US008236957B2 (12) United States Patent (10) Patent No.: US 8.236,957 B2 Rezaie et al. (45) Date of Patent: Aug. 7, 2012 (54) PROCESS FOR MAKING FOREIGN PATENT DOCUMENTS MORPHINAN-6O-OLS WO WO 2007/121114 10/2007 WO WO 2008,137672 11, 2008 (75) Inventors: Robert Rezaie, Blackstone Heights OTHER PUBLICATIONS (AU); Timothy S. Bailey, Blackstone Heights (AU) International Search Report PCT/AU2009/000925, Aug. 19, 2009. Sargent, et al “Hydroxylated Codeine Derivatives”, Journal of (73) Assignee: Janssen Pharmaceutica B.V. (BG) Sir "S.R.E.E.Eine, Journal of - r Organic Chemistry, 1960, pp. 773-781. (*) Notice: Subject to any disclaimer, the term of this Burke, et al., “Probes for Narcotic Receptor Mediated Phenomena. patent is extended or adjusted under 35 11. Synthesis of 17-Methyl- and 17-Cyclopropylmethyl-3, U.S.C. 154(b) by 437 days. 14-Dihydroxy-4.5o-Epoxy-6B-Fluoromorphinans (FOXY and CYCLOFOXY) as models of Opioid Ligands suitable for Positron (21) Appl. No.: 12/538,545 Emission Transaxial Tomography.” Heterocycles, vol. 23, 1985, pp. 99-106. 22) Filed: Aug. 10, 2009 Brine, et al., “Ring C Conformation of 6B-Naltrexol and (22) g. U, 6O-Naltrexol. Evidence from Proton and Carbon-13 Nuclear Mag (65) Prior PublicationO O Data tic Resonance" Journal of Organic Chemistry, vol. 41, No. 21 1976, pp. 3445-3448. US 201O/OO36128A1 Feb. 11, 2010 Olsen, et al., “Conjugate Addition Ligands of Opioid Antagonists. Methacrylate Esters and Ethers of 60- and 6B-Naltrexol'. J. Med. Related U.S. Application Data Chem., 1990, vol. 33, pp. 737-741. Lutz, et al., “Reduction Studies in the Morphine Series. IX. (60) Provisional application No. 61/188,574, filed on Aug. Hydroxycodeinone.” Journal of Organic Chemistry, vol. 4, 1939, pp. 11, 2008. 220-233. Goto, et al., “Formation of (+) Dihydrocodeine and (+) (51) Int. Cl. Dihydromorphine from Sinomenine.” Proceedings of the Imperial CO7D 489/08489/02 (2006.01) Alleryoto, et gy).al. (+)-pinyarocodein 5R. EP andA (+) phUihydromorphin dromorphi aus Sinomenin.” Justus Liebigs Annalender Chemie. 1941, vol. 547, pp. (52) U.S. Cl. ........ grrrrr. 546/44; 546/45 194-200 (cumulative). (58) Field of Classification Search .................... 546/44, 546/45 Primary Examiner — Charanjit Aulakh See application file for complete search history. (74) Attorney, Agent, or Firm — Kiera K. Mathey (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The present invention provides a process whereby morphi 3,830,819 A 8, 1974 Grew et al. nan-6-ones can be converted Stereospecifically to the corre 5,208,338 A 5, 1993 de Costa et al. sponding morphinan-6C.-ols by catalytic hydrogenation 5,336,483. A 8, 1994 de Costa et al. under basic conditions. 5,756,745 A 5, 1998 Kavka et al. 6,887,999 B1 5, 2005 Likhotvorik et al. 33 Claims, No Drawings US 8,236,957 B2 1. 2 PROCESS FOR MAKING opioid ligands Suitable for positron emission transaxial MORPHINAN-6O-OLS tomography.” Heterocycles, 23, 1985, 99-106.) Similarly, lithium aluminum hydride or sodium borohy CROSS-REFERENCE TO RELATED dride reduction of 8,14-dihydroxydihydrocodeinone APPLICATIONS 5 (oxycodone) leads to epimeric dihydroxydihydroco deines(oxycodols) (Sargent et al., “Hydroxylated This application claims priority from U.S. Provisional codeine derivatives”,Journal of Organic Chemistry, 23, Application Ser. No. 61/188,574 filed Aug. 11, 2008, the 1247-1251, (1958)). contents of each of which are hereby incorporated by refer Similarly, reduction of naltrexone with either sodium boro ence in their entirety. 10 hydride in tetrahydrofuran or lithium tri-sec-butylboro hydride in tetrahydrofuran at -78°C. gave 6C.-maltrexol FIELD OF THE INVENTION contaminated with traces of the 6? epimer. (Brine et al., “Ring C conformation of 6f-naltrexoland 6C.-naltrexol. This invention relates to a process for the manufacture of Evidence from Proton and Carbon-13 nuclear magnetic morphinan-6C.-ols stereo-specifically and in high chemical 15 resonance.” Journal of Organic Chemistry, 41, (1976) yield by catalytic hydrogenation of the corresponding mor 3445-3448.) phinan-6-ones under alkaline conditions. Other literature report the reduction of naltrexone to 6C.-naltrexol, e.g. L. D. Olsen et al., J. Med. Chem., BACKGROUND OF THE INVENTION 1990, 33, 737-741 or the reduction of 3-O-tert-bu 2O tyldimethylsilyl protected naltrexone to the correspond Morphinan-6C.-ols, including such compounds as dihydro ing alpha isomer (G. A. Brine et al., J. Org. Chem., 1976, codeine, oxymorphol, oxycodol and nalbuphine are impor 41 (21), 3445-3448) by using L-selectride in THF at tant morphine derivatives due to their behaviour as potent -78°C. Traces of the beta isomer formed during the analgesics orantagonists. Some prior synthetic routes to these reduction were removed by chromatography or recrys compounds include: 25 tallization. from codeine or morphine, where the 6O.-stereochemistry The main drawbacks of the aforementioned procedures of the 6-hydroxy morphinan was already fixed by the from the literature are low selectivities of the reductions (for stereo-chemistry of the natural product (see for example mation of 5-10% beta-isomer) resulting in a tedious proce U.S. Pat. No. 6,887,999 for the hydrogenation of dure for the removal of the contaminant. Such removal codeine to dihydrocodeine), 30 requires either several recrystallizations giving an unaccept Reduction of the 7,8-didehydro derivatives morphinan-6- able loss of yield or a purification by column chromatogra ones using metal hydride reducing agents (e.g. sodium phy, which is not a commercially viable procedure. In case of borohydride, lithium tri-sec-butyl borohydride) fol the preparation of 6C.-maltrexol from naltrexone, L-selectride lowed by hydrogenation to give the pure 6O-isomer of was used as reducing agent at very low temperatures of -78° the corresponding morphinan-6-ol. (Sargent et al., 35 C., or 3-O-tert-butyldimethylsilyl protected naltrexone was “Hydroxylated codeine derivatives”,Journal of Organic used, making the process more complicated and expensive Chemistry, 23, 1247-1251, (1958), and A. C. Currie et due to the need for special refrigerating equipment and/or al., J. Chem. Soc., 1960, 773.) This strategy was also expensive protecting groups. used to convert 14-hydroxynormorphinones preferably In contrast to the metal hydride reducing agents tradition to the 6C-epimer of the corresponding 14-hydroxydihy 40 ally used for the reduction of ketones to alcohols, hydroge dromorphine (preferably N-O-bis(ethoxycarbonyl)- nation does not require very low temperatures, or prior pro 14-hydroxynormorphinone to N-O-bis(ethoxycarbo tection of the 3-hydroxy group, followed by de-protection to nyl)-14-hydroxydihydronormorphine; Kavka, the desired 3-hydroxy-6C.-morphinol and is operationally “Preparation of nalbuphine having low levels of simpler and creates little or no waste during the processing. |B-epimer, U.S. Pat. No. 5,756,745). Similarly, Chenget 45 Few examples exist for the hydrogenation of the ketone group al. converted methoxymethyl-protected naloxone to the of morphinan-6-ones. corresponding 6-C. epimer using potassium and sodium Hydrogenation of dihydrohydroxycodeinone (also known tri-sec-butylborohydride (Na and K-selectride respec as oxycodone) in 10% aqueous acetic acid as solvent and tively), sodium triethylborohydride and sodium triac platinum oxide as catalyst gave a mixture of 6C- and etoxyborohydride in high chemical yield and >99% 50 6,3-epimers of oxycodol with the 6O-epimer being the selectivity for the C-epimer (Stereoselective reduction major product (Lutz R. E., and Small L., “Reduction of a morphinone, WO 2007/121114). U.S. Pat. Nos. studies in the morphine series. X. Hydroxycodeinone.” 5,208,338 and 5,336,483 describe the preparation of Journal of Organic Chemistry, 4, 220-233, (1939)). In radiolabeled N-substituted-6-iodo-3, 14-dihydroxy-4, this solvent mixture the reaction clearly was not stereo 5-O-epoxymorphinans (Scheme 4) which includes the 55 selective. Selective reduction of the 6-carbonyl group using K-se There is only one example of a hydrogenation of a morphi lectride, specifically described for the synthesis of nan-6-one to a morphinan-6-ol. Hydrocodone was 6.C.-maltrexol from naltrexone. TLC measurements indi hydrogenated in ethanol as solvent using platinum oxide cated the absence of the epimeric 6.f3-isomer. as catalyst (Grew and Powles, “Manufacture of 1-Dihy By contrast, reduction of oxymorphone (the morphinan-6- 60 drocodeine' U.S. Pat. No. 3,830,819). The epimeric one saturated at the 7.8 position) using Sodium borohy purity of the morphin-6-ol product was not mentioned in dride promoted formation of the 6O. morphinan-6-ol this example. contaminated with significant amounts of the 63 isomer. There remains a need for an efficient stereo-selective and (Burke and Rice., “Probes for narcotic receptor medi environmentally friendly route to the pure 6C.-epimer of mor ated phenomena. 11. Synthesis of 17-methyl- and 17-cy 65 phinan-6-ols, particularly 14-hydroxymorphinan-ols. clopropylmethyl-3, 14-dihydroxy-4,5C.-epoxy-6?-fluo Increasingly, morphinan-6-ones and 14-hydroxymorphinan romorphinans (FOXY and CYCLOFOXY) as models of 6-ones are being used as intermediates in the synthesis of the US 8,236,957 B2 3 4 corresponding morphinan-6-ols because they are available Another embodiment of the invention is the process conveniently and in high yield from opiate raw materials wherein R' is selected from H. thebaine and oripavine, both of which became commercially C-C alkyl, or C-C cycloalkylC-C alkyl. Preferably, available in large quantities only relatively recently. R" is selected from hydrogen, methyl, ethyl, propyl SUMMARY OF THE INVENTION The present invention is drawn to a process for producing O a morphinan-6C.-ol compound of formula (IIa) 10 IIa Illustrative of the invention is the process wherein the amount of the morphinan-6(3-ol compound of formula (IIb) is less than 0.5 per cent, preferably, less than 0.20%, more 15 preferably, less than 0.10% and most preferably, less than O.05%.