盐酸他喷他多的合成工艺改进及绝对构型的确定

Synthesis of Tapentadol Hydrochloride and Determination of Its Absolute Configuration

本研究对盐酸他喷他多(1)的合成工艺进行了优化。以间甲氧基苯丙酮(2)为起始原料,使用L-脯氨酸代替盐酸为催化剂,经Mannich反应得3-二甲胺基-1-(3-甲氧基苯基)-2-甲基-1-丙酮(3),ee值由68%提高至85%;3继而用L-二苯甲酰酒石酸拆分得(S)-3-二甲胺基-1-(3-甲氧基苯基)-2-甲基-1-丙酮(4),收率从65%提高到94%。4经格氏反应得(2S,3S)-1-二甲胺基-3-(3-甲氧基苯基)-2-甲基-3-戊醇(5);本研究通过调整加料顺序,有效减少了异构体杂质的产生,使5的纯度达99.2%。5再经酯化、催化氢化、脱甲基及成盐得1,总收率约65%(以2计)。本研究还采用单晶X射线衍射法确定1的绝对构型为(1R,2R)-型。

The synthetic process of tapentadol hydrochloride （1） was improved. 3-Dimethylamino-1- （3- methoxyphenyl）-2-methyl-l-propanone （3） was synthesized via Mannich reaction from 1-（3-methoxyphenyl）-1- propanone （2） ; The ee value of compound 3 was increased from 68 % to 85 % by using L-proline instead of hydrochloric acid. Then 3 was resolved with L-dibenzoyl tartaric acid to afford （S） -3-dimethylamino-1- （3-methoxyphenyl） -2-methyl- 1-propanone （4） with a yield of 94% . After a Grignard reaction, （2S,3S）-1-dimethylamino-3-（3-methoxyphenyl）-2- methyl-3-pentanol （5） was obtained; In this step, the formation of isomer impurities was effectively reduced by changing the feed order, and the purity of 5 was increased to 99.2%. Then compound 5 was subjected to esterification, catalytic hydrogenation, demethylation and salification to prepare 1 with an overall yield of 64.9% （based on 2）. The absolute configuration of I was determined by a single crystal X-ray diffraction method to be （1R,2R） -type.