Research work presented here describes an approach to achieve
the enantiopure escitalopram (1) via didesmethyl escitalopram
(4), which is easily resolvable compared to citalopram (1a)
through diastereomeric salt crystallization. The resolved intermediate (didesmethylcitalopram) was subsequently used for the
preparation of the desired drug. This simple modification of
the substrate makes a remarkable difference in the chemical
resolution process. The first resolution of didesmethylcitalopram
(±)-4 to furnish (+)-4, a novel key intermediate to assemble
escitalopram (1) was achieved via diastereomeric salt resolution
using (−)-di-p-toluoyltartaric acid (DPTTA). The resolution
conditions were optimized; a key feature of this process is the
addition of specific quantity of water at a specific temperature
to the reaction mixture.
An improved large-scale synthesis of lansoprazole 1 an anti-ulcer drug is described. The synthesis commences with condensation of 2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl-4-(2, 2, 2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a solvent to yield thioether 4. Subsequently, 4 was selectively oxidized to 1 by using sodium hypochlorite, a mild, economic, and eco-friendly oxidizing agent. A systematic investigation of crystallization parameters in the final stage, which enabled us to control the water content in the final API to <0.10%, were also discussed. (As recommended by USP 28 monograph (The United States Pharmacopeia: USP 28: NF 23United States Pharmacopeial ConventionRockville, MD20051110.)
An investigation into the Kumada cross coupling reaction was conducted by developing a reliable, efficient procedure for the Grignard reagent and its subsequent cross coupling reaction. Safe Mg metal activation as well as a moisture-free system was created by using MeMgCl reagent and improved the efficiency of the Grignard reaction. The established coupling reaction was successfully demonstrated at the multikilogram (50 kg) scale, and the coupling product was purified by using an agitated thin film evaporator (ATFE) technique.
An efficient and alternative synthesis of enantiomerically pure
(3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one (S)-(+)-2), a
key intermediate in the synthesis aprepitant (1), is described.
The key resolution of N-benzylglycinamide, (±)-9, is achieved
via diastereomeric salt crystallization using (+)-di-p-toluoyltartaric acid (DPTTA) as the resolving agent to furnish (S)-(+)-9. Alkylation of (S)-(+)-9 with 2-bromoethanol followed by
stereocontrolled cyclization of obtained (S)-(+)-10 afforded the
desired enantiomer (S)-(+)-2 with good yields and enantiopurity
(>98%). The reaction conditions were optimized to make the
process robust in order to implement at the commercial scale.
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