摘要
以苯甲酸阿格列汀(1)的工业化生产路线为基础,制备了苯甲酸阿格列汀的7个有关物质:2,2'-[[6-氯-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1,5(2H)-基]-二(亚甲基)]二苯甲腈(7)、2-[[5-溴-6-氯-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基]甲基]-苯甲腈(8)、2,2'-[[6-乙氧基-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1,5(2H)-基]-二(亚甲基)]二苯甲腈(9)、(R)-2-[[3-甲基-2,4-二氧代-6-[(哌啶-3-基)氨基]-3,4-二氢嘧啶-1(2H)-基]甲基]苯甲腈(10)、(R)-2-[[6-[3-[[3-(2-氰苄基)-1-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]氨基]哌啶-1-基]-3-甲基-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基]甲基]苯甲腈(11)、(R)-2-[[3-甲基-6-[3-[(1-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)氨基]哌啶-1-基]-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基]甲基]苯甲腈(12)、(R)-N-[1-[3-(2-氰基苄基)-1-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基]哌啶-3-基]苯甲酰胺(13),并通过1HNMR、13CNMR和MS对其结构进行确证.其中7、9、12、13的合成为首次报道.
Abstract
In this article,based on the industrial synthetic route of alogliptin benzoate(1),seven related substances of 1 were synthesized,namely 2,2'-[[6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1,5(2H)-diyl]-bis(methylene)]-dibenzonitrile(7),2-[[5-bromo-6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl]-methyl]benzonitrile(8),2,2'-[[6-ethoxy-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1,5(2H)-diyl]bis(methylene)]-dibenzonitrile(9),(R)-2-[[3-methyl-2,4-dioxo-6-[(piperidin-3-yl)amino]-3,4-dihydropyrimidine-1(2H)-yl]methyl]-benzonitrile(10),(R)-2-[[6-[3-[[3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]amino]-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl]methyl]benzonitrile(11),(R)-2-[[3-methyl-6-[3-[(1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-yl)amino]piperidin-1-yl]-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl]methyl]benzonitrile(12),(R)-N-[1-[3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-yl]piperidin-3-yl]benzamide(13).Their structures were confirmed by 1H NMR,13C NMR and MS.The synthesis of 7,9,12,and 13 were reported at the first time.
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