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

Abstract

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.

Cobalt-Catalyzed Direct C–H Thiolation of Aromatic Amides with Disulfides: Application to the Synthesis of Quetiapine

“…To demonstrate the synthetic usefulness, we applied this newly established method in synthesizing Quetiapine, which is an atypical antipsychotic agent approved for the treatment of schizophrenia and bipolar disorder . The traditional synthetic route for accessing Quetiapine was based on the cross-coupling of benzenethiols with aryl halides, , while our synthetic strategy was based on the direct C–H thiolation of benzamides (Scheme ). The thiolation of 2-benzamido­pyridine 1-oxide ( 1n ) with 1,2-diphenyl­disulfane afforded the desired product 3n on gram scale.…”

Unconventional Synthetic Process of Fasudil Hydrochloride: Costly Homopiperazine Was Avoided

“…First, the cheaper inorganic acid hydrochloric acid (HCl) was used instead of trifluoroacetic acid (TFA) for the deprotection of the Boc group at 50–55 °C . Then, the intramolecular nucleophilic substitution proceeded smoothly to construct the homopiperazine ring in the presence of NaOH, KI, and TBAB . Finally, product 1 was produced by the salification with HCl in ethanol at 0–5 °C.…”

“…18 Then, the intramolecular nucleophilic substitution proceeded smoothly to construct the homopiperazine ring in the presence of NaOH, KI, and TBAB. 19 Finally, product 1 was produced by the salification with HCl in ethanol at 0−5 Reaction condition: 13 (1.0 mmol), base (2.0 equiv), TBAB (0.05 equiv), and stirring of solvent for 0.5 h, and addition of 1,3-dihalogenated reagent (x equiv). b Isolated yield.…”

Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

“…Pyridine analogues 2–15 , pyrazine analogues 20–22 , and benzene analogue 27 were prepared according to our previously reported method. 17 e Other analogues were synthesized following a similar procedure to that of quetiapine 22 and additional sulfur oxidation.…”