Improving The Synthetic Technology Of Captopril

Captopril is an important chiral drug in treatment of hypertension. Because of its high efficacy, less toxic side effects and less drug capacity, those attract the attention of chemical pharmaceutical industry. The traditional route for captopril synthesis is thioacetic acid route. However, the thioacetic acid route which exist some problems, such as, serious pollution and low yield and so on. Using 2-methacylic acid and hydrogen bromide as the starting material synthesis has the predominance, such as low pollution and mild reaction conditions. So this path is thought to be the best industrial production method. In this paper, relevant researches are carried out to explore the conditions in synthesis process.Firstly, the preparation of 3-R(R= - bromine, - chlorine)-2-methylpropanoic acid was studied. The addition reactions of thioacetic acid, hydrogen chloride, and hydrogen bromide with 2-methacylic acid were studied, respectively. The experiment results show that: hydrogen sulfide gas is formed during the addition of thioacetic acid, which leads to serious pollution. Hydrogen chloride gas is inert in this reaction, resulting in slow response, indicating that it does not have the practical feasibility. The addition reaction of hydrogen bromide gas is easy to control, and has mild reaction conditions with low pollution. Therefore, the ultimate route for synthesis of 3-bromo-2-methylpropanoic acid is confirmed by using 2-methacylic acid and hydrogen bromide gas.Secondly, the chiral separation for racemic compound of 1-[3-bromo-2- methylpropionyl]-pyrrolidine-2-carboxylic dicyclohexyl amine salt was studied. The chiral separation is attained by using the direct crystallization method. Furthermore, the effects of acetonitrile and ethyl acetate were investigated. The experiment results show that: separation of chiral substance by using mixed solvent crystallization method can not get good rotation, hard to solidify, and low yield. However, using the single solvent (ethyl acetate) crystallization method can easily crystallize the product with good optical characteristic. The greatest advantages are high yield (48%) and avoiding the use of toxic substance (acetonitrile). Therefore, using the single solvent crystallization method that separate dicyclohexyl amine salt is finally adapted.Then, the re-crystallization of 1-[3-bromo-2(S)-methylpropionyl]-pyrrolidine -2-carboxylic acid was also studied. Traditional method of re-crystallization is using ethyl acetate-hexane, we found it can be directly using C instead of using organic solvent, which eliminate the environmental pollution and reduces the cost.Finally, the condition of hydrosulfide reaction was studied. Hydrosulfide group is easily to be oxidized during reaction process, and existing in captopril products. This can bring to the loss of product quality and reduction of yield. In this paper, through the method of double A and B combination that can directly obtain solid captopril disulphide, then get captopril by reduction. The experiment results show that: this method can be obtained directly, without any oxidants, easy operation and, high yield. The final product comply with pharmacopoeia standard (melting point:103-104℃; content: 97%; specific rotation: 127°).This paper investigates the technological conditions of synthesis of captopril, which using 2-methacylic acid and hydrogen bromide as the starting materials. This method has laid a good foundation for future industrial production.