Previous Methods for their preparation:Both hydrocodone and hydromorphone have been prepared in the past by a variety of processes including hydrogenation of codeinone (Arch. Pharm. (1920), 258, 295), oxidation of dihydrocodeine (DE 415097; U.S. Pat. No. 2,715,626), oxidation of dihydromorphine (J. Org. Chem. (1950) 15, 1103, U.S. Pat. No. 2,628,962; U.S. Pat. No. 2,654,756; U.S. Pat. No. 2,649,454), by electrolytic reduction of morphine (J. Pharm. Soc. Japan (1936), 56, 44 and (1942), 62, 347) or by catalytic rearrangement of either codeine or morphine (DE 623821, Appl. Radiat. Isot. (1987) 38, 651). However, all these processes involve a two-step process which is not cost-effective.
Catalytic rearrangement of morphine has been described using palladium black. It is not possible, however, to carry out this process on a large scale that would be suitable for manufacturing since the procedure affords 30-35% of the undesired o-desmethylthebainone along with the desired product. Isolation of the pure product is very tedious and requires extensive purification.Present Invention:A new one-step route to hydrocodone and hydromorphone has been found giving greater than 80% yield requiring minimal purification by simple methods.Large Scale Preparation of HydrocodoneA 2 liter four-necked round-bottomed flask equipped with a mechanical stirrer, gas sparging tube, gas outlet and a thermometer was flushed with nitrogen and charged with anhydrous methanol (500ml). The solvent was de-oxygenated by bubbling nitrogen through it for 10 to 15 minutes. Bis(bicyclo[2.2.1.]hepta-2,5-diene)rhodium(I)tetrafluoroborate (1.88 g, 0.005M) and 1,4-bis(diphenylphosphino)butane (2.17 g, 0.0051M) were added under nitrogen and the solution was stirred for 30 minutes at ambient temperature. The solution was hydrogenated by sparging hydrogen gas for 30 minutes; at this point, the colour of the solution changed from orange to tan-yellow.
Excess hydrogen was removed by bubbling nitrogen through the solution for 10 minutes. Next, codeine (150 g, 0.5M) was added to the stirred solution under a stream of nitrogen. After stirring the reaction mixture for 5 to 15 minutes, hydrocodone started to precipitate out as fine crystals, methylene chloride (300 ml) was added to dissolve all the solids. The dark-red coloured homogeneous solution was stirred for 1 hour. After completion of the reaction, the solution was concentrated under vacuum at ambient temperature to about half of its original volume. The precipitated product was filtered, slurried on the filter with cold methanol (100 ml), washed with methanol (1.times.100 ml), and dried under vacuum for 16 hours at 60 DEG to 70 DEG C. to afford 124.5 g (83%) of hydrocodone as a free base.
Preparation of HydromorphoneA 100 ml three-necked round-bottomed flask equipped with a magnetic stirrer, gas inlet, gas outlet and a thermometer was flushed with nitrogen and charged with anhydrous methanol (10 ml) and methylene chloride (5 ml). The solvent was de-oxygenated by bubbling dry nitrogen through it for 10 minutes. Under a stream of nitrogen, bis(bicyclo[2.2.1.]hepta-2,5-diene)rhodium(I)tetrafluoroborate (112 mg, 0.0003M) and 1,4-bis(diphenyl-phosphino)butane (130 mg, 0.00031M) were added and the orange solution was stirred for 15 minutes at ambient temperature. Next, the solution was hydrogenated by bubbling hydrogen gas for 10 minutes. Excess hydrogen was removed by bubbling nitrogen through the solution for 5 minutes. The solution of the catalyst was warmed to 40 DEG C. and morphine (2.14 g, 0.0075M) was added under a moderate stream of nitrogen. The dark coloured solution was stirred for 4 hours at 40 DEG C. The @1 H NMR of the crude indicated 88% of hydromorphone, 8% of unreacted morphine and 3 to 4% of an unidentified by-product. After removal of the solvents under vacuum, the crude hydromorphone was isolated by flash chromatography (ethyl acetate/methanol 3:1) as a brown solid (1.21 g, 56%) which was purified by recrystallisation from ethanol (25 ml) to give >98% pure hydromorphone (0.75 g, 35%).
Patent US5847142
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