西司他丁中间体合成工艺研究
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摘要
西司他丁是一种肾脱氢二肽酶抑制剂,它与亚胺培南复配的抗菌药物—泰能在临床上应用广泛。其合成包含两个关键中间体即S-(+)-2,2-二甲基环丙烷甲酸与7-氯-2-氧代庚酸乙酯的合成。本论文采用了环丙烷化法合成了中间体S-(+)-2,2-二甲基环丙烷甲酸；采用格氏法合成了7-氯-2-氧代庚酸乙酯,重点研究其工艺条件。并通过MS、1H NMR、IR等对各种产物及其中问体进行了表征,探讨了反应机理。
以异戊烯酸为原料,经酯化、环丙烷化、水解、拆分得到了S-(+)-2,2-二甲基环丙烷甲酸。其中合成异戊烯酸甲酯的最佳工艺条件为：n(异戊烯酸)：n(甲醇)=1：3,离子液体[MIMPS][HSO4]催化,加热回流反应3h,产品收率达到94.4%,纯度为99%。2,2-二甲基环丙烷甲酸甲酯的最佳工艺条件为：n(异戊烯酸甲酯)：n(二溴甲烷)：n(锌粉)=1：4：8,乙酰氯作为催化剂,溶剂为二氯甲烷,回流反应12h,反应收率达到72.6%。2,2-二甲基环丙烷甲酸甲酯在NaOH条件下水解,加热回流3h,可得到目标产物2,2-二甲基环丙烷甲酸,收率为98%。2,2-二甲基环丙烷甲酸拆分的最佳工艺为：n(2,2-二甲基环丙烷甲酸)：n(氯化亚砜)=1:1.2,回流条件下反应3h；n(2,2-二甲基环丙烷甲酸)：n((S)-扁桃酸甲酯)=1:1,0-5℃条件下反应3h,总收率为23%。
以1-溴-5-氯戊烷为原料,经格氏反应、加成、水解反应得到7-氯-2-氧代庚酸乙酯。7-氯-2-氧代庚酸乙酯的最佳工艺为：n(1-溴-5-氯戊烷)：n(镁)：n(草酸二乙酯)=1:1.1:1。格氏反应温度为恒温30℃；加成反应的温度为-25℃,反应时间为1h,反应收率达到58%以上,纯度达到98%以上。
Cilastatin is an important inhibitor of dehydropeptidase-1, which can enhance the antibacterial activity of Imipenim and has widely clinic applications. It was synthesized through two key intermediates S-(+)-2,2-dimethylcyclopropanecarboxylic acid and 7-chloro-2-oxohepanoate. S-(+)-2,2-dimethylcyclopropanecarboxylic acid was synthesized through cyclopropanation; and the ethyl 7-chloro-2-oxohepanoate was synthesized through Grignard method. The target compounds and intermediate products were charcaterized by MS, 1H NMR and IR, and the reaction mechanism was discussed in this paper.
Using 2-methylbutenoic acid as starting material, the intermediate S-(+)-2,2-dimethylcy-clopropanecarboxylic acid was synthesized via esterification, cyclopropanantion, hydrolysis and resolution. Methyl senecioate was obtained with 94.4% yield and 99% purity under the optimun reaction conditions which the raw material molar ratio was n(2-methylbutenoic acid): n(CH3OH)=1:3, reacted 3h at reflux temperature in the presence of [MIMPS][HSO4] as catalyst.2,2-dimethyl cyclopropanecarboxylate was obtained with 72.6% yield under the optimun reaction conditions which the raw material molar ratio was n(Methyl senecioate): n(CH2Br2):n(Zn)=1:4:8, reacted 12h at reflux temperature in the presence of ethanoyl chloride as catalyst, and the solvent was dichloromethane.2,2-dimethyl cyclopropanecarboxylic acid was obtained with 98% yield via hydrosis, reacted 3h at reflux temperature in the presence of NaOH. S-(+)-2.2-dimethylcyclopropanecarboxylic acid was obtained with 23% yield under the optimun reaction conditions which the raw material molar ratio was n(2,2-dimethylcyclopropanecarboxylic acid):n(SOCl2)=1:1.2, reacted 3h at reflux temperature; n(2,2-dimethylcyclopropanecarboxylic acid):n((S)-Methyl 2-hydroxy-2-phenyl-acetate)=1:1, reacted 3h at 0-5℃.
The intermediate ethyl 7-chloro-2-oxohepanoate was synthesized via two steps:through addition of mono-Grignard reagent of 1-bromo-5-chloro-pentane to diethyl oxalate. The optimun reaction conditions were as follows:n(1-bromo-5-chloro-pentane):n(Mg):n(diethyl oxalate)=1:1.1:1. The reaction of Grignard reagent was taken at 30℃; and the reaction of addition was taken at -25℃for 1h. The yield of ethyl 7-chloro-2-oxohepanoate was up to 58% and higher than 98% purity(by GC).
以异戊烯酸为原料,经酯化、环丙烷化、水解、拆分得到了S-(+)-2,2-二甲基环丙烷甲酸。其中合成异戊烯酸甲酯的最佳工艺条件为：n(异戊烯酸)：n(甲醇)=1：3,离子液体[MIMPS][HSO4]催化,加热回流反应3h,产品收率达到94.4%,纯度为99%。2,2-二甲基环丙烷甲酸甲酯的最佳工艺条件为：n(异戊烯酸甲酯)：n(二溴甲烷)：n(锌粉)=1：4：8,乙酰氯作为催化剂,溶剂为二氯甲烷,回流反应12h,反应收率达到72.6%。2,2-二甲基环丙烷甲酸甲酯在NaOH条件下水解,加热回流3h,可得到目标产物2,2-二甲基环丙烷甲酸,收率为98%。2,2-二甲基环丙烷甲酸拆分的最佳工艺为：n(2,2-二甲基环丙烷甲酸)：n(氯化亚砜)=1:1.2,回流条件下反应3h；n(2,2-二甲基环丙烷甲酸)：n((S)-扁桃酸甲酯)=1:1,0-5℃条件下反应3h,总收率为23%。
以1-溴-5-氯戊烷为原料,经格氏反应、加成、水解反应得到7-氯-2-氧代庚酸乙酯。7-氯-2-氧代庚酸乙酯的最佳工艺为：n(1-溴-5-氯戊烷)：n(镁)：n(草酸二乙酯)=1:1.1:1。格氏反应温度为恒温30℃；加成反应的温度为-25℃,反应时间为1h,反应收率达到58%以上,纯度达到98%以上。
Cilastatin is an important inhibitor of dehydropeptidase-1, which can enhance the antibacterial activity of Imipenim and has widely clinic applications. It was synthesized through two key intermediates S-(+)-2,2-dimethylcyclopropanecarboxylic acid and 7-chloro-2-oxohepanoate. S-(+)-2,2-dimethylcyclopropanecarboxylic acid was synthesized through cyclopropanation; and the ethyl 7-chloro-2-oxohepanoate was synthesized through Grignard method. The target compounds and intermediate products were charcaterized by MS, 1H NMR and IR, and the reaction mechanism was discussed in this paper.
Using 2-methylbutenoic acid as starting material, the intermediate S-(+)-2,2-dimethylcy-clopropanecarboxylic acid was synthesized via esterification, cyclopropanantion, hydrolysis and resolution. Methyl senecioate was obtained with 94.4% yield and 99% purity under the optimun reaction conditions which the raw material molar ratio was n(2-methylbutenoic acid): n(CH3OH)=1:3, reacted 3h at reflux temperature in the presence of [MIMPS][HSO4] as catalyst.2,2-dimethyl cyclopropanecarboxylate was obtained with 72.6% yield under the optimun reaction conditions which the raw material molar ratio was n(Methyl senecioate): n(CH2Br2):n(Zn)=1:4:8, reacted 12h at reflux temperature in the presence of ethanoyl chloride as catalyst, and the solvent was dichloromethane.2,2-dimethyl cyclopropanecarboxylic acid was obtained with 98% yield via hydrosis, reacted 3h at reflux temperature in the presence of NaOH. S-(+)-2.2-dimethylcyclopropanecarboxylic acid was obtained with 23% yield under the optimun reaction conditions which the raw material molar ratio was n(2,2-dimethylcyclopropanecarboxylic acid):n(SOCl2)=1:1.2, reacted 3h at reflux temperature; n(2,2-dimethylcyclopropanecarboxylic acid):n((S)-Methyl 2-hydroxy-2-phenyl-acetate)=1:1, reacted 3h at 0-5℃.
The intermediate ethyl 7-chloro-2-oxohepanoate was synthesized via two steps:through addition of mono-Grignard reagent of 1-bromo-5-chloro-pentane to diethyl oxalate. The optimun reaction conditions were as follows:n(1-bromo-5-chloro-pentane):n(Mg):n(diethyl oxalate)=1:1.1:1. The reaction of Grignard reagent was taken at 30℃; and the reaction of addition was taken at -25℃for 1h. The yield of ethyl 7-chloro-2-oxohepanoate was up to 58% and higher than 98% purity(by GC).
引文
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