Facile Synthesis of 1,4-Dihydropyridine Monocarboxylic Acids and Unsymmetric Dicarboxylates via Quaternary Ammonium Salts of 2-Aminoethyl 1,4-Dihydropyridine-3,5-dicarboxylates

Abstract

Useful 1,4-dihydropyridine unsymmetric dicarboxylates [nitrendipine (1), nicardipine (2)] and monocarboxylic acid 4 were prepared from unsymmetric 2-aminoethyl methyl 1,4-dihydropyridine-3,5-dicarboxylates 2 and 3 via their corresponding quaternary ammonium salts 5–9.

Notes

The symbols in parentheses indicate the configuration of piperidine C-3 position and dihydropyridine C-4 position, respectively.

Compound 3 gave two spots on TLC¹⁷ (50:50:1 CH₂Cl₂/EtOAc/Et₃N as a developing solvent). The isomer giving a higher R_f spot under this condition was (3R ^∗, 4R∗)-isomer and named α-isomer.⁶ Moreover, it was also reported that the α-isomer preferentially crystallized with good selectivity by fractional crystallization of the hydrochloride of 3 ⁶

The racemic compound (α)-3 was named benidipine, and its hydrochloride have been manufactured as Coniel® by Kyowa Hakko Kogyo Co., Ltd.

Details of synthetic study of benidipine hydrochloride will be published elsewhere by T. Ogasa et al.

Compound 11 (R¹=H, R²=R³=CH₃, X=I) was prepared by a similar manner described in experimental section.

Silica gel plate is Merck Art 11798 from Merck Co., Ltd. in Germany.