-20050929-C00059
wherein R and R′ represent C1-C10 alkyl, C2-C10 alkenyl or C3-C10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents being trans, and at least one of R and R′ not being methyl.
53. Any of the following compounds
(3S,4S)-3,4-diethyl-cyclopentanone;
(3R,4R)-3,4-diethyl-cyclopentanone;
(3S,4S)-3-ethyl-4-methyl-cyclopentanone;
(3R,4R)-3-ethyl-4-methyl-cyclopentanone;
(3S,4S)-3-methyl-4-propyl-cyclopentanone;
(3R,4R)-3-methyl-4-propyl-cyclopentanone;
(3S,4S)-3-ethyl-4-propyl-cyclopentanone;
(3R,4R)-3-ethyl-4-propyl-cyclopentanone.
US11/074,250 2000-06-28 2005-03-07 Cyclic ketones, their preparation and their use in the synthesis of amino acids Abandoned US20050215816A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/074,250 US20050215816A1 (en) 2000-06-28 2005-03-07 Cyclic ketones, their preparation and their use in the synthesis of amino acids

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0015771.9 2000-06-28
GB0015771A GB2364049A (en) 2000-06-28 2000-06-28 Cyclic ketones and their use in the synthesis of amino acids
US10/312,065 US6872856B2 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids
PCT/GB2001/002900 WO2002000584A1 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids
US11/074,250 US20050215816A1 (en) 2000-06-28 2005-03-07 Cyclic ketones, their preparation and their use in the synthesis of amino acids

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US10/312,065 Continuation US6872856B2 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids
PCT/GB2001/002900 Continuation WO2002000584A1 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids

Publications (1)

Publication Number Publication Date
US20050215816A1 true US20050215816A1 (en) 2005-09-29

Family

ID=9894534

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/312,065 Expired - Fee Related US6872856B2 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids
US11/074,250 Abandoned US20050215816A1 (en) 2000-06-28 2005-03-07 Cyclic ketones, their preparation and their use in the synthesis of amino acids

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/312,065 Expired - Fee Related US6872856B2 (en) 2000-06-28 2001-06-28 Cyclic ketones, their preparation and their use in the synthesis of amino acids

Country Status (24)

Country Link
US (2) US6872856B2 (en)
EP (1) EP1296921A1 (en)
JP (1) JP2004501884A (en)
KR (1) KR100778953B1 (en)
CN (1) CN1438985A (en)
AP (1) AP2002002699A0 (en)
AU (2) AU6620801A (en)
BR (1) BR0112076A (en)
CA (1) CA2411808A1 (en)
EA (1) EA200201202A1 (en)
GB (1) GB2364049A (en)
HR (1) HRP20021017A2 (en)
HU (1) HUP0301306A2 (en)
IL (2) IL153704A0 (en)
IS (1) IS6636A (en)
MA (1) MA26921A1 (en)
MX (1) MXPA03000076A (en)
NO (1) NO20026198L (en)
NZ (1) NZ523218A (en)
OA (1) OA12298A (en)
PL (1) PL359107A1 (en)
WO (1) WO2002000584A1 (en)
YU (1) YU93702A (en)
ZA (1) ZA200300243B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2364049A (en) * 2000-06-28 2002-01-16 Warner Lambert Co Cyclic ketones and their use in the synthesis of amino acids
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
CA2615490A1 (en) * 2005-07-18 2007-01-25 Pharmacia & Upjohn Company Llc Stereoselective synthesis of 3,4-disubstituted cyclopentanones and related compounds
CN102190536A (en) * 2010-03-08 2011-09-21 华东理工大学 Method for organically catalyzing asymmetric conjugated addition of ketene and organic phosphorus compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024175A (en) * 1974-12-21 1977-05-17 Warner-Lambert Company Cyclic amino acids
US4087544A (en) * 1974-12-21 1978-05-02 Warner-Lambert Company Treatment of cranial dysfunctions using novel cyclic amino acids
US5134238A (en) * 1990-05-24 1992-07-28 Brigham Young University Chiral copper amine complexes
US6872856B2 (en) * 2000-06-28 2005-03-29 Warner-Lambert Company Cyclic ketones, their preparation and their use in the synthesis of amino acids

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254708A (en) * 1987-06-16 1993-10-19 Nissan Chemical Industries, Ltd. Substituted cyclic ketones, substituted cyclic enones, and process for producing the same
US5480962A (en) 1993-07-22 1996-01-02 Eastman Chemical Company Copolyesters having repeat units derived from succinic acid
HUP0004310A3 (en) * 1997-10-27 2001-11-28 Warner Lambert Co Cyclic amino acids, and derivatives thereof and pharmaceutical compositions comprising the said compounds as active agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024175A (en) * 1974-12-21 1977-05-17 Warner-Lambert Company Cyclic amino acids
US4087544A (en) * 1974-12-21 1978-05-02 Warner-Lambert Company Treatment of cranial dysfunctions using novel cyclic amino acids
US5134238A (en) * 1990-05-24 1992-07-28 Brigham Young University Chiral copper amine complexes
US6872856B2 (en) * 2000-06-28 2005-03-29 Warner-Lambert Company Cyclic ketones, their preparation and their use in the synthesis of amino acids

Also Published As

Publication number Publication date
JP2004501884A (en) 2004-01-22
CA2411808A1 (en) 2002-01-03
NZ523218A (en) 2004-06-25
US6872856B2 (en) 2005-03-29
PL359107A1 (en) 2004-08-23
AP2002002699A0 (en) 2002-12-31
KR20030016311A (en) 2003-02-26
NO20026198D0 (en) 2002-12-23
ZA200300243B (en) 2004-06-14
AU2001266208B2 (en) 2006-11-23
HRP20021017A2 (en) 2004-02-29
YU93702A (en) 2006-08-17
WO2002000584A1 (en) 2002-01-03
NO20026198L (en) 2002-12-23
GB2364049A (en) 2002-01-16
IS6636A (en) 2002-11-28
GB0015771D0 (en) 2000-08-16
HUP0301306A2 (en) 2003-08-28
MXPA03000076A (en) 2003-10-15
EA200201202A1 (en) 2003-06-26
KR100778953B1 (en) 2007-11-27
EP1296921A1 (en) 2003-04-02
MA26921A1 (en) 2004-12-20
CN1438985A (en) 2003-08-27
OA12298A (en) 2004-03-18
IL153704A0 (en) 2003-07-06
BR0112076A (en) 2003-09-02
AU6620801A (en) 2002-01-08
IL190490A0 (en) 2008-11-03
US20030187296A1 (en) 2003-10-02

Similar Documents

Publication Publication Date Title
US20050215816A1 (en) Cyclic ketones, their preparation and their use in the synthesis of amino acids
AU2001266208A1 (en) Cyclic ketones, their preparation and their use in the synthesis of amino acids
CN1122039C (en) Process for reducing prochiral ketone to produce optically active alcohol of high optical purity
AU741832B2 (en) Method for substituted 4-phenyl-4-cyancyclohexanoic acids
JP4800482B2 (en) (2S, 4R, 9S) -Octahydro-1H-indole-2-carboxylic acid production method and intermediates thereof
US4350641A (en) 4-Tert.-butoxyphenylglycinonitrile and the preparation of D-(-)- and L-(+)-4-hydroxyphenylglycine
US6921832B2 (en) Optically active fluorine-containing compounds and processes for their production
US20030083520A1 (en) Process for preparing bicyclic amino acid
JP4529419B2 (en) Optically active fluorine-containing compounds and methods for producing them
Hayashi et al. A Diastereocontrolled Route to (R)-(-)-Baclofen Using a Cyclopentanoid Chiral Building Block
JP2786300B2 (en) Stereoselective process for producing optically active S, S- or R, R-β-amino alcohols
JP2542843B2 (en) Novel norbornane derivative and method for producing the same
US8658806B2 (en) Process for preparing optically active antrocin
US20030050497A1 (en) Process and intermediates for preparing a cyclohexylnitrile
JP2003171354A (en) Method for producing optically active amine compound or salt thereof
JPH08277256A (en) Optically active (s)-2-benzyloxycarbonylamino-1-(4-methoxyphenyl)ethanol and its production
JPH0769960A (en) Process for producing optically active 2-norbornanone
JPH07316086A (en) Production of 1,2,2,-trimethylcyclopentyl methyl ketone, derivative and 3,4,5,5-tetramethyl3-cyclohexene derivative and 7-oxa-1,5,5,6-tetramethylbicyclo(4.1.0)heptane derivativ
CA2397296A1 (en) Process and intermediates for preparing a cyclohexylnitrile
JPH0967382A (en) Production of optically active 4-trimethylsilyl-3butyn-2-ol
JP2007238526A (en) Process for producing optically active homoallyl primary amine using asymmetric 2-aza-corp rearrangement
JP2001025395A (en) Method for producing optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one
JP2001025396A (en) Method for producing optically active 4-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one
JPH09241258A (en) 2-oxazolidinone derivative
AU2004205303A1 (en) Process and intermediates for preparing a cyclohexylnitrile

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION