New chemical synthetic approach to captopril (SQ 14,225)

Abstract

The renin-angiotensin-aldosterone system plays an important role in the pathogenesis of hypertension in man. A component of this system, angiotensin I-converting enzyme (a peptidyldipeptide hydrolase, EC 3.4.15.1), has been known which converts the relatively inactive decapeptide angiotensin Ⅰ to the potent vasoconstrictor octapeptide angiotensin Ⅱ. Angiotensin I-converting enzyme also has been designated as kininase Ⅱ or bradykininase, because it inactivates bradykinin, a nonapeptide hormone of blood plasma that has vasodilating effect. Competitive inhibition of angiotensin I-converting enzyme has received considerable attention for the treatment of hypertension in mankind. Recently M. A. Ondetti, D. W. Cushman and their colleagues have reported the development of catopril (SQ 14,225), an orally active competitive inhibitor of angiotensin I-converting enzyme. However, the chemical synthetic method of captopril developed by M. A. Ondetti $\underline{et al}$. shows a very low yield and also has fault that $\underline{L}$-proline $\underline{tert}$-butyl ester, which we have difficulties in preparing, was used. Such a synthetic scheme also requires the tedious column operation in order to separate and remove acetate derivatives or side products produced during the ammonolysis of acetyl group used to protect the 3-mercapto function. So as to overcome this drawbacks, new chemical synthesis of captopril was approached in this research, and contained the following scheme : (1) the conjugate (or 1,4) addition of anhydrous hydrogen chloride to the methacrylic acid (2) the preparation of acyl chloride by means of thionyl chloride in the presence of $\underline{N}$, $\underline{N}$-dimethylformamide as a catalyst (3) the direct $\underline{N}$-acylation reaction of $\underline{L}$-proline by the Schotten-Baumann procedure (4) the resolution of diastereomeric acyl $\underline{L}$-proline by using of dicyclohexylamine (5) the substitution of chloride by sodiu...