US008546572B2 (12) United States Patent (10) Patent No.: US 8,546,572 B2 Patel et al. (45) Date of Patent: Oct. 1, 2013 (54) PROCESS FOR THE PREPARATION OF (58) Field of Classification Search MORPHINANEANALOGUES USPC ...................................................... 546/45, 44 See application file for complete search history. (75) Inventors: Nileshkumar Sureshbhai Patel, Baroda (IN); Srinivasu Kilaru, Baroda (IN); Rajamannar Thennati, Baroda (IN) (56) References Cited U.S. PATENT DOCUMENTS (73) Assignee: Sun Pharmaceutical Industries Limited, Mumbai (IN) 2007/0167474 A1* 7/2007 Schmidhammer ............ 514,279 * cited by examiner (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Primary Examiner — Charanjit Aulakh U.S.C. 154(b) by 258 days. (74) Attorney, Agent, or Firm — Sughrue Mion, PLLC (21) Appl. No.: 12/935,831 (57) ABSTRACT (22) PCT Filed: Mar. 23, 2009 The present invention relates to an improved process for (86) PCT NO.: PCT/N2009/000203 preparing morphinane analogues of formula (1) S371 (c)(1), (2), (4) Date: Dec. 16, 2010 Formula 1 (87) PCT Pub. No.: WO2O09/122436 PCT Pub. Date: Oct. 8, 2009 (65) Prior Publication Data US 2011 FO152527 A1 Jun. 23, 2011 (30) Foreign Application Priority Data Mar. 31, 2008 (IN) ........................... 722AMUMA2008 (51) Int. C. CO7D 489/08 (2006.01) wherein the substituents R. R. R. R. Rs and Y have the CO7D 489/02 (2006.01) same meanings as defined in the specification. (52) U.S. C. USPC ............................................... 546/45; 546/44 2 Claims, No Drawings US 8,546,572 B2 1. 2 PROCESS FOR THE PREPARATION OF -continued MORPHINANEANALOGUES CROSS REFERENCE TO RELATED APPLICATIONS This application is a National Stage of International Appli cation No. PCT/IN2009/000203, filed on Mar. 23, 2009, which claims priority from Indian Patent Application No. 10 722/MUM/2008, filed on Mar. 31, 2008, the contents of all of Naltrexone which are incorporated herein by reference in their entirety. FIELD OF INVENTION 15 This present invention relates to a novel, improved process for the synthesis of certain morphinane analogues. BACKGROUND OF THE INVENTION The present invention relates to a novel process for prepa ration of morphinane analogues i.e compounds of formula I. The morphinanes may be characterised by a common chemi 25 cal structure that of a cyclic tertiary amine represented by following structure: Naloxone 30 35 40 These analogues exert their effect at the opioid receptors in the central nervous system and other tissues and are useful as pharmaceutical Substances for treatment of pain, drug abuse 45 and various other disorders. Because of the high potency and diverse uses of the morphinane derivatives in therapy for human as well as for veterinary use, there is an increasing demand for medicinal morphinanes. Some of the morphinane Nalbuphine analogues known in the art are as follows: 50 55 60 65 Buprenorphine Namefene US 8,546,572 B2 3 -continued / -continued N 10 ( OH Nalorphine HO O , 15 Semorphone 25 30 Naltrindole 35 The prior known processes for preparation of the morphi nane analogues generally begin with thebaine or its O-dem ethylated derivative, oripavine. Thebaine occurs naturally in plant sources from which it is extracted and purified by an Cyprenorphine 40 expensive and laborious procedure. Thebaine-producing plants require special agronomical and environment condi tions which can further increase the final cost of thebaine extracted thereform. Consequently, there is a need for a pro 45 cess of preparation of morphinane derivatives which gives high yields of quality products and which uses safer solvents and reagents. The process for the preparation of morphinane derivatives comprises mainly of two steps starting from thebaine or ori 50 pavine namely the N-demethylation and N-alkylation. The following patent references generalize the state of art for the N-dealkylation of thebaine or oripavine. U.S. Pat. No. 3.433,791 (as referred to as 791) discloses endoethano northebaine and nororipavine derivatives, includ 55 ing, N-cyclopropylmethyl-6, 14-endoethano-7-(2-hydroxy 2-methyl-2-tertbutyl)-tetrahydronororipavine commonly known as Buprenorphine. The 791 patent describes N-dem ethylation of endoethano thebaine and oripavine derivatives in a two step process, first step involving formation of N-cy 60 ano derivative using cyanogen bromide followed by hydroly sis of the N-cyano derivative to yield the N-demethylated product. The process gives a lower yield (-70%) of the N-demethylated product and further requires the use of cyanogen bromide, which is toxic and requires great precau Diprenorphine 65 tions for use in large scale. The following scheme 1 outlines the process of preparation of buprenorphine as disclosed in the 791 patent. US 8,546,572 B2 Scheme 1 N1 N1 N1 (s () MVK . Pd(C O MeO O OMe MeO O OMe MeO O OMe thebaine t-Bu MgCl H CN R OH a-KOH R OH aCNBr. R OH MeO O OMe MeO O OMe MeO O OMe Cyclopropyl carbonyl chloride LiAlH4 N1 N1 HossKOH r MeO O OMe HO O OMe Buprenorphine Canadian Patent No. 2597350, discloses preparation of 40 or oripavine derivatives. The process gave higher yields, noroxymorphone derivatives like naltrexone and naloxone. It which is near the theoretically calculated value, of the discloses N-demethylation of noroxymorphone using ethyl N-demethylated derivative with good purity. The use of alkali chloroformate in presence of basic conditions to prepare iodide along with an Calkylchloroformate and a base, noroxymorphone carbamate which is hydrolyzed to form the according to the present invention, has not been disclosed 45 heretobefore for N-demethylation of the morphinane ana N-demethylated derivative. More specifically, it describes the logues. N-demethylation of diacetyloxymorphone to form diacety Further, N-alkylation of the morphinane analogues is loxymorphone carbamate, which is then hydrogenated to described in several references, for example, U.S. Pat. No. yield noroxymorphone i.e. the N-demethylated derivative. 3,332,950 (referred to as 950 hereinafter), which discloses The yield of the N-demethylated product is ~65% based on 50 14-hydroxydihydronormorhinones, specifically, naltrexone the starting material used. Further, European Patent No. and methods of preparing the same. The 950 patent discloses 164290 discloses a similar process for preparation of 14-hy two methods for N-alkylation of morphinane derivatives dis droxymorphinanes with lower yields. It was found by us that closed therein. In one of the methods, N-alkylation is carried with the use of ethylchloroformate for N-demethylation of 55 out in a two-step reaction. The first step involves use of compounds of formula I of the present invention, the reaction cyclopropylcarbonyl chloride to obtain a carbonylalkyl sub did not go to completion and the yields obtained were lower. stituted compound which was Subjected to reduction using Also, U.S. Pat. No. 4,141,897 discloses use of vinyl chlo lithium aluminium hydride (LiAlH4), in the second step to roformate for N-demethylation of N-alkyl-14-hydroxymor generate the N-alkylated compound. The method is disadvan phinans, however, the process Suffers from disadvantages in 60 tageous in that it involves a two-step reaction for N-alkyla that the yield obtained is 70-85%, the instability of the reagent tion, uses highly reactive, pyrophoric metal hydride reagent leads to variable output and its delicate preparation requires like LiAlH and affords yield of approximately 33% starting high cost. from noroxymorphone. In another method (Scheme 2) 14-hy The process of present invention does not use toxic droxydihydronormorphinone is treated with cyclopropylm reagents like cyanogen bromide for N-demethylation, instead 65 ethyl bromide in DMF to prepare naltrexone. The method uses an Calkylchloroformate along with an alkali iodide employs high temperatures and prolonged reaction time (7 and a heterogenous base, for the N-demethylation of thebaine days) yet achieves only a 60% of theoretical yield. US 8,546,572 B2 8 of an alkali. Also U.S. Pat. No. 5,849,915 which discloses Scheme 2 certain buprenorphine analogues, prepares endoetheno H derivatives of morphinanes by reacting thebaine with methyl N vinyl ketone in a molar ratio of about 1:1746. OH The process as disclosed in the 791 and the 915 patent for preparation of buprenorphine or its precursors Suffers from -- disadvantages, in that the process is low yielding, for example, in the 791 patent the yields of the product obtained 10 at each step is in the range of 25-70% with the overall yield of HO O O only 4.5%. The prior art process for preparation of endoet hano compounds as disclosed in the 915 patent uses a large 14-hydroxydihydronomorphinone excess of methylvinylketone which is not only expensive but DMF, 70° C., also is lachrymatic in nature, which causes inconvenience in D v --one week 15 large scale synthesis. The hydrogenation step, as disclosed Br recrystallized from above, uses high hydrogen pressure ~58 psi furnishing yield cylopropyl methyl acetOne of only ~60%. The grignard reaction employs a combination bromide of benzene and diethylether as solvent, which not only gives a low yield on ~25%, but is also not advisable because of known carcinogenicity of benzene. Further, the O-demethy lation reaction requires harsh environment i.e. high tempera N tures in presence of an alkali which may cause an irreversible OH damage to the phenolic moiety as observed in poor yield, obtained for this reaction. 25 The process of the present invention is advantageous in that it uses of methylvinylketone in a quantity which is only four times the molar quantity of thebaine, yet furnishes a high HO O O yield of ~90%. Further, the hydrogenation reaction is carried Niatrexone 30 out at atmospheric pressure in 10% aqueous acetic acid, fur N-cyclopropylmethyl nishing -83.0% yield.