Base‐Promoted Isomerization of cis‐Lactam to trans‐Lactam of Asenapine and Optimization of Crystallization Process of Asenapine Maleate Salt: An Antipsychotic Drug

Abstract

We have described the development of commercially scalable synthetic process for Asenapine, an antipsychotic drug. This involved the isomerization of cis‐lactam compound 5 to required trans‐lactam compound 6 and followed by isolation without chromatographic technique. The isolation process was executed up to 10 kg batch scale and achieved with good yield and high purity of trans‐lactam compound 6. We have also developed a crystallization process to obtain the stable and pure microcrystalline monoclinic form of asenapine maleate even after micronization with desirable particle size, which was previously unpredictable from the reported crystallization process.

Thermodynamics, Solubility, and Crystallization of 1,5-Pentylenediamine Hydrochloride in Mixed Solvent Systems

“…Antisolvent followed by cooling crystallization was conducted by preheating the 750 g·L –1 PDAH solution (10 mL) to 50 °C, then adding 60 mL of ethanol dropwise at a rate of 0.6 mL·min –1 while stirring at 300 rpm. Subsequently, the ethanol flow was stopped, and the solution was cooled to 0 °C.…”

“…According to the solubility data, a 750 g•L −1 PDAH solution was prepared by dissolving PDAH in water. The PDAH was then crystallized out of the solution by cooling and antisolvent crystallization, 30 as well as combinations of these methods (cooling followed by antisolvent crystallization; simultaneous cooling and antisolvent crystallization; and antisolvent followed by cooling crystallization 31 ). Each experiment was repeated three times under the same conditions.…”