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  • Zhaiwei Lin Et Al - Process For Manufacturing Oxycodone

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    Zhaiwei Lin et al- Process for Manufacturing Oxycodone

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    61 Ansichten5 Seiten

    Zhaiwei Lin Et Al - Process For Manufacturing Oxycodone

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    PoloGreen

    Copyright:

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    6 76) oO ep 2) co (2) 68) 66) United States Patent Lin et al. PROCESS POR MANUFACTURING OXYCODONE Inventors: Zhalwel Lin, 301 Skylane De, Apt. A3, Plymouth, IN (US) 46563; Charles Ausilium Franels, 205-2 La Porte ‘Ave, Valparaiso, IN (US) 46383; Christopher Are Kaldahl, 400, Hiawatha Ave., Apt 311, LaPor (US) 46350, Kazimierz Grregorz Antezak, 545 8, Shore Dr, Culver, IN iy (Us) 46511; Vijal Kumar, 67 Whitewood De, Morris Plains, NI (US) 07950 Notice: Subject to any disclaimer, the term ofthis pateat is extended or adjusted under 35 USEC. 154th) by 3 days, Appl. No. 10/485,202 Filed: Jun. , 2003, Im. CW? COTD 515/08; CO7D 515/06 US.c S46i44; 546745, Field of Search 546/44, 45 References Cited US. PATENT DOCUMENTS ADKSMO_A. + 811077 Rapopod eta am283 A+ 91084 Schwan SIISBIS A © 1/989. Sehwarte Su12975 A * 5/1992 Wallace 083 121900 Huang ea. 000983 A+ 72000 Muay eh e786? BL 12001 Chiu tal FOREIGN PATENT DOCUMENTS 0043 617 AL 971990 comason US00686437081 US 6,864,370 BL Mar. 8, 2005, (20) Patent No. (5) Date of Patent: OTHER PUBLICATIONS Helvetica Chimica Acta, vol, 60 (1977), pp. 2135-2137, Arch. Pharm. Pharm, Med. Chem., (1996), pp. 325-326 Heterocycles, vol. 49 (1988), pp. 43-47. Journal ofthe Chemical Society, Ot. 1960, pp. 4139-4140. Journal of Medicinal Chemistry, vol. 17 (1974), 1117. * cited by examiner Primary Esaminer Rita Desai on Oxycodone is manufactured in high yields and with «high purity using codeine of a salt of cadeine a8 the starting ‘material. The manvfacturing process involves the following steps: (@) codeine or a codeine salt (e.g, codeine phosphate) is ‘converted into the intermediate N-carboalkoxy- of N-carboaryloxynoreadeine, (b) the. intermediate N-cachoalkoxy- or N-carboaryloxynorcodeine resulting from step (a) is oxi- dized to yield the. intermediate. Necarboalkoxy- oF N-carboaryloxynoreodeinooe; (©) the. intermediate N-carboalkoxy- ‘Necarhoaryloxynorcodeinone resulting from step (b) is ‘enolized with & base aod the resultant enolate is thereat ‘methylated to yield the intermediate N-earboalkoxy- of Necarbearyloxynonthebaine; (a) the. intermediate N-carhoalkoxy- or ‘Necarboaryloxynorthebaine resulting from step (@) is reduce to yield thebaine; (6) the thebsine resulting ftom step (d) is oxidized t0 yiekd the intermediate 14-hydroxycodeinone; and (9 the intermediate 14-hydroxyeodeinone resulting from step (0) is hydrogenated to yield oxycodone. ABSTRACT 18 Claims, No Drawings US 6,864,370 BL 1 PROCESS FOR MANUFACTURING ‘OXYCODONE, FIELD OF THE INVENTION Oxycodone is manufactured in high yields and in highly pure form by a multistep manufacturing process that utilizes ‘exeine or a codeine sll as the starting material BACKGROUND OF THE INVENTION Oxycodone is & well know narcotic employed for pain management, Page 1245 of the thircenth edition Merek Index states that oxycodone may be prepared by catalytic reduction of hydroxycodeinone, its oxime, bromination products or by reduction of hydoxycodeinone with sodium hydrosulite ‘The prior act deseribes several methods for oxycodone using codeine or a salt thercof as the staring. material Codeine along with morphine, thebaine and oripavine may be extracted from poppy strav—see U.S. Pat, No 6,067,749 issued May 30, 2000 to Fis etal Codeine is also readily Prepared by the methylation of morphine, which is present Jn poppy straw in a higher percentage than that of eodeine. US. Pat, No, 6,177,567 BI issued Jun, 23, 2001 10 Chi tal. discloses a method for the preparation of oxycodone And salts thereof which involves the oxidation of codeine 10 ‘exeinone, formation of a dienolsilyl ether congener of ‘odeinone in strong amine base, oxidation ofthe dienolsill ‘eller congener using peracetic acid and bydogenation ofthe 14-hydroxycodeinone product. In ananicle by Ivor Brown and M. Mactin-Smith appear- ing on pp. 4139-1140 of the Journal of The Chemical Society (October, 1960), the authors disclose several meth ‘ods for the oxidation of cadeine to 1-hydeoxycodeinone (Gwhich may then be reduced to oxyeodone) involving the use of oxidants such as manganese dioxide or ehromic oxide in aeetic acid US. Pat, No. 6,008,355 issued Dee. 28, 1999 to Huang et al. iseloses two methods for preparing oxycodone from ‘oxeine, The first method involves oxidizing codeine so 38, to form codeinone and thereafcr converting the cndeione to oxyeodone in a two-step, one-pot reaction involving the reaction of eoxeinone with hydrogen peroxide in Water in the presence of an aeid at about 15 0 about 70°C. to fon hydroxycodsinone and then catalytically hytrogenating L4-hydroxycodeinone in its original reaction mixture 10 form oxycodone, ‘The second method disclosed in the "355 patent involves oxidizing codeine so as 10 form codeinone, reacting ‘odeinone with an aeylating agent in water or a solubilizing solvent mixture in the presence of an acid at about 15 10 about 70° C. to form acyldienolate, oxidizing the dienolate to L-bydroxycodeinone and then catalytically hydrogenal- ing 14-hydroxyeodeinone in its original resetion mixture 10 form oxycodone. Allof the prior art methods for preparing oxycodone from codeine or a salt thereof are disadvantageous from a com= ‘mercial manufacturing point of view in several respects: The purity of the oxycodone is relatively low, thereby requiring ‘considerable additional costly purification steps (and ‘dant loss of yield) t raise the purity to an acceptable level, ‘A second disadvantage of prior art methods is that they reqqire the use of expensive reagents and the reactions are ‘very time-consiming and are quite sensitive to reaction conditions. Thirlly, and most importantly, the prior art, % o 2 nethods result in poor yields or the oxycodone and therefore such methods are unsuitable for commercial manulacturing operations. OBJECT OF THE INVENTION It is the principal object of this invention to prepare oxyeodone with a high level of purity and sulficeally high Yields so as to rest in a commercially feasible manut {uring operation DETAILED DESCRIPTION OF THE. INVENTION ‘The process of the invention for the manufacture of coxyeodone comprises the following seps (@) converting codeine or @ codeine salt into the interme diate Necarboalkoxy- of Necasboaryloxynorcodeine: (©) oxidizing the intermediate N-carboalkoxy- of [N-carboaryloxynorendeine to yield the intermediate [Necatboatkoxy- of N-carboaryloxynorendeinone, (©) enolizing the intermediate N-carboalkoxy- or [Necarboaryloxyaorcndinone with a base and methy~ lating the resultant enolate to yield the intermediate [N-carboalkoxy- or N-carboaryloxynorthehaine; (2) reducing the intermediate N-carboalkoxy- or N-catboaryloxyaorthebaine 0 yield thebaine; (©) oxidizing the thebaine to yield the intermediate ‘Mhydroxyeodeinone; and (9 bydeogenating the intermediate 14-hydroxyeodeinone to yield oxyendone Step (a) may be carried out by eeucting the codeine or a codeine salt, e-,codeine phosphate, with a chloroformate in the presence of an alkali metal carbonate or alkali metal bicarbonate and an inet solvent, Preferably the chorotor- ‘mate is a methyl, elyl or phenykeloroformate, The alkali ‘metal is ypieally sodium of potassium, Suitable examples of the inert solvent that may be used in step (8) inelude ‘methylene eblorde, chloroform, 1,2-dichloroethane and the like. Typically, the selected chloroformate willbe utilized in fn amount of about 15 to about 80 moles per mole of ‘deine or ence salt. In genera, the inert solvent wil be preseat inthe amount of about 10 10 about 60, preferably 20 {0 25, ites per kilogram of codeine or the selected codeine salt The reaction involved instep (3) may be earied out at ‘temperature of about Oo about 85° C,, preferably 42-70" CC, eg, when the selected inert solvent is ebloroform, the reaction is typically catied out under reflux at 65° C. The reaction time will typically be in the range of about 10 10 about 72 hours, preferably 10/10 24 hours. The restion in step (a) proceeds smoothly and completion of the reaction ‘may be determined by high-pressure quid chromatograph. Preferably, the intermediate N-carboalkoxy- oF Necarhoaryloxynorcodene is not isolated, and step (6) is cere out inthe same reaction vessel as employed for sep ©). ‘Step (b) may be carried out by oxidizing the intermediate Necachoalkoxy: or N-carboaryloxynoreodeine with a si able oxidizing agent in the presence of an inert solves (sich may be the same inert solvent as employed in step (@)) Suitable oxidizing agents include aluminum alkoxide land ketone; a potassium alkoxide and a ketone; dimethyl Slfoxide in the presence of oxalyl chloride; manganese oxide; potassium dichromate in the presence of sulfuric cid; and aie in the presence of palladium (Il) acetate. The preferred oxidizing agent comprises manganese dioxide. In ‘general, the oxidizing agent will be used in an amount of US 6,864,370 BL 7 about 7 to about 9 moles per mole of Necarboalkoxy- or N-carhoaryloxynorcodeine ‘Useful inert solvents for carrying out step (b) include chlorinated hydrocarbons such as chloroform, methylene ‘chloride 12-dichlorbethane and the like; Bydrocarbons such ashenzenc or toluene; esters such as ethyl acetate; and ethers ‘such as teirydrofuran. The preferred solvents ae chloro- form and toluene. In general, the inert solvent will be utilized in an amount of about 10 10 about 50, preferably 20 1 25 ters perky of the intermediate resulting from step (2) The oxidation reaction of step (b) may be earied cut at temperatures of about 0 to about 60" C, preferably 20-25° CC Typically, the oxidation reaction for step (6) will ental a reaction time of about 6 to about 49, preferably 18 to 24, hows, Preferably, the intermediate N-catboalkoxy- or Necatboaryloxynoreedeinone produced in step (b) is. o0t ‘solated, and step (@) is carded out in the stme reaction ‘vessel a5 employed for step (b). Tn step (e), the intermediate N-cerboalkoxy- of N-carbouryloxyaoreodeinone produced in step (b) is eno- lized using a base in an inert solvent and the resultant

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