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Ep 2398808 B1 (19) TZZ ¥Z_T (11) EP 2 398 808 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 489/08 (2006.01) 20.11.2013 Bulletin 2013/47 (86) International application number: (21) Application number: 10704301.0 PCT/US2010/024372 (22) Date of filing: 17.02.2010 (87) International publication number: WO 2010/096416 (26.08.2010 Gazette 2010/34) (54) Process for the reductive alkylation of normorphinans VERFAHREN ZUR REDUKTIVEN ALKYLIERUNG VON NORMORPHINANEN Procédé d’alkylation réductrice des normorphinanes (84) Designated Contracting States: • WOODS, Sharon AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Florissant HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Missouri 63034 (US) PT RO SE SI SK SM TR (74) Representative: Beckmann, Claus (30) Priority: 17.02.2009 US 153021 P Kraus & Weisert Patent- und Rechtsanwälte (43) Date of publication of application: Thomas-Wimmer-Ring 15 28.12.2011 Bulletin 2011/52 80539 München (DE) (73) Proprietor: Mallinckrodt LLC (56) References cited: Hazelwood, MO 63042 (US) WO-A1-2006/035195 WO-A1-2009/012005 (72) Inventors: • HUDSON, Edmund, C. Clayton Missouri 63105 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 398 808 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 398 808 B1 Description FIELD OF INVENTION 5 [0001] The present invention generally relates to a method for the synthesis of N-alkylated morphinans. In particular, the process provides a method for reducing an iminium salt formed from the reaction of a normorphinan and a carboxal- dehyde. BACKGROUND OF THE INVENTION 10 [0002] N-alkylated morphinans are important pharmaceuticals, typically used as analgesics, opiate agonists, and opiate antagonists. With the increasing use of these agents, a practical and effective method of preparation of these compounds is vital to synthesizing diverse N-alkyl substituted morphinans. WO2006/035195 discloses a process for preparing N-alkylated morphinans. 15 [0003] Currently, the methods for synthesis of N- alkylated morphinans known in the art have at least one of two primary limitations: (a) their dependence on a transition metal catalyst, and (b) the use of hydrogen gas as a source of hydrogen for the alkylation. Transition metal catalysts are expensive and toxic, which requires testing of the finished product to ensure that the final product does not contain more than a specified parts per million of the transition metal. Additionally, hydrogen gas is hazardous, and methods of synthesis typically employ high pressures. Some prior art methods have 20 incorporated a borohydride to catalyze the reaction. It was desired to avoid this method because the side products are difficult to separate from the desired product, and the reactions may require lower temperatures, -20° to - 30° C, when a keto group is present. In light of the current limitations, there is a need for an efficient, costeffective method of the synthesis of N-alkylated normorphinans. 25 SUMMARY OF THE INVENTION [0004] The present invention provides processes for the synthesis of N- alkylated morphinans from the corresponding normorphinan compounds. [0005] One aspect of the present invention encompasses a process for the preparation of an N- alkylated morphinan. 30 The method comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R10, wherein R10 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form the N- alkylated morphinan comprising NR10 at position 17. 35 [0006] In an additional aspect, the current invention encompasses a process for the preparation of a compound comprising Formula (IIIa). The process comprises: (a) contacting a compound comprising Formula (Ia) with an alkylating agent comprising R10 in the presence of a proton acceptor to form a compound comprising Formula (IIa); and (b) contacting the compound comprising Formula (IIa) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to 40 form a compound comprising Formula (IIIa) according to the following reaction scheme: 45 50 55 2 EP 2 398 808 B1 5 10 15 20 25 30 wherein: R2, R6, and R7 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydro- carbyl, and {-}OR11; R3, and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, 35 halogen, and {-}OR11; R5 is selected from the group consisting of hydrogen, and hydroxyl; R8 is selected from the group consisting of {=}O, and hydroxyl; R10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting 40 group; and X is selected from the group consisting of oxygen and sulfur. [0007] In another aspect the current invention encompasses a process for the preparation of a compound comprising Formula (IIIb). The process comprises: (a) contacting a compound comprising Formula (Ib) with an alkylating agent 45 comprising R10 in the presence of a proton acceptor to form a compound comprising Formula (IIb); and (b) contacting the compound comprising Formula (IIb) with a reducing agent selected from the group consisting of formic acid, methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof, to form a compound comprising Formula (IIIb) according to the following reaction scheme: 50 55 3 EP 2 398 808 B1 5 10 15 20 25 30 wherein: R1, R2, R6, R7, and R9 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {-}OR11; R3, and R 4 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, 35 halogen, and {-}OR11; R5 is selected from the group consisting of hydrogen, and hydroxyl; R8 is selected from the group consisting of (=)O, and hydroxyl; R10 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and R11 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl protecting 40 group. DETAILED DESCRIPTION [0008] The present invention provides an efficient process for the production of N- alkylated morphinans in high yield. 45 In particular, the process of the present invention avoids the use of toxic metal catalysts and dangerous hydrogen gas. Moreover, the process of the invention may be conducted in a one-pot process, without isolation or purification of the intermediate products. (a) Process for the synthesis of N-alkylated morphinans 50 [0009] One aspect of the present invention provides an efficient process for the production of N- alkylated morphinan compounds. The process comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylating agent comprising R10, wherein R10 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the group consisting of formic acid, methyl formate, 55 formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form the N-alkylated morphinan comprising NR10 at position 17. [0010] Generally, the normorphinan comprises any compound having a morphinan structure, in which the nitrogen at position 17 comprises a secondary amine. It will be understood by one skilled in the art that the "nor" compound may 4 EP 2 398 808 B1 be produced by methods known in the art or purchased as a starting material. Non- limiting examples of normorphinans include norcodeine, normorphine, northebaine, nororipavine, noroxymorphone, nordihydromorphine, nordihydroco- deine, norhydrocodone, norhydromorphone, noroxycodone, nordextromethorphan, nordextrorphan, norlevomethor- phan, norlevorphanol, norbuprenorphine, noroxymomorphol, noroxycodol norsinomenine, nordihydrosinomenine, and 5 combinations thereof. In a preferred embodiment, the normorphinan comprises noroxymorphone. [0011] The N-alkylated morphinan comprises any morphinan compound comprising a tertiary amine at position 17, wherein the amine at position 17 comprises a hydrocarbyl or substituted hydrocarbyl group. Suitable examples of N- alkylated morphinans include, but are not limited to codeine, morphine, thebaine, oripavine, oxymorphone, dihydromor- phone, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxycodeinone, naloxone, naltrexone, nalbuphine, 10 nalmefene, nalfurafine, morphinone, ethylmorphine, butorphanol, dextromethorphan, dextrorphan, levomethorphan, lev- orphanol, buprenorphine, sinomenine, dihydrosinomenine, and combinations thereof. In a preferred embodiment, the N-alkylated morphinan comprises naltrexone, nalbuphine, or 6-ketonalbuphine. [0012] In general, the R 10 group used to alkylate the nitrogen at position
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