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    Preparation of Oxycodone, Oxymorphone & DerrivativesEP1000065A1

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    Preparation of Oxycodone, Oxymorphone & DerrivativesEP1000065A1

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    Preparation of Oxycodone, Oxymorphone & DerrivativesEP1000065A1

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    EP 1 000 065 B1 —*DV Hopiiaches Patentamt (19) ) European Patent Office Office européen des brevets (12) (45) Date of publication and mention of the grant ofthe patent: 46.03.2005 Bulletin 2005/11 (21) Apotcation number: 98984219.4 (22) Date of fling: 10.07.1998 (it) EP 1 000 065 B1 EUROPEAN PATENT SPECIFICATION (51) Inti, CO7D 489/02, CO7D 489/08, AG1K 31/485 (86) International application number: PCT/US1998(013592 (87) International publication number: ‘Wo 1999/002529 (21.01.1999 Gazette 1999/03) (54) PREPARATION OF OXYMORPHONE, OXYCODONE AND DERIVATIVES HERSTELLUNG VON OXYMORPHON, OXYCODON UND DERIVATEN DAVON PREPARATION D'OXYMORPHONE, D'OXYCODONE ET DE DERIVES ASSOCIES (84) Designated Contracting States: AT CH DE DK ES FI FR GB LINL SE (80) Priority: 11.07.1997 US a93464 (43) Date of publication of application 17.05.2000 Bulletin 2000/20 (73) Proprietor: Penick Corporation Newark, NJ 07114-2114 (US) (72) Inventors: + HUANG, Bao-Shan Newark, NJ 07114-2114 (US) CHRISTODOULOU, Aris New York, NY 10021 (US) + LU, Yansong Edison, NJ 08820 (US) + dl, Ben-¥i Edison, NJ 08820 (US) (74) Representative Forstmeyer, Dietmar, Dr. rer. nat., Dipl-Chem. et al Boeters & Bauer, Bereiteranger 15 81841 Mnchen (DE) (86) References cited: US-A- 4.668 685 US-A- 5.112975 US-A- 4795 813, HUTCHINSON | ET AL: “Synthesis and opioid binding properties of 2-chloroaerylamido derivatives of 7,8-dihydromorphinans” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB, OXFORD, vol.6,no, 13, 9July 1996 (1996-07-09), pages 1563-1566, XP004175754 ISSN: 0960-894X J. FISHMAN ET AL.: "Preparation of Morphine-6-3H and its Isotopic Stability in Man and in Rat" J. MED. CHEM. vol. 17, 1974, pages 778-781, xP001005470 + D, SHEL'METS! ET AL.: “Synthesis of new ‘morphine derivatives. |, Morphine derivatives substituted on the nitrogen and at position 3." PHARM. CHEM. J., vol. 6, 1968, pages 202-306, xP001000143 ‘A.NINAN ET AL.: "An improved synthesis of noroxymorphone" TETRAHEDRON, vol. 48, no. 82, 1992, pages 6709-6716, XP002169890 + SEKI: "Studies on the Morphine Alkaloids and Its Related Compounds. XVIl. One-Step Preparations of Enol Ether and Pyrrolidiny! Dienamine of Normorphinone Derivatives” CHEMICAL AND PHARMACEUTICAL BULLETIN.JP,TOKYO, vol. 18, no. 4, 1970, pages 671-676, XP002078242 ISSN: 0009-2363 Remarks: The fle contains technical information submitted after the application was fled and nat included inthis specification Note: Within nine months from the publication ofthe mention of the grant ofthe European patent, any person may give notice to the European Patent Office of opposition to the European patent granted, Notice of opposition shal be fled in ‘a writen reasoned slatement, it shall nt be deemed lo have been filed untl the oppostion fee has been paid. (Art 99(1) European Patent Convention), Pam Joom, 70% PRAISE) 2% 2% EP 1.000 065 Bt Deseription BACKGROUND OF THE INVENTION 41) Field ofthe Invention [0001] This invention relates in general to process for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derwvatives including oxy- ccodone, oxymorphone, noroxymorphone, and naltrexone. Noroxymorphone isa key intermediate for the production of Important narcotic analgesics and antagonists. In another aspect, the Invention is directed to certain novel intermedi: ates 2) Background Art [0002] 14-Hydroxy-substituted morphine derivatives are important narcotic analgesics and/or antagonists. These drugs include oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and nalmefene. They are readily synthe- sized from thebaine, which is a minor component of gum opium. As the supply of thebaine is limited and the demand is incroasing, therefore, the price of thebaine is high. As @ resull, many allernative approaches have been made for the preparation of 14-hydroxymorphine derivatives, [0003] The reported efforts for preparing these narcoties bearing a 14-hydoxy group from readily abundant starting ‘materials morphine or codeine (a minor component of gum opium, which may also be synthesized by methylation of morphine) are summarized asthe following: (1) the conversion of codeine to thebaine through dihydrocodeinone (5.4% yield, H. Rapoport et al, J Am. Chem, Soc., vol. 89, 1967, p. 1942 and H. Rapoport, etal, J, Org. Chem., vol 15, 4950, p. 1103), codeinone (20% yield |, Sekl, Chem. Pharm. Bull, vol, 18, 1970, p. 871 and H. Rapoport, etal. J. Am. Chem. Soc, vol. 77, 1955, p. 480) or &-methyl ether of codeine (using manganese dioxide, 67% yield, A.B, Barber, et al, J. Med, Chem., vol. 18, 1976, p. 1074); (2) the oxidation of codeinone pyrroliiny| di-enamine to 14-hydroxycodel- ‘none (80 - 40% yield, i. Seki, Chom. Pharm. Bull, vol. 18, 1970, p. 671); (8) the direct allylic oxidation of codeine to the corresponding 14-hydroxy derivatives with chromic acid (H.L. Hulmes, etal, J. Am. Chem. Soc, vol. 69, 1847, p 1966), manganese dioxide (I. Brown, etal, J. Chem. Soc., 1960, p. 4138), and selenium dioxide plus t-butyl hydrogen peroxide (M.A. Schwartz, ot al, J. Med. Chem. vol. 24, 1981, p. 1525); and (4) the six-stop transformation of codeine to norexycodone (62% yield) and noroxymerphone (43% yield) using photochemically generated singlet oxygen (M, A. Schwartz, et al,, J, Med. Chem. vol. 24, 1981, p. 1525): Hutchinson etal, discloses the "Synthesis and opioid binding properties of 2-chloroacrylamide derivatives of 7,8- includes benzyl, substituted benzyl and benzyloxyearbonyl () the second step is to oxidize the 3(0)-protected morphine to 3[0}-protected-morphinone having the formula: 2% 2% EP 1 000 065 BI by any of the prior art methods such as Swem oxidation (OMSO/acid halide or acid anhydride). (c) the third step isto convert the 3(0)-protected-morphinone to the 14-thydroxy-3-(O)-protected-morphinone using the techniques disclosed in this invention as set forth in the conversion of codeinone to 14-hydroxycedainone in the synthesis of oxycodone, The intermediate, 3(0)}-protected-codeinone dienol acylate, is a novel compound having the formula: AD ao wherein P and Ri are as defined above; preferably P; is acetyl and P, is benz. (4) depending onthe parteular protection group, P oP, the fourth step is ether () to fist produce the 7.@-double bond of 3-(0)-P,-protected morphinone and then to remove the protection group by acid or base hydrolysis to produce oxymorphone or (i) o hydrogenate the 7.8-double bond and deprotect simultaneously the $-(0}Pp-pro tected morphinone to oxymarphone [0019] This synthesis of oxymorphone trom morphine wherein P, is acetyl can be illustrated below: 0 2% 2% EP 1 000 065 BI 40" AN oxynorphone \Whorein the hyphenated two digits below each formula identiis this corresponding examples as previously indicated, [0020] The synthesis of oxymorphone from morphine wherein P, is benzyl can be shown as follows: 1" 2% 2% EP 1 000 065 BI 0 norphine at ae ‘oxynorphone [0021] For the synthesis of noroxymorphone trom morphine in another embodiment ofthis invention, morphine is. Converted to 8-benzylmorphine, which is acetylated to 6-acetyl-S-benzimorphine having the formula Ou £ 6-acetyl-3-benzylmorphine is N-de-methylated with 1-chloroethy|chloroformate or eyanagen bromide and followed by ‘acid hydrolysis to 3-benzylnormorphine. 3-Benzyinormorphine is reacted with benzyl halide in the presence of a base such as sodium or potassium bicarbonate to produce 3,17-) and 49 (29, [CHgCOF) EXAMPLE 37 Preparation of 17-cyolopropyimathy/-14-hydroxynorcodeinon (5-7) from 17-cyelopropylmethyinorcodeinone (6-5) b H02 in HCOOH [0064] solution of 17-cyclopropyimethyinorcodeinone (0.20 g, 0.59 mmol), formic acid (90 %, 0.304 g), water (0.504 25 2% 2% EP 1 000 065 BI 9), EtOAc (0.27 9), and hydrogen peroxide (20%, 0.17 g) was heated at 42-49° C for 16 hr, added water (20 mi), basified with Na,CO, (1.02 g), and extracted with EIOAc (80 mi & 2 x 20 mi). The combined extract was washed with Water, dried over anhydrous sodium sulfate, and evaporated in vacuo to drynoss to give 17-cyclopropyimethy-t4-hy-

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