(R)-Chloro Acid was an intermediate in the synthesis of a candidate drug in development. This paper describes the approach taken to develop a reverse classical resolution to give (R)-Chloro Acid. Knowledge of the eutectic position and eutectic solubility were key to the development of this process.

Experiments using Quinine as the resolving agent gave a eutectic position of 0.02 (resolvability = 0.98, max. = 1[1][2]) and a potential yield of 49 % at 100 % diastereomeric excess (d.e), however, it was found that the undesired salt, (S)-Chloro Acid Quinine, crystallised from solution. We chose to exploit the excellent eutectic position of the Quinine salts by developing a reverse classical resolution process, i.e. keeping the desired salt, (R)-Chloro Acid Quinine, in solution. The eutectic solubility was fundamental to achieving a process with practical working volumes and finding a suitable solvent proved to be a challenge. Batch mobility issues complicated the determination of the eutectic solubility. Roche Resolution software [3] was used as a guide to the optimum concentration and thus process volumes.