(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 18 February 2010 (18.02.2010) WO 2010/017573 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 489/08 (2006.01) BOlJ 23/42 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 489/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/AU2009/000925 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 2 1 July 2009 (21 .07.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/188,574 11 August 2008 ( 11.08.2008) 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): TAS- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, MANIAN ALKALOIDS PTY LIMITED [AU/AU]; TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, 160 Birralee Road, Westbury, Tasmania 7303 (AU). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (75) Inventors/Applicants (for US only): BAILEY, Timothy ML, MR, NE, SN, TD, TG). S. [AU/AU]; 5 Canopus Drive, Blackstone Heights, Tas mania 7259 (AU). REZAIE, Robert [AU/AU]; 83 Published: Bayview Drive, Blackstone Heights, Tasmania 7250 — with international search report (Art. 21(3)) (AU). (74) Agent: ADAMS PLUCK; Suite 3, Level 1, 20 George Street, Hornsby, New South Wales 2077 (AU). (54) Title: PROCESS FOR MAKING MORPHINAN-6 α-OLS (57) Abstract: The present invention provides a process whereby morphinan-6-ones can be converted stereospecifically to the corresponding morphinan-6 α-ols by catalytic hydrogenation under basic conditions. PROCESS FOR MAKING MORPHINAN-όα-OLS FIELD OF THE INVENTION This invention relates to a process for the manufacture of morphinan-6 α-ols stereo- specifϊ cally and in high chemical yield by catalytic hydrogenation of the corresponding morphinan-6-ones under alkaline conditions. BACKGROUND OF THE INVENTION Morphinan-6 α-ols, including such compounds as dihydrocodeine, oxymorphol, oxycodol and nalbuphine are important morphine derivatives due to their behaviour as potent analgesics or antagonists. Some prior synthetic routes to these compounds include; • from codeine or morphine, where the 6α- stereochemistry of the 6-hydroxy morphinan was already fixed by the stereo-chemistry of the natural product (see for example US 6887999 for the hydrogenation of codeine to dihydrocodeine), • Reduction of the 7,8-didehydro derivatives morphinan-6-ones using metal hydride reducing agents (e.g. sodium borohydride, lithium tri-sec-butyl borohydride) followed by hydrogenation to give the pure 6α- isomer of the corresponding morphinan-6-ol. (Sargent et al., "Hydroxylated codeine derivatives", Journal of Organic Chemistry, 23, 1247 - 1251, (1958), and A.C. Currie et al., J. Chem. Soc, 1960, 773.) This strategy was also used to convert 14-hydroxynormorphinones preferably to the 6α-epimer of the corresponding 14- hydroxydihydromorphine (preferably N-O 3-bis(ethoxycarbonyl)-14- hydroxynormorphmone to N-O 3-bis(ethoxycarbonyl)-14- hydroxydihydronormorphine; Kavka, "Preparation of nalbuphine having low levels of β-epimer", US 5756745). Similarly, Cheng et al. converted methoxymethyl-protected naloxone to the corresponding 6-αepimer using potassium and sodium tri-sec-butylborohydride (Na and K-selectride respectively), sodium triethylborohydride and sodium triacetoxyborohydride in high chemical yield and > 99% selectivity for the α-epimer (Stereoselective reduction of a morphinone, WO 2007/121 114). US Patent Nos. 5,208,338 and 5,336,483 describe the preparation of radiolabeled -substituted-6-iodo-3, 14- dihydroxy-4,5- α-epoxymorphinans (Scheme 4) which includes the selective reduction of the 6-carbonyl group using Z-selectride, specifically described for the synthesis of 6α-naltrexol from naltrexone. TLC measurements indicated the absence of the epimeric 6β-isomer. • By contrast, reduction of oxymorphone (the morphinan-6-one saturated at the 7,8 position) using sodium borohydride promoted formation of the 6αmorphman-6- ol contaminated with significant amounts of the 6β isomer. (Burke and Rice., "Probes for narcotic receptor mediated phenomena. 11. Synthesis of 17-methyl- and 17-cyclopropylmethyl-3,14-dihydroxy-4,5 α-epoxy-6β-fluoromorphinans (FOXY and CYCLOFOXY) as models of opioid ligands suitable for positron emission transaxial tomography." Heterocycles, 23, 1985, 99 - 106.) • Similarly, lithium aluminum hydride or sodium borohydride reduction of 8,14- dihydroxydihydrocodeinone (oxycodone) leads to epimeric dihydroxydihydrocodeines (oxycodols) (Sargent et al., "Hydroxylated codeine derivatives", Journal of Organic Chemistry, 23, 1247 - 1251, (1958)). • Similarly, reduction of naltrexone with either sodium borohydride in tetrahydrofuran or lithium tri-sec-butylborohydride in tetrahydrofuran at -78°C gave 6α-naltrexol contaminated with traces of the 6β epimer. (Brine et al., "Ring C conformation of 6β-naltrexol and 6α-naltrexol. Evidence from Proton and Carbon- 13 nuclear magnetic resonance." Journal of Organic Chemistry, 41, (1976) 3445 - 3448.) • Other literature report the reduction of naltrexone to 6oc-naltrexol, e.g. L.D. Olsen et al., J. Med. Chem., 1990, 33, 737-741 or the reduction of 3-0-tert- butyldimethylsilyl protected naltrexone to the corresponding alpha isomer (G.A. Brine et al., J. Org. Chem., 1976, 41(21), 3445-3448) by using I-selectride in THF at -78°C. Traces of the beta isomer formed during the reduction were removed by chromatography or recrystallization. The main drawbacks of the aforementioned procedures from the literature are low selectivities of the reductions (formation of 5-10% beta-isomer) resulting in a tedious procedure for the removal of the contaminant. Such removal requires either several recrystallizations giving an unacceptable loss of yield or a purification by column chromatography, which is not a commercially viable procedure. In case of the preparation of 6α-naltrexol from naltrexone, Z-selectride was used as reducing agent at very low temperatures of -78°C, or 3-(9-ter£-butyldimethylsilyl protected naltrexone was used, making the process more complicated and expensive due to the need for special refrigerating equipment and/or expensive protecting groups. In contrast to the metal hydride reducing agents traditionally used for the reduction of ketones to alcohols, hydrogenation does not require very low temperatures, or prior protection of the 3-hydroxy group, followed by de-protection to the desired 3-hydroxy- 6α-morphinol and is operationally simpler and creates little or no waste during the processing. Few examples exist for the hydrogenation of the ketone group of morphinan-6-ones. • Hydrogenation of dihydrohydroxycodeinone (also known as oxycodone) in 10% aqueous acetic acid as solvent and platinum oxide as catalyst gave a mixture of 6α- and 6β- epimers of oxycodol with the 6α- epimer being the major product (Lutz R.E., and Small L., "Reduction studies in the morphine series. X. Hydroxycodeinone." Journal of Organic Chemistry, 4, 220 - 233, (1939)). In this solvent mixture the reaction clearly was not stereo-selective. • There is only one example of a hydrogenation of a morphinan-6-one to a morphinan-6-ol. Hydrocodone was hydrogenated in ethanol as solvent using platinum oxide as catalyst (Grew and Powles, "Manufacture of 1- Dihydrocodeine" US 3830819). The epimeric purity of the morphin-6-ol product was not mentioned in this example. There remains a need for an efficient stereo-selective and environmentally friendly route to the pure 6α-epimer of morphinan-6-ols, particularly 14-hydroxymorphinan-ols. Increasingly, morphinan-6-ones and 14-hydroxymorphinan-6-ones are being used as intermediates in the synthesis of the corresponding morphinan-6-ols because they are available conveniently and in high yield from opiate raw materials thebaine and oripavine, both of which became commercially available in large quantities only relatively recently. SUMMARY OF THE INVENTION In one aspect of the invention there is provided a process for producing a morphman- βα-ol compound of formula (Ha) Ha and pharmaceutically acceptable salts thereof, comprising hydrogenating a morphinan-6-one compound of formula (I) I in an aqueous solvent and a water soluble base wherein the aqueous solvent is selected from the group consisting of water and a mixture of water and a water-miscible co- solvent in the presence of a catalyst at a pH between about 8.5 and about 14 (preferably, between about 11 and about 14, more preferably, between about 12.0 and about 13.5) to provide the compound of formula (Ha) having less than one percent of a morphinan-6 β-ol compound of formula (lib) wherein 1 C3-C6 R is selected from hydrogen, C1- C1Oalkyl, cycloalkylCi - C 10 alkyl, -C(O)-C i-Cioalkyl or -C(O)-OC i-C 10 alkyl; and 2 3 3 3 R is selected from H, OR or OC(O)R wherein R is selected from hydrogen or C1- C 10 alkyl. One embodiment of the present invention is the process wherein the catalyst is platinum; preferably, platinum oxide. Another embodiment of the invention is the process wherein R 1 is selected from H, Ci - Ce alkyl, or C3-C6 cycloalkylCi - Ce alkyl.