磷酸西他列汀的合成

Synthesis of Sitagliptin Phosphate

2,4,5-三氟苯乙酸与丙二酸单乙酯钾盐经亲核取代、脱羧、不对称还原、酯水解、与苄氧胺盐酸盐反应后经Mitsunobu反应得到(R)-1-苄氧基-4-(2,4,5-三氟苄基)-氮杂环丁烷-2-酮,再经水解开环后与5,6,7,8-四氢-3-三氟甲基-1,2,4-三唑并[4,3-a]吡嗪盐酸盐经缩合并脱保护基得到西他列汀,最后与磷酸成盐得到磷酸西他列汀,总收率约58%,光学纯度99.8%。

Sitagliptin phosphate was synthesized from 2,4,5-trifluorophenylacetic acid by substitution with ethyl potassium malonate, decarboxylation, asymmetric reduction, hydrolysis, reaction with O-benzyl hydroxylamine hydrochloride and then Mitsunobu reaction to give （R）-l-benzyloxy-4-（2,4,5-trifluorobenzyl）-2-azacyclobutanone, which was subjected to hydrolysis and then condensation with 5,6,7,8-tetrahydro-3-trifluoromethyl-l,2,4-triazolo L4,3- a] pyrazine hydrochloride, followed by deprotection and salification with an overall yield of about 58 %, with an optical purity of 99.8 %.