Practical Process for synthesizingR-Tetrahydropapaverine─A Key Intermediate of Cisatracurium Besylate (Nimbex)

In this paper, a practical process to synthesize the key intermediate R-tetrahydropapaverine of cisatracurium besylate was proposed. First, tetrahydropapaverine hydrochloride (1.HCl) was prepared from inexpensive and commercially available 2-(3,4-dimethoxyphenyl)ethanamine (2) and 3,4-dimethoxybenzeneacetic acid (3) through a one-pot process. The yield and purity of the product were up to 85.4 and 98.1% on a 150 g scale, respectively. Then, a new resolution process was developed to prepare R-tetrahydropapaverine by using a half equivalent of N-acetyl-d-phenylalanine, and the obtained R-tetrahydropapaverine had a yield of 28.1% and 98.0% ee on a 120 g scale. Furthermore, the S-isomer was racemized to 1.HCl in the one-pot process with 77.7% isolated yield and 99.0% purity.