An Improved and Single Pot Process for the Production of Quetiapine Hemifumarate Substantially Free from Potential Impurities

An improved and single pot process for the preparation of Quetiapine hemifumarate (1), an antipsychotic drug, free from potential impurities is reported with an overall yield of 80%. The reported process for its preparation suffers from the drawback of producing potential impurities identified as 11-piperazin-1-yldibenzo[b,f][1,4]thiazepine (6), 2-(4-dibenzo[b,f][1,4]thiazepin-11-ylpiperazin-1-yl)ethanol (10), dimer (9), and N-methyl-N-phenyldibenzo[b,f][1,4]thiazapine-11-amine (14). Elimination of these impurities in the process is achieved by chlorination of 3 followed by in situ condensation of obtained 4 with highly pure 8 and subsequently establishing the pH based workup to obtain free base 2, which is further converted to quetiapine hemifumarate salt free from all these impurities. In this report, different aspects of process development such as scheme selection, optimization of different process parameters, identification, synthesis, origin and control of impurities, and development of an accurate analytical method during the development of a scalable process for quetiapine hemifumarate are discussed.