(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 February 2010 (11.02.2010) WO 2010/017504 Al (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07C 269/04 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US2009/053 196 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 7 August 2009 (07.08.2009) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (25) Filing Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/087,056 7 August 2008 (07.08.2008) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 61/086,821 7 August 2008 (07.08.2008) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (71) Applicants (for all designated States except US): XENO- ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, PORT, INC. [US/US]; 3410 Central Expressway, Santa MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, Clara, CA 9505 1 (US). GLAXO GROUP LIMITED TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [GB/GB]; Glaxo Wellcome House, Berkeley Avenue, ML, MR, NE, SN, TD, TG). Greenford, Middlesex UB6 ONN (GB). Declarations under Rule 4.17: (72) Inventors; and — as to the identity of the inventor (Rule 4.17 (ϊ)) (75) Inventors/Applicants (for US only): RAILLARD, Stephen, P. [US/US]; 964 Trophy Drive, Mountain — as to applicant's entitlement to apply for and be granted View, CA 94040 (US). MANTHATI, Suresh, K. a patent (Rule 4.1 7(H)) [IN/US]; 175 Calvert Drive, Apt. D102, Cupertino, CA — as to the applicant's entitlement to claim the priority of 95014 (US). LIU, Peng [CN/US]; 709 Swedeland Road, the earlier application (Rule 4.1 7(Hi)) King Of Prussia, PA 19406 (US). DAI, Qunying [CN/US]; 709 Swedeland Road, King Of Prussia, PA Published: 19406 (US). YIN, Hao [CN/US]; 709 Swedeland Road, — with international search report (Art. 21(3)) King Of Prussia, PA 19406 (US). — before the expiration of the time limit for amending the (74) Agents: WALKER, David et al; 370 Seventeenth Street, claims and to be republished in the event of receipt of Suite 4700, Denver, CO 80202 (US). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: METHODS OF SYNTHESIZING 1-(ACYLOXY)-ALKYL CARBAMATE PRODRUGS (57) Abstract: The present disclosure relates to methods of synthesizing l-(acyloxy)-alkyl carbamate prodrugs and to intermedi- ates used in the methods. Formula I METHODS FOR SYNTHESIZING 1-(ACYLOXY)-ALKYL CARBAMATE PRODRUGS [001] This application claims priority to U.S. Provisional Application Serial Nos. 61/087,056 filed August 7, 2008, and 61/086,821 filed August 7, 2008, each of which is incorporated by reference in its entirety. Field [002] Methods of synthesizing l-(acyloxy)-alkyl carbamate prodrugs of amine- containing drugs such as gabapentin, pregabalin, baclofen, and tranexamic acid, and intermediates used in the methods are disclosed. Background [003] The oral bioavailability of certain drugs can be improved by conversion to prodrugs. Certain prodrugs are derivatives of the parent drug in which a functional group is "masked" by a promoiety. Following administration to a patient the prodrug is metabolized to release the parent drug. [004] The 1-(acyloxy)-alkyl functionality is an example of a promoiety that has been used to functionalize amino containing drugs such as gabapentin, pregabalin, baclofen, and tranexamic acid. Gabapentin ([l-(aminomethyl)cyclohexyl]acetic acid) is an FDA approved drug that is marketed for the treatment of post herpetic neuralgia and epilepsy. l-{[( -Isobutanoyloxyethoxy)carbonyl]aminomethyl}-l-cyclohexane acetic acid is a 1- (acyloxy)-alkyl carbamate prodrug of gabapentin that has utility in the treatment of epilepsy (Gallop et al, WO 02100347), pain (Gallop et al, WO 02100347), particularly neuropathic pain or pain associated with irritable bowel syndrome, anxiety (Gallop et al, WO 02100347), particularly general anxiety disorder, alcohol dependency or ethanol withdrawal syndrome (Gallop et al, WO 02100347), restless legs syndrome (Barrett and Canafax, WO 2005027850), migraine prophylaxis (Barrett and Cundy, US 20080161393), fibromyalgia (Barrett and Cundy, US 20080161393), and hot flashes (Barrett and Gallop, WO 2004089289), particularly hot flashes associated with menopause. Pregabalin ((S)-3- (aminomethyi)-5-methyl-hexanoic acid) is an FDA approved drug that is marketed for the treatment of post herpetic neuralgia, fibromyalgia, and epilepsy. Pregabalin is not absorbed from the lower gastrointestinal tract and exhibits a short half life in vivo, and therefore frequent dosing is required to maintain therapeutic levels in the body. (3S)-{[l-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid, (3S)- {[1-isobutanoyloxyisobutoxy] carbonylaminomethyl} -5-methyl-hexanoic acid, and (3S)-{[l-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid are examples of l-(acyloxy)-alkyl carbamate prodrugs of the GABA analog pregabalin, (3S)-aminomethyl-5- methyl-hexanoic acid, which exhibit high bioavailability as pregabalin when dosed either orally or directly into the colon of a mammal (Gallop et ah, US 6,972,341 and US 7,186,855; and Yao et al, U.S. Application Nos. 12/358,454 and 12/358,507 filed January 23, 2009). [005] The l-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of R- baclofen ((R)-4-amino-3-(4-chlorophenyl)butanoic acid). Gallop et al, US 7,109,239 and US 7,300,956 disclose 1-(acyloxy)-alkyl carbamate prodrugs of R-baclofen such as (3R)-4- {[(lS)-2-methyl-l-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4- chlorophenyl)butanoic acid. R-Baclofen is known to be useful for treating spasticity and gastro-esophageal reflux disease (van Herwaarden et ah, Aliment. Pharmacol. Ther. 2002, 16(9), 1655-62; Ciccaglione and Marzio, Gut 2003, 52(4), 464-70; Andrews et ah, US 6,1 17,908; and Fara et ah, WO 02096404); in promoting alcohol abstinence in alcoholics (Gessa et ah, WO 0126638); in promoting smoking cessation (Gessa et ah, WO 0108675); in reducing addiction liability of narcotic agents (Robson et ah, US 4,126,684); in the treatment of emesis (Bountra et ah, US 5,719,185); as an anti-tussive for the treatment of cough (Kreutner et ah, US 5,006,560); as well as for treating neuropathic and musculoskeletal pain (Benson et ah, US 200901 18365), movement disorders such as dystonia and hiccups; peripheral nerve disorders such as muscle stimulation disorders; spinal cord disorders such as spastic paraparesis; cranial nerve disorders such as glossopharyngeal neuralgia and trigeminal neuralgia; multiple sclerosis; and cerebral palsy. [006] The l-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of tranexamic acid ( rarø-4-(aminomethyl)-cyclohexanecarboxylic acid). For example, Zerangue et ah, US 7,351,740, disclose l-(acyloxy)-alkyl carbamate prodrugs of tranexamic acid such as 4-({[(2- methylpropanoyloxy)ethoxy]carbonylamino}methyl)cyclohexanecarboxylic acid, which is a l-(acyloxy)-alkyl carbamate prodrug of tranexamic acid. Tranexamic acid is known to be useful in treating bleeding such as excessive menstrual bleeding (menorrhagia), bleeding associated with cardiac surgery, upper gastrointestinal hemorrhage, blood loss in patients with advanced cancer, bleeding that occurs during dental procedures in hemophiliacs, and skin conditions such as wound healing, epidermal hyperplasia, skin roughening, unwanted skin pigmentation, and tumor metastasis (Zerangue et ah, US 7,351,740). [007] Methods of synthesizing 1-(acyloxy)-alkyl carbamate prodrugs are disclosed in Gallop et ah, US 6,818,787, US 6,927,036, US 6,972,341, US 7,186,855, and US 7,227,028; Raillard et ai, US 7,232,924; Gallop and Bhat, WO 200501001 1; and in Alexander, US 4,760,057, US 4,916,230, and US 5,684,018. [008] Other methods of synthesizing 1-(acyloxy)alkyl carbamate prodrugs are more recently disclosed by Raillard et at., U.S. Provisional Application No. 61/087,038 filed August 7, 2008. Summary [009] Methods of synthesizing 1-(acyloxy)-alkyl carbamate prodrugs are disclosed. [0 10] In a first aspect, methods of synthesizing a compound of Formula (I) or a salt thereof are disclosed comprising: reacting a compound of Formula (V) or a salt thereof with a primary or secondary amine-containing drug HNR9R10 to provide a compound of Formula (Ia): (I) and, when R 1 1 is a leaving group in the compound of Formula (Ia), the method comprises reacting the compound of Formula (Ia) or a salt thereof with a carboxylic acid of formula R1- COOH in the presence of an organic base, or with a salt of a carboxylic acid of formula R1- COOH to provide the compound of Formula (I) or a salt thereof; wherein: 1 R is chosen from C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, phenyl, substituted phenyl, and C7- phenylalkyl; R 1 1 is chosen from a leaving group and -OC(O)-R 1; 2 3 R and R are independently