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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%。
The ortho-difluorobenzene is converted to the (2R, 2R) -2- (3,4-difluorophenyl) ring by the Friedel-Crafts acylation, asymmetrically reduced with borane under CBS catalysis and reacted with triethyl phosphonoacetate (1R, 2S) -2- (3,4-difluorophenyl) ring was prepared by salt-formation of D-mandelic acid with Huffman degradation after ammonolysis Propylamine D-mandelate in 32% overall yield. With the legal system its enantiomer (1S, 2R) -2- (3,4-difluorophenyl) cyclopropylamine L-mandelate and racemic 2- (3,4-difluorophenyl ) Cyclopropanamine oxalate. A chiral HPLC method was established for the determination of (1R, 2S) -2- (3,4-difluorophenyl) cyclopropanamine D-mandelate with an ee value of 99.9%.