2) United States Patent Casner et al. (54) PREPARATION OF OXYCODONE. (75) Inventors: Michael Lawrence Casner, Pitman, NI Dung, Boothwya, PA, 5), Erno M. Keskeny, Wilmington, (US): Fin Lo, Fulletzoa, CA US) (73) Assignoe: Johnson Matthey Publi Limited ‘Company, London (GB) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 USC. 154(6) by 0 days. (21) Appl. No. 117234,627 (22) Filed: Sep. 23, 2005 6s) Prior Publication Data US 2006)0111383 AL May 25, 2006 G0) Foreign Application Priority Data Sep. 23. 2004 (GR) o421149.6 (1) Incl. CozD 4898 (2006.01) co7D 48974 (2006.01) a 546145; 546/44 (58) Field of Classitication Search ‘44, S464 ‘Sce application file for complete search history. 66) References Cited USS. PATENT DOCUMENTS 6008255 12/1999 Huang ta 'US007153966B2 US 7,153,966 B2 Dec. 26, 2006 (10) Patent No. (4s) Date of Patent: 6090.98 4 6.77567 BL 6864370 BL 20050222188 AL 772000, Mud 12001 Chine al 72001. Chia ea 62002 Chia ea 32005 Lin tal 102005 Chapnan eta FOREIGN PATENT DOCUMENTS Dss9 015 AL 1999 (OTHER PUBLICATIONS Roland. Kraig. st al, “Optimization of the Synthesis of Oxyeodone and ®-Mathyloxyeodone” 4voh Pharm. Pharm. Med. ‘Ghem vl. 329, 1996, pp 328326 Primary Examiner —Charaajit S. Aulakh (14) Atornes, Agent, or Firm —RatnerPrestia. on ABSTRACT A process for preparing oxyeadone of an oxycodone st ‘wherein the oxyeodone or oxycodone salt has ow levels of impurities (especially 14-hydroxyeodeinone) is disclose The process comprises the steps of ) preparing a mixture comprising oxyeodone and a solvent and odjusting the pl ofthe mixture to less than 6; and subsequently ') exposing the mixture to hydrogenation reagents For 3 period of af Teast 1 hour 12 Claims, No DravvingsUS 7,153,966 B2 1 PREPARATION OF OXYCODONE CROSS REFERENCE TO RELATED "APPLICATIONS (IF APPLICABLE) ‘This application claims priority of Pritish Patent Appli= cation No. 0821149 6, fled Sep. 23, 2004 FIELD OF THE INVENTION ‘The present invention relates to a process for preparing ‘oxyeadone having low levels of impurities, In particular the process is useful for preparing oxyeodone with low levels of ‘cf -unsaturated ketones BACKGROUND OF THE INVENTION ‘Oxycodone is a narcotic analgesic having the structure (0 cH. Zh * hy ° ‘Oxycodone can be maniafactured from the natural prodiact thebaine (ID) by a well-known process as disclosed in US. Pat. No. 6,090,983: 2 \ 0 ‘Thebaine (Il) or a salt thereof is reacted with hydrogen peroxide in isopropanol, water and formic seid, producing L-hydroxycodeinone (Il). The double bond in the 14-hy- “droxyeodeinone (IID) is reduced by reaction with hydrogen, jn the presence of a PUBaSO, catalyst, providing oxye- ‘odone (I). o SUMMARY OF THE INVENTION Recently there has been @ cancer about the presence of 65 ‘cpunsaturated ketone impurities in pharmaceutical prod Uuels. L4-hydroxyeodeinone (II) is an c.feunsaturated 2 ketone, and unsurprisingly, small quantities of this com- pound may be found in oxyeexone(). The present inventors Dave sought to provide a method for preparing oxycodone having low levels of impurities and in particular, low levels of a,f-unsaturated ketone impurities, preferably below 10 Ppm. “Accordingly, the present invention provides a process for preparing oxycodone oF an oxycodone salt, wherein the fxyeodione of oxycodone salt has low levels of impurities, comprising the steps of ) preparing a mixture comprising oxyeodone and solvent and adjusting the pH ofthe mixture to Tess than 6; and subsequently ») exposing the mixture to hydrogenation reagents Fora period of at least | hour The inventors have Fond that this process surprisingly provides oxyeodone with low levels of cpunsaturated Kelone impurities, i, l4ehydroxyeodeinone at less than 15 ‘pm. The inventors have found that onder to achieve low levels of 14-hydroxyeodeinone, the pH must be adjusted before the hydrogenation stp. Suitably the mixtures heated after the pHT of the mixture is adjusted, so that the process comprises the steps of 8) preparing. a mixture comprising oxyeodone and 3 solvent, adjusting the pH of the mixture © Jes than 6 and heating the mixture atthe temperature of at least 55° C. for a peri of at least 1 hour; and subsequently >) exposing the mixture to hydrogenation reagents fora period of atleast | hour This process provides oxycodone with very low levels of cafeunsitumted ketone impurities, i.e. M4-bydmonyeo- Seinone at less than $ ppm DETAILED DESCRIPTION OF THE INVENTION The mixture comprising oxycodone anda solvent can be prepared by a number of methods. In a frst method, oxye- ‘done base or a salt of oxycodone, prepared and isolated using any of the methods known to those skilled in the art is mixed with a solvent Io form the mixture, In a second ‘method, 14-hydroxyeodeinone is hydrogenated ina solvent using known hydrogenation reagents, thereby providing ‘mixture comprising oxycodone and a solvent In a third vethod, 4 mixture comprising thebaine and a solvent is subjected to oxidation conditions (eg. hydrogen peroxide in Tommie acid and water), followed by hydrogenation cond sions, thereby providing a mixture comprising oxycodone and a solvent, Other methods of preparing « mixture com- prising oxyeodone and a solvent may be known to those stalled in the a, “The pl of the mixture is adjusted to less than 6, suitably less than 5, more suitably less than 3 and preferably about 1 The pil is suitably adjusted by the addition of @ strong avid such as concentrated hydrochloric acid to the mixture Preferably at least one equivalent of acid is added to the anixture. ‘The solvent in the mixture is suitably an organi solvent such a5 isopropanol, ethanol or SD3A (a 95:5 mixture of ethanol methanol). Preferably the mixture futher comprises ‘After the pH is adjusted, the mixture is suitably heated to temperature of at least 55°C., preferably atleast 60° C, and ‘ost preferably about 70-75° The temperature is suitably ‘ot higher than the boiling point ofthe solvent. The mixture is suitably heated for a period of at least 1 how, preferably at least 3 hours and most preferably between 5-10 hoursUS 7,153,966 B2 3 Svitable hydrogenation reagents are well known to the skilled person and typically include a hydrogenation catalyst ‘and either hydrogen ora hydrogen transfer agent, such as sodium hypophosphite. Prefered hydrogenation eatalysts ‘are precious metal eataysts such as palladium or platinum dispersed on a support material sch as earbon of barium sullte- Ina preferred embodiment, precious metal catalyst js added to the mixture and hydrogen is passed through the mixture at a pressite of 10 psi or more (162 kPa or more) ‘The hydrogenation step is suitably caried out at a tempera ture ofa least ambient, preferably ata temperature between room temperature aad 70° C. The temperature should be suficent to dissolve the solids in the mixture, thereby proving a solution. The mixture is expose tothe hydro- enaton reagents for atleast 1 hour, suitably at least 2 hours and preferably about 6 hours Te product of step (b) is a mixture comprising oxye> ‘done and a solvent. Hydrogenation catalysts may be removed by filtering the mixture. purified oxycodone salt may be obianed from the mixture by reducing the tempers- ture, ad allowing the salt to erystllse ou. For example, hydrochloric acd was used in step (a, the hydrochloride salt ‘of oxycodone will be prodiced. Alternatively, oxycodone base may be provided by adding @ base such as sodium hydroxide tothe mixture and allowing the mixture 10 cool. If precious metal catalysts are used in the hydrogenation step, itis possible that unacceptable levels of the metals will remain in the final produet (desirably the heavy metal ‘content ofthe final product is less than 20 ppm). In one ‘embovdiment of the peesent invention, the oxyeodone oF ‘oxycodone st proaced in step (b) is subjected to a farther process wherein @ mixture comprising the oxycodone or ‘oxycodone salt and a solvent is treated with charcoal Suitably the mixture i heated to a temperature of approx. 60-65" C., the charcoal is added, the mixture is sired at 60-65° C. for $10 10 hours and the hot mixture is filtered to remove the charcoal. Cooling the hot mixture provides the ‘oxyeakione salt or oxyeodione, Suitably the weight ratio of ‘oxyeodone or oxyeodone salt to charcoal is between 20:1 and 1:1, preferably about $:1. The charcoal is suitably a ‘charcoal such as Dareo® G60 (Norit, USA) ‘Oxyeadane oF an oxycodone salt produced according t0 the process of the invention fas low levels of af-unsature ated Ketones and is advantageously incorporated into phar ‘maceutical products EXAMPLES ‘The following examples ae illustrative but no limiting of the invention Preparation of Oxyeadone Base: Route A. ‘Thebaine (15.94 g) was addod to 2250 mi flask. Water (18 ml) was added and the mixture was stired at room tem- perature. Formic acid (42 ml) was added over 3 minutes and then the mixture was cooled in an ice bath. Hydrogen peroxide (309%, 67 g) was added and the mixture was stirred Tor 1 hour, The mixture was removed from the ice bath allowed to warm to room temperature and then heated to 48° CC for2 hours, The mixture Was teamsfereed to a hydroge= nation botle. A$ wt % palladium on carbon catalyst (2 2) ‘as added and hydrogen was passed through the mixture at approximately 20 psi for 15 hours. ‘The catalyst was removed by passing the mixture though a pad of celite and Finsing the filtered solid with waterformic acid (3:1, 8 ml). The mixture was cooled in an ie bath and 25% sodium, 0 o 4 hydroxide (109 ml) was added dropwise over SO minutes to increase the pH to 9-10. The mixture was stirred for 1 hour and 15 minutes and the solid product was filtered, rinsed ‘with cold water and dried under vacuum pump for 3 hots. ‘The prodiet was oxyoodone hase (14.152 g, 87.7% yield) and contained 178 ppm ofthe frunsaturated ketone impu- rity, L4-hydroxycodeinone, Preparation of Oxycodone Base: Route B Thebsine (100.0 g dry weight) was dissolved in 85% ormie acid (2523 g). 3% Hydrogen peroxide (43.6 g) was added over & period of about two hours. The mixture was Simed for three hours. Ammonium hydroxide solution was ‘added to the mixture to inerease the pl¥ to 8-9. The solid precipitate was filtered and Washed with water and ethane ‘The solid was dried on the fier and in an oven. ‘The product was |4-hydroxyeodeinone (150.52 g damp, 7532 p dry weight, 75% yield) ‘The 14-tydroxyvodeinone (39.45 g of the damp solid) was dissolved in water (81.13 ml) and 80% acetic acid (16.17 mi). 10 st % palladium on carbon catalyst (0.33 3 ‘wet weight, 0.16 g dry weight) was added and hydrogen was passed through the mixture for about 6 hous at about 12 ps. The mixture was filered to remove the catalyst, Aa eno- ium hydroxide solution was added tothe mitre up to pH 9. The solid preipitate was washed with water and wilh ethanol, and was dried. The produet was oxycodone (18.8, 7% yield, Compuative Example 1 Heating and Reerystallisation of Oxyeodone 13.257 g of oxyeodone prepared via Route A was added to 8250 ml flask, An ethanol/methanol mixture (70m) was Added to the flask and the mixture was stired at room emperature, heated t reflux (78° C.) for 1 hour, cooled 10 ‘mom temperure and then sted at rom temperature. The ‘mixture was cooled ia an ice bath for 30 minutes and the solid product was filtered and rinsed with an ethanol ‘methanol mixture. The solid was deed under vacuum for 3 hours. The product was oxyeodone base (11.395 g, 85.95%) ‘and contained 210 ppm of the .f-unsaturated ketone impu- iy, L4-hydroxycodeinone, Dissolving the oxycodone, beating to 78° C. for 1 hour and reerystallising did not reduce the amount of [4-hydroxy- eodeinone in the oxyeodone. Comparative Fxample 2 Heating and Reerystallisation of Oxycodone 11 gof the oxycodone prosuct from comparative example 1 was added to-# 250 ml Bask. An ethanol methanol mitre (55 mil) was added tothe Mask and the mixture was stirted at room temperature, heated to rellux (78° C.) for | howe, ‘cooled to room temperature and then stired at room tem- perature. The mixture was cooled in an ice bath for 35 ‘minutes andthe soli product was feed and rinsed with an ccthanol/methanol mixture, The solid was dried “under vacuum overnight, The product was oxyeodane base (10.682 g, 97.1%) and contained 165 ppm of the ai ‘unsaturated ketone impurity, M4-hydroxycodeinone. A second step of dissolving the oxycodone, heating 0 78° for | hour and recrystallising did aot significantly reduce the amount of 14-hydroxyeadeinone in the oxycodone,