A simple, efficient and highly economic process for the production of donepezil hydrochloride (1), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde (2), and the introduction of operationally simple chemistry at the penultimate stage wherein 2 is reacted with 5,6-dimethoxy indanone (3) in the presence of sodium hydroxide and a phase transfer catalyst (PTC) in a biphasic solvent to furnish the intermediate 4, which is reduced and directly treated with hydrochloric acid to furnish highly pure donepezil hydrochloride with desired polymorphic form. The improved process provides donepezil hydrochloride at considerably lower cost and allows the omission of hazardous chemicals.

Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.

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.

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