A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D₂-Receptor Antagonist

Abstract

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation

“…It has received great attention, as it can minimize the number of reaction steps, cost, development time, execution time, and environmental impact of synthesis . In our ongoing interest in developing one-pot reactions to meet the metrics of “green chemistry”, herein we report a new synthetic method for the production of Rebamipide ( 1 ), starting from the reaction of 4-(bromo­methyl)­quinolin-2­(1 H )-one ( 2 ) with diethyl (acetyl­amino)­propane­dioate ( 3 ) in aqueous NaOH solution, giving diethyl (acetyl­amino)­[(2-oxo-1,2-dihydro­quinolin-4-yl)­methyl]­propane­dioate ( 4 ), followed by decarboxylation using Krapcho conditions [DMSO–H 2 O–NaBr ( in situ )] to provide a mixture of ethyl 2-(acetyl­amino)-3-(2-oxo-1,2-dihydro­quinolin-4-yl)­propanoate ( 5 ) as major product and 2-(acetyl­amino)-3-(2-oxo-1,2-dihydro­quinolin-4-yl)­propanoic acid ( 6 ) as minor product in DMSO as the single organic solvent. Acid hydrolysis of compounds 5 and 6 gave 2-amino-3-(2-oxo-1,2-dihydroquinolin-4-yl)­propanoic acid dihydrochloride dihydrate ( 7 ), which further reacts with 4-chloro­benzoyl chloride ( 8 ) to produce Rebamipide ( 1 ) as shown in Scheme .…”