摘要
邻二氟苯经傅-克酰化、用硼烷在CBS催化下不对称还原、与膦酰基乙酸三乙酯反应得(1R,2R)-2-(3,4-二氟苯基)环丙基甲酸乙酯,氨解后进行霍夫曼降解,最后与D-扁桃酸成盐制得替卡格雷关键中间体(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐,总收率32%。同法制得其对映异构体(1S,2R)-2-(3,4-二氟苯基)环丙胺L-扁桃酸盐及外消旋体2-(3,4-二氟苯基)环丙胺草酸盐。并建立了(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐的手性HPLC检测方法,ee值99.9%。
(1R,2S) -2- (3,4-Difluorophenyl) cyclopropylamine [ (1R,2S) -1] D-mandelate, the key intermediate of ticagrelor, was synthesized from 1,2-difluorobenzene via Friedel-Crafts acylation, CBS reduction, cyclopropanation, ammonolysis, Hofmann degradation followed by salt formation with D-mandelic acid with an overall yield of 32%. The enatiomer of (1R,2S)-1 D-mandelate and 1 oxalate were synthesized by the similar procedures, and the analytical method of chiral HPLC was established. The value of enantiomeric excess of (1R,2S)-1 D-mandelate was 99.9%.
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2014年第4期315-317,321,共4页
Chinese Journal of Pharmaceuticals