The resolution process for schizophrenia candidate drug ulotaront hydrochloride(SEP-363856,1)had been optimized in this study.By screening five common resolving agents,namely L-malic acid,L-lactic acid,L-tartaric acid,L-camphorsulfonic acid,and L-camphoric acid,the best one was determined to be L-tartaric acid,and the optimal equivalent was found to be 0.3.The recrystallization solvent and its amount were also optimized,and 25 volumes of anhydrous ethanol was used to obtain(S)-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethylamine L-tartrate(8).Compound 8 was treated with aqueous potassium hydroxide and subsequent salt formation with HCl in ethyl acetate,then 1 was obtained with ee value of 99.0％.The optimized resolution yield increased from 27％(original research process)to 38％,and the total yield increased from 14％(original research process)to 21％.
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