An efficient process for recycle S-valsartan from the racemic coproduct via diastereomeric crystallization by using natural dehydroabietylamine as the enantioselective recognition media

Abstract

This work aimed to recycle the S-valsartan by the chiral separation of the R- and S-valsartan mixture, where R- is an undesired coproduct formed in the production of S-valsartan. 1H NMR analysis and molecular simulation calculation indicated the dehydroabietylamine (DHAA) has well chiral recognition ability to the two enantiomers of valsartan. DHAA was employed to the resolution of R- and S-valsartan via diastereomeric crystallization successfully. The ethyl acetate saturated with H2O is a suitable solvent for the resolution. The four main parameters affecting the enantio-separation results, such as the molar ratio DHAA/valsartan, the liquid–solid ratio of solvent/valsartan, reaction temperature and crystallization temperature were evaluated and optimized by employing a Box-Behnken design and response surface methodology (RSM). Notably, an excess DHAA and the crystallization temperature rising are not beneficial to the chiral resolution of R- and S-valsartan. By RSM analysis, the optimal resolution parameters within the experimental ranges were 1.02 M ratio of DHAA/valsartan, 5.0 mL/g liquid–solid ratio of solvent/valsartan, reaction temperature of 75℃, and crystallization temperature of 5℃, respectively. At the above resolution conditions, the chiral separation of R- and S-valsartan gave the purity of 99.1% and recovery yield of 87.2% for the S-valsartan. This work provides an industrially viable and efficient separation of the two enantiomers of valsartan, especially for recycle S-valsartan from the R- and S-valsartan mixture waste, promoting sustainable development for the manufacturing of S-valsartan.