Resolution of (+-)-2.4-dichlorophenyl acetate-BM methanol solvates by Preferential Crystallisation in methanol. Study of the productivity in the system (+)-2.4-dichlorophenyl acetate-BM - (-)-2.4-dichlorophenyl acetate-BM - Methanol

摘要

Racemic BM is a pharmaceutical product that crystallizes as a stable racemic compound, and therefore cannot be resolved by Preferential Crystallization. However, it was found that its derivative, the methanol solvate of the salt formed with 2,4-dichlorophenylacetic acid, exists as a stable conglomerate without any detectable partial solid solution under thermodynamic equilibrium. The isothermal section of ternary phase diagram [(-)-Methanol solvate-(+)-Methanol solvate- Methanol] was studied at 30 deg C and the boundaries of the stable domains were determined by means of DITA (Discontinuous Isoperibolic Thermal Analysis). The resolution of this derivative was carried out at 2 litre scale in pure methanol by using the Auto Seeded Programmed Polythermic Preferential Crystallization (AS3PC) process and the results were compared with those obtained using the classical Seeded Isothermal Preferential Crystallization (SIPC) process. The AS3PC process appears more efficient than the SIPC process in terms of purity of the crops (optical purity), yield, and easiness of scale up. Nevertheless, the productivity of the system [(+)-2.4-dichlorophenyl acetate-BM - (-)-2.4-dichlorophenyl acetate-BM - Methanol] remains quiet modest. Further attempts of Preferential Crystallization were carried out by increasing temperature in order to enhance the productivity.