Process Research and Impurity Control Strategy of Esketamine

Abstract

An improved synthesis of (S)-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the (S)-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity. The ICH-grade quality (S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.

Synthesis and crystal characteristics of nirmatrelvir

“…Therefore, impurities 22 and 23 would affect the conversion of 8 , and this specific reaction conversion needed to be improved through reaction screening. 11…”

“…LC/MS was carried out on an LC/MS system consisting of an 1260 LC system equipped with a single quadrupole mass detector and electrospray ionization (ESI) interface (Agilent Technologies, Santa Clara, CA, USA). 11…”

Process for (S)-Ketamine and (S)-Norketamine via Resolution Combined with Racemization

“…Resolution of Ketamine and Norketamine. Based on the literature 20 and the previous work of our group, 25,30 the chiral resolution of racemic ketamine was carried out in acetone/water at a ratio of 15:1 with the frequently-used L-(+)-tartaric acid as the resolution agent. The resulting tartrate of ketamine was obtained in a yield of 41% with 99.5% chiral purity.…”

“…Although (R)-1 isomer does not seem to achieve easy racemization, we have successfully converted the undesired (R)-1 back to the racemic ketamine through the reversible reaction under the catalysis of a Lewis acid in our previous study. 25,30 According to our early research, the order of catalytic capability of some commonly used Lewis acids was as follows:…”

“…Although ( R )- 1 isomer does not seem to achieve easy racemization, we have successfully converted the undesired ( R )- 1 back to the racemic ketamine through the reversible reaction under the catalysis of a Lewis acid in our previous study. , According to our early research, the order of catalytic capability of some commonly used Lewis acids was as follows: AlCl 3 ≈ MgCl 2 > FeCl 3 > ZnCl 2 > BF 3 > CaCl 2 . Finally, we deemed AlCl 3 to be the most appropriate catalyst in view of its good catalytic capacity and removability.…”