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Wo 2008/127646 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 23 October 2008 (23.10.2008) WO 2008/127646 A2 (51) International Patent Classification: Not classified AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (21) International Application Number: EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, PCT/US2008/004699 IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, (22) International Filing Date: 10 April 2008 (10.04.2008) MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, (25) Filing Language: English PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 60/922,994 11 April 2007 (11.04.2007) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): BIOVER- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), DANT, INC. [US/US] ; 7330 Carroll Road, San Diego, CA European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, 92121 (US). FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (72) Inventors; and CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): NOTZ, Wolfgant, Reinhard, Ludwig [DE/US]; 4386 Idaho Street, #1, Declarations under Rule 4.17: San Diego, CA 92104 (US). SCOTT, Robert, William — as to applicant's entitlement to apply for and be granted a [US/US]; 7049 Cantaberra Ct., San Diego, CA 92129 patent (Rule 4.17(U)) (US). ZHAO, Lishan [CN/US]; 6564 Red Knot Street, — as to the applicant's entitlement to claim the priority of the Carlsbad, CA 9201 1 (US). TAO, Junhua [US/US]; 12142 earlier application (Rule 4.17(Ui)) Darkwood Road, San Diego, CA 92129 (US). (74) Agents: SEIDMAN, Stephanie, L. et al; Bell Boyd & Published: Lloyd LLP, 3580 Carmel Mountain Road, Suite 200, San — without international search report and to be republished Diego, CA 92130 (US). upon receipt of that report — with sequence listing part of description published sep a (81) Designated States (unless otherwise indicated, for every rately in electronic form and available upon request from kind of national protection available): AE, AG, AL, AM, the International Bureau (54) Title: TRANSAMINASE-B ASED PROCESSES FOR PREPARATION OF PREGABALIN (57) Abstract: Provided herein are compounds and processes to prepare intermediates and precursors of pregabalin and related compositions, and processes for the preparation of pregabalin. TRANSAMINASE-BASED PROCESSES FOR PREPARATION OF PREGABALIN Related Applications Benefit of priority is claimed herein to U.S. Provisional Patent Application Serial No. 60/922,994, filed April 11, 2007, to Wolfgang Reinhard Ludwig Note, Robert William Scott, Lishan Zhao and Junhua Tao, entitled "TRANSAMINASE- BASED PROCESSES FOR PREPARATION OF PREGABALIN ANDROGEN RECEPTOR MODULATOR COMPOUNDS AND METHODS." Where permitted, the disclosure of the above-referenced U.S. provisional application is incorporated herein by reference in its entirety. Field Provided herein are compounds and processes to prepare intermediates and precursors of pregabalin and related compositions, and processes for the preparation of pregabalin. Background (S)-Pregabalin, otherwise known as (3S)-3-(aminomethyl)-5-methylhexanoic acid, is a biologically active compound. This compound is an anticonvulsant drug, a drug for treatment of neuropathic pain, an adjunct therapy for partial seizures, and a drug for anxiety disorders (e.g., see U.S. Pat. Nos. 5,563,175, 6,001,876 and 6,127,418). (S)-Pregabalin activates L-glutamic acid decarboxylase (GAD) and promotes production of gamma-aminobutyric acid (GABA), a major inhibitory neurotrasmitter. (S)- Pregabalin binds to voltage-dependent calcium channels in the central nervous system. (S)-pregabalin (Lyrica® (Pfizer, Inc.)) is approved outside the U.S. for treating various peripheral neuropathic pain indications, such as diabetic and post herpetic neuropathic pain, and adjunctive therapy for partial epilepsy in adults. In the United States, (S)- pregabalin (Lyrica® (Pfizer, Inc.)) is approved for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, and for the adjunctive treatment of partial onset seizures in adults. There are several synthetic methods for preparing pregabalin (Hoekstra et al., Org. Proc. Res. Dev. 1:26 (1997); Burk et al., J. Org. Chem. 68: 5731 (2003); Sammis and Jacobsen, JACS 125:4442-4443 (2003); PCT Pat. App. Publication WO2006/1 10783; U.S. Pat. No. 6,891,059; and U.S. Pat. Pub. 2005283023). For example, U.S. Patent No. 6,891,059 describes the asymmetric hydrogenation of a cyano-substituted olefin. This produces an optically enriched cyano compound, which is reduced to obtain (S)-pregabalin. U.S. Pat. Pub. 2005283023 describes an enzymatic resolution process with the possibility of recycling of the wrong enantiomer. U.S. Pat. Pub. Sammis and Jacobsen report a method that uses an aluminum salen catalyst to add hydrogen cyanide to an alpha-beta unsaturated imide (JACS, 125:4442-4443, 2003). An alternative method that proceeds through a substituted lactam is described in WO2006/1 10783. Each of these syntheses is either inefficient, expensive or poses difficulty for the large scale production of (S)- pregabalin. Hence, a need exists for an efficient, cost effective, and safe method for the large-scale synthesis of (S)-pregabalin. Accordingly, among the objects herein, it is an object to provide alternative pathways for synthesis of (S)-pregabalin. Summary Provided are processes for the production of (S)-pregabalin ((3S)-3- (aminomethyl)-5-methylhexanoic acid). Provided are methods to synthesize racemic and enantiomerically enriched intermediates toward pregabalin. In one embodiment, the method includes chemical or enzymatic amine transfer or amination of an aldehyde precursor. Also provided are methods for synthesis of racemic and enantiomerically enriched intermediates in the synthesis of pregabalin. Also provided are methods for separation of such racemic intermediates into their respective enantiomers. Provided herein are compounds of formula I: where R is selected from among methyl, ethyl, n-butyl, z-butyl, pentyl, hexyl, heptyl, octyl, nonyl, C1-C9 heteroalkyl, cycloalkyl, aryl and heteroaryl. In some embodiments, R is C1-C3 alkyl. In some embodiments, R is n-butyl or isobutyl. In some embodiments, R is C3-C aryl. Also provided herein are methods for producing pregabalin. In one embodiment, the method includes hydrolyzing a compound of formula I: in R is an alkyl, alkenyl or aryl, to afford an aldehyde intermediate of formula II n M is hydrogen or a salt; and subjecting the aldehyde intermediate of formula II to chemical or enzymatic amine transfer or amination conditions to yield pregabalin: In some embodiments, the compound of formula I is prepared by reacting 4- methylpentanal with diisobutylamine and an alkyl-3-halo-propanoate. Also provided are methods for producing pregabalin, which include a) reacting diisobutylamine and 4-methylpentanal to produce an aldehyde intermediate of the structure: b) hydrolyzing the reaction product of step a) to yield a compound of formula II: where M is hydrogen or a salt, which cyclizes to form a compound of the structure: c) animating the reaction product of step b) to produce pregabalin. In another embodiment, provided herein is a method for producing pregabalin that includes reacting 4-methylpentanal with diisobutylamine and an alkyl-3-halo- propanoate to produce an aldehyde intermediate of formula I: aminating the aldehyde intermediate to produce a hexanoate intermediate of the structure: cyclizing the hexanoate intermediate to produce a lactam of the structure: treating the lactam with hydrochloric acid followed by addition of triethylamine to yield pregabalin. In another embodiment, provided herein is a method for producing pregabalin that includes a) reacting 4-methylpentanal with glyoxylic acid hydrate to produce a compound of the following structure: b) reducing asymmetrically the reaction product of step a) by chemical or enzymatic reduction to produce a compound of the following structure: c) aminating the reaction product of step b) to produce pregabalin. In another embodiment, provided herein is a method for producing pregabalin that includes a) treating 5-hydroxy-4-isobutylfuran-2(5//)-one: with base to yield a compound of the structure: where M is hydrogen or a salt; b) enzymatically or chemically reducing the product of step a) to produce a compound of the structure: ,where M is hydrogen or a salt; and c) chemically or enzymatically amidating the product of step c) followed by reduction to provide pregabalin. In some embodiments, the compound of formula I is a racemic mixture. In some embodiments, the compound of formula I is the S-enantiomer. In some embodiments, the compound of formula II is a racemic mixture. In some embodiments, the compound of formula II is the S-enantiomer. In one embodiment, the amination step is performed chemically under conditions wherein the desired S-stereochemistry is obtained hi one embodiment, chemical amination includes treating with an ammonia source. In other embodiments, the amination step is performed enzymatically under conditions wherein the desired S-stereochemistry is obtained. In some embodiments, the enzyme is a transaminase. In some embodiments, the transaminase is selected from among an Alcaligenes denitrificans transaminase, a Bordetella bronch-iseptica transaminase, a Bordetella parapertussis transaminase, a Brucella melitensis transaminase, a Burkholderia mallei transaminase, a Burkholderia pseudomallei transaminase, a Chromobacterium violaceum transaminase, an Oceanicola granulosus HTCC2516 transaminase, an Oceanobacter sp.
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