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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。
In this study, the optimization of the synthesis of tapentadol hydrochloride (1) was optimized. Starting from methoxyphenylacetone (2) and using L-proline instead of hydrochloric acid as catalyst, Mannich reaction gave 3-dimethylamino-1- (3-methoxyphenyl) -2 3-propanone (3), the ee value increased from 68% to 85%; 3 and then separated with L-dibenzoyltartaric acid to give (S) -3-dimethylamino- Methoxyphenyl) -2-methyl-1-propanone (4), the yield increased from 65% to 94%. 4 was Grignard reaction (2S, 3S) -1-dimethylamino-3- (3-methoxyphenyl) -2-methyl-3-pentanol (5); This study by adjusting the feeding sequence , Effectively reduce the formation of impurity impurities, so that the purity of 5 99.2%. 5 and then by esterification, catalytic hydrogenation, demethylation and salt was 1, the total yield of about 65% (2 dollars). The single crystal X-ray diffraction method was also used to determine the absolute configuration of 1 as (1R, 2R) -type.