抗2型糖尿病药西他列汀关键手性中间体的合成研究

目的合成2型糖尿病治疗药西他列汀的关键手性中间体。方法以2,4,5-三氟苯乙酸为原料,与2,2-二甲基-1,3-二烷-4,6-二酮缩合、脱羧得到3-氧代-4-(2,4,5-三氟苯基)丁酸甲酯,然后与R-α-苯乙胺缩合、不对称还原、脱除苄基保护基,再经Boc保护、水解得到西他列汀关键手性中间体(R)-3-(叔丁氧羰基氨基)-4-(2,4,5-三氟苯基)丁酸。结果与结论以总收率59.5%合成了西他列汀关键手性中间体,该合成路线具有步骤少、操作简便、收率高、立体选择性好、反应条件温和的特点。

Synthesis of the key intermediate of type 2 diabetes drug sitagliplin

The synthesis of sitagliptin has been accomplished by the coupling of （R）-3-（ tert-butoxycarbon- ylamino ）-4-（ 2,4,5-trifluorophenyl ）butanoic acid （1） with fused heterocycle fragment. The key intermediate 1 has been obtained through seven steps from 2,4,5-trifluorophenylacetic acid, which is easily transformed into methyl 3-oxo-4-（ 2,4,5-trifluorophenyl ） butanoate by condensation with 2,2-dimethyl-1,3-dioxane-4, 6-dione and then decarboxylation in methanol. Treatment of methyl 3-oxo-4-（ 2,4,5-trifluorophenyl） butano- ate with （R）-ot-phenylethylamine, followed by asymmetric reduction with sodium cyanoborohydride （NaBH3CN） provided two diastereoisomers, which are separated by silic~t gel chromatography. The chiral auxiliary group was removed by hydrogenation, followed by protection of amino group by Boc20 and hy- droxylation of methyl ester to give the key intermediate 1 with a yield of 59.5 %. In the literature the key in- termediate（ 1 ） was obtained from the corresponding enamine by asymmetric hydrogenation, which required very expensive metal catalyst and strict reaction conditions. In our improved process, it was easily prepared by reduction of the （R）-ot-phenylethylarnine-derived enamine in 83% yield. The structure of the desired compounds are confirmed by NMR and MS analysis and in good agreement with those reported. The deve- loped method featured as simple starting materials, mild reaction conditions, ease operations, high stereoselec- tivity and good yield.