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United States Patent 11» Mudryk et al. [5] PREPARATION OF OPLAT INTERMEDIATES AND USES OF SALTS {75} Inventors: Bogdan Mudryk, East Windsor ster Sapino, Sewell, bath of Semen Dung Boston Pas Al Sebastian, Deptford, Nh [73] Assigace: Johnson Matthey Public Limited Company, London, United Kingdom [21] Appl. No.: 09/107,509 [22], Filed: Jun. 30, 1998 [30] Foreign Application Priority Data Jue, 30, 1997 [GB] United Kingdom oman [51] Int. C1? Co7p 471/08 [52] US. Cl S648; 546/45, [58] Field of Search 54644, 45 [56] References Cited USS. PATENT DOCUMENTS 3,894,026 7/1975 ‘Sohar etal. 250/285 54085,480 81977. Rapoport. 250/285 Grass Silom Schwarz 304158 R 4795313 1/1989 Schwartz Stoi4s 512975 5/1992 Wallace 546/45 FOREIGN PATENT DOCUMENTS 902 257 Wigs Germany US006090943A_ uy) Patent Number: 6,090,943 [45] Date of Patent: Jul. 18, 2000 1.260699 1/1972 United Kingdom OTHER PUBLICATIONS Schwartz et al, J. Med. Chem., vol. 2 1525-1528 (1981) (XPO02078240), Noble, Synthesis, pp. 1-6, 1970 (XP002078241). Seki, Chem. Pharm. Bull., vol. 18, No. 4, pp. 671-676 (4970) (XPO02078242), Thara_ et al, Synlett, No. 6, pp. 435-436 (1993) (XP002078243). “Houben Weyl: Methoden der Organischen Chemie, Bd Vila” (1978), George Thieme Verlag, Stuttgart, p. 161 (XP002078244). “Houben Weyl: Methoden der Organischen Chemie, Bd E15”, (1993), George Thieme Verlag, Stuttgart, pp. 201-205 (XP002078245). No. 12, pp. Primary Examiner—Alan L. Rotman Attorney, Agent, or Firm—Pillsbury, Madison & Sutro LLP (57) ABSTRACT ‘A process forthe preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of anslogous |4-hydroxymorphinones. 4 Claims, No Drawings 6,090,943 1 PREPARATION OF OPIATES, INTERMEDIATES AND USES OF SALTS. ‘This invention relates to a process for the preparation of | thebaine and analogues thereof, and fo a novel intermediate useful in such a process. In particular, the invention relates to the preparation of thebaine from N-methyl morphinans, its isolation asa salt and the use of the salt in the preparation ‘of Nemethyl-14-hydroxymorphinones, ‘Thebaine is an N-methylmorphinan having the structure a: “ cH. CH cme ‘Thebaine and analogous compounds containing a dienol ether or a dienol ester are useful intermediates in. the preparation of L4-hydroxymorphinans, such as oxycodone, naltrexone, nalbuphine and naloxone. Oxycodone is the ccortesponding 14-hydroxy-N-methylmorphinone baving the structure (B): ® cu Unfortunately, thebaine is expensive and is not always readily available in industrially required quantities. Sobat et al, US. Pat. No, 3,894,026, disclose a method for producing thebaine, but the Starting material is salutaridinol, which is itself not readily available. Therefore, it is desirable 10 prepare thcbaine or its analogues, directly or though known intermediates, from more readily available morphinans such as codeine and morphine. Codeine isthe coreesponding 6-OH monoenolether ana- logue of thebaine. Rapoport etal, US. Pat. No. 4,045,440, provide a method for producing thebaine fom codeine via the intermediate cexdeine methyl ether. This method requires a 90-second reaction time in preparation ofthe intermediate, and is thus not suitable for use on an indusrial scale. The method also requires. a 24-hour reaction period for conversion of the intermediate to thebaine, and employs « heterogeneous catalyst, manganese dioxide, or the transformation, leading to further dificulties on seale-up. Schwartz, US. Pat, Nos. 4,872,253 and 4,795,813 and J Med. Chem. 24, 1525 (1981) provides a methed for pro- ducing certain dienol ester analogues of thebaine having the structural formula (C): 0 as os ss 4s ss 6s o RHO, watt T RHO’ wherein R" is lower alkyl, R'is eyano or acyl, and R'is acyl. These thebaine analogues, in whieh the N-methyl group has been replaced by R', are useful as intermediates for naloxone, naltrexone and nalbuphine, but are not useful as intermediates to L4-hydroxy-morphinan compounds hav- ing an N-methyl group, such as oxyceslone or oxymorphone For these compounds, thebaine is the desired intermediate, since it has the required N-methyl substituent, Further, the method of Schwartz, which employs a reae- tioa temperature of 80-100° C. to introduce the R’? acyl group, may not readily be extended to preparation of an Nemethyl dienol ester, since at such a temperature, the N-methyl group would also be acylated, leading to by-products and reduced yield, Extension of this method to the preparation of N-methyl dienol etber compounds, such asthebaine, is also not feasible. At the esetion temperatures employed to introduce R™, not only would the N-methyl group be alkylated, leading to by-products and reduced yield, but the alkylating agent would be destroyed by reaction with the base employed inthe proces. Wallace, U.S. Pat. No. 5,112,975, employs. a process similar to that of Schwartz to prepare compounds of struc- tural formula (C), but wherein the R'? is an alkoxyearbonyl substituent, This process differs from that disclosed. by ‘Schwartz in that the ultimate starting material is morphine, rather than codeine, but has limited use as a method for preparing thebaine or thebaine analogues with N-alkyl sub- stitution for the same reasons given in the preceding para- graph, British patent number 1,260,699 discloses a method for preparation from codeine of dienol ethers analogous to thebaine. However, the method used for isolation of these dienol ethers is lengthy, requiring a chromatographic separation, and gives a low yield of the produet. For these reasons, this method is not useful for large-scale preparation of thebaine. It has now been found possible to provide an efficient, high-yielding process for the preparation of thebaine ot thebaine analogues (ie. having N-CH, substitution) con- twining a dienol ester of a dienol ether, from moxphinone, codeinone or analogues thereof which contain an a,f- unsaturated ketone via a novel alkoxylated intermediate ‘Accordingly, the present invention provides a process for the preparation of a compound of formula (I) oF salt thereat 6,090,943 ® Ro” wherein R? and R® are the same or different and each is a protecting group; and RE is lower alkyl, allyl or lower alkyl substituted by” cycloalkyl; said process comprising the reaction of the ‘compouad of formula (I): aw RM SNe | mo" wherein R! and R? are as hereinbefore defined; and M is an alkali metal or a quaternary ammonium cation; with a ‘compound of formula R°X, wherein R’ is as hereinbefore defined and X is a leaving group; and, optionally, but preferably, the reaction of the compound of formula (I) so prepared with an acid, such as L-tatari acid, to give a salt such as the bitartrate, of the compound of formula (), Preferred protecting groups inthe definition of Rand R are selected from alkyl or acyl groups. Preferred alkyl groups are selected from lower alkyl, trilkylsiyl,alkyldiar- Ybsilyl and acyl, although they may also be selected from aryl and alkylaryl, any of which alkyl and aryl groups may be substituted by halo, Preferred aryl groups are phenyl. Preferred acyl groups are selected from those of formula R°CO-, wherein R'is selected from lower alkyl, lower alkyl substituted by halo or phenyl, and aryl, such as phenyl and substituted phenyl. R" is preferably selected from lower alkyl, phenyl or substituted phenyl. Preferably, alkyl groups herein have from 1-6, more preferably 14, carbon atoms; and aryl groups herein are phenyl, optionally substituted by alkyl andor halo, such as chloro. Tnan especially preferred aspect of the present invention, the compounds prepared by the above process are com: ppounds of formula (I) wherein RY, R and R® may be the same or different and each is lower alkyl, for example Cy. alkyl, such as C,_, alkyl and preferably methyl or ethyl. Ta a particularly preferred aspect, the compound prepared is thebaine or a salt thereof, preferably the bitartrate salt, Suitable agents R°X used in the preparation of the com- pounds of formula (I) include those alkylating or acylatin agents where R° is preferred as defined hereinbefore. Suit able leaving groups X are hal, alkanoate, benzoate, substi tuted benzoate, alkyl sulphate, alkyl ‘sulphonate, aryl sulphate, arylsulphonate, halosulphonate, haloalkylsulphonate, tetra-alkylimmonium halide and