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.

Recently, we published a synthesis of escitalopram (S-1) consisting of the resolution of didesmethylcitalopram (3) and subsequent methylation of S-didesmethylcitalopram (S-3) (Org. Process Res. DeW. 2007, 11, 289-292). Some of our observations regarding citalopram resolution and C-alkylation of a benzofuran analogue (2) to produce didesmethylcitalopram (3) were disputed by Dr. Dancer of H. Lundbeck (preceding article). A detailed response to his comments regarding stabilization of the 3-chloroproylamine free base by dilution with certain solvents, its storage and handling, optimized experimental conditions for C-alkylation to prepare didesmethylcitalopram, and a corrected process for citalopram resolution are included.

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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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