4-(1-氨基)乙基苯甲酸甲酯合成新工艺的研究

Study on a new process for synthesis of methyl 4-(1-amino)ethyl benzoate

摘要:

对(S/R)-1-苯乙胺合成(S/R)-4-(1-氨基)乙基苯甲酸甲酯的工艺进行了研究。原料(S/R)-1-苯乙胺先经氨基保护、再经苯基对位溴代合成(S/R)-N-(1-(4-溴苯基)乙基)-2,2,2-三氟乙酰胺（III）；III再与正丁基锂通过锂卤交换得到苯基锂中间体，再与二氧化碳加成并水解得到(S/R)-4-(1-(2,2,2-三氟乙酰氨基)乙基)苯甲酸（IV）；IV在氯化亚砜和甲醇的共同作用下通过一锅法合成实现氨基脱保护基和羧基甲酯化得到目标产物 (S/R)-4-(1-氨基)乙基苯甲酸甲酯盐酸盐（V）。该工艺已成功应用于2.5 kg /批次产品的生产, 总摩尔收率~38%。

Abstract:

A new process to synthesize methyl (S/R)-4-(1-aminoethyl)benzoate from (S/R)-1-phenylethan-1-amine was studied. The starting material (S/R)-1-phenylethan-1-amine was trifluoroacetylated and then subsequent para-bromo substitution on phenyl ring gave (S/R)-N-(1-(4-bromophenyl)ethyl)-2,2,2-trifluoroethane (III). Next, lithium–halogen exchange of compound III with n-BuLi followed by the addition of CO2 and hydrolization afforded (S/R)-4-(1-(2,2,2-trifluoroacetamido)ethyl) benzoic acid (IV). The methyl (S/R)-4-(1-aminoethyl)benzoate hydrochloride (V) was accomplished after the amine deprotection and methyl esterification using thionyl chloride and methanol in a one-pot manner. This process has been successfully scaled up at a 2.5 kg scale in a molar yield of ~38%.