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.

Tulobuterol is a selective β2-adrenoceptor agonist and has been widely utilized as a therapeutic agent for the treatment of asthma. Synthesis of tulobuterol has achieved many important progresses over the past decades and has gradually become one of the research hotspots in organic chemistry. This study aimed to explore a novel synthesis route to synthesize tulobuterol hydrochloride (1), an active ingredient of Chlobamolie Hydrochloride Tablets. In the study, 1 was obtained from the cost-effective, commercially available 2-chloroacetophenone through the key steps including the reactions of bromination, NaBH4 reduction, and amination. Process-related impurities were also investigated. 1 was obtained with excellent purity (99.96%) in 53% overall yield without the need for chromatographic purification. The developed method is green, facile, and cost-effective; thus, it is suitable for the industrial-scale production of 1.