A kind of synthetic method of oxymorphone hydrochloride
A technology for oxymorphone hydrochloride and oxymorphone, which is applied in the field of oxymorphone synthesis, can solve the problems of high hydrogenation temperature, incomplete reaction, poor product appearance and purity, etc., achieves easy availability of raw materials, avoids the generation of impurities, Simple to use effects
Active Publication Date: 2016-04-06
北京华素制药股份有限公司
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Problems solved by technology
However, due to the limitations of the existing synthesis process, oxycodone contains incompletely hydrogenated α, β unsaturated ketones, and compounds with this unsaturated ketone structure have potential genotoxicity
The existing demethylation methods are hydrobromic acid method and methionine method, wherein the hydrobromic acid method reacts incompletely, and the appearance and purity of the product are relatively poor; in U.S. Patent No. 5,071,985 methionine demethylation has been used to obtain oxymorphone, but α, β unsaturated ketones are not controlled
In CN101652371A, α and β unsaturated ketones are controlled, but the hydrogenation temperature is too high, and new impurities are easily produced
Method used
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Embodiment 1
[0048] A. Synthesis of Oxycodone
preparation example A-1
[0050] In a 20L reaction kettle, add 1000g of oxycodone hydrochloride and 5000mL of purified water, stir to dissolve, then lower the temperature to 5-10°C and stir for 1 hour. Add 650 mL of ammonia water, stir for 2 hours, let stand for 1 hour, filter the solid, and dry under reduced pressure at 55°C for 6 hours to obtain 873.9 grams of off-white solid. Yield: 97.5%.
preparation example A-2
[0052] In a 20L reaction kettle, add 1000g of oxycodone hydrochloride and 5000mL of purified water, stir to dissolve, then lower the temperature to 5-10°C and stir for 1 hour. Add 114 g of sodium hydroxide, stir for 2 hours, let stand for 1 hour, filter the solid, and dry under reduced pressure at 55°C for 6 hours to obtain 853.3 g of off-white solid. Yield: 95.2%.
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The invention discloses a synthesis method of oxymorphone hydrochloride. The synthesis method mainly comprises the following steps of: 1) alkalifying to obtain free alkali by taking oxycodone hydrochloride as an initial a raw material; 2) carrying out a demethylation reaction to obtain oxymorphone; 3) carrying out a hydrogenation reaction on the oxymorphone under acidic condition; and 4) salifying the hydrogenated product with hydrochloric acid to obtain the target product oxymorphone hydrochloride. The synthesis method disclosed by the invention has the advantages of available raw materials, high product purity and is easy to operate and is applicable to industrial production.
Description
technical field [0001] The technical field of pharmaceutical compounds of the present invention, more specifically, relates to a synthetic method of oxymorphone. Background technique [0002] Oxymorphone hydrochloride is a potent semi-synthetic opioid analgesic used for the relief of moderate to severe pain and is available in dosage forms such as injections, suppositories, tablets, or delayed-release tablets. It is necessary to obtain a synthetic process for high-purity oxymorphone and its salts. [0003] The known methods for synthesizing oxymorphone all use thebaine isolated from opium poppy as a starting material, undergo oxidative hydrogenation to obtain oxycodone, and then demethylate to obtain oxymorphone. However, due to the limitations of the existing synthesis process, oxycodone contains incompletely hydrogenated α, β unsaturated ketones, which have potential genotoxicity. The existing demethylation methods are hydrobromic acid method and methionine method, where...
Claims
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IPC IPC(8): C07D489/08
Inventor 米春来房雪松刘攀峰魏淑冬边玢姚文静龙永鹏
Owner 北京华素制药股份有限公司