Substrate Modification Approach to Achieve Efficient Resolution:  Didesmethylcitalopram:  A Key Intermediate for Escitalopram

Abstract

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.

Formation of solid solutions between racemic and enantiomeric citalopram oxalate

“…The structural features of this salt gave an insight into why the classical resolution of citalopram by direct crystallization with a chiral acid has so far been unsuccessful. It has been stated that resolution could be achieved using (−)‐O‐O′‐di‐ p ‐toluoyl‐( R,R )‐tartaric acid,8 but the reported results could not be reproduced 9…”

Lipase-catalyzed remote kinetic resolution of citalopram intermediate by asymmetric alcoholysis and thermodynamic analysis

“…Optically active citalopram is usually obtained by chromatographic separation of the racemic citalopram, diol acetate, using chiral stationary phase [12]. Moreover, stereoselective crystallization of the diastereomeric salts of the racemic citalopram [13], didesmethylcitalopram [14], is also used. However, these methods involve consumption of enantiomerically pure reagents and relatively low yields.…”

Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram

“…We chose 4-methoxyphenylboroxine 2a as the aryl boron reagent for the rhodium-catalyzed nueclophilic addition to acetophenone.T he reaction was performed in tert-butyl methyl ether (MTBE) under nitrogen for 18 hours with acetophenone (0.10 mmol), 4-methoxyphenylboroxine (0.20 mmol), and K 2 CO 3 as the base in the presence of [{Rh(C 2 H 4 ) 2 Cl} 2 ]( 1.5 mol %) and (R,R,R,R)-WingPhos (3.6 mol %; Table 1, entry 1). To further improve the yield, employment of various inorganic salts as additives was studied (entries [14][15][16][17][18]. As olvent study (entries [8][9][10][11][12] proved that MTBE is among the best for this transformation.…”

“…As lightly better yield was achieved when the reaction was performed at 100 8 8C(entry 13). To further improve the yield, employment of various inorganic salts as additives was studied (entries [14][15][16][17][18]. Gratifyingly,a ne xcellent yield (98 %) and ee value (> 99 %) were achieved when magnesium bromide was added (entry 18).…”

“…Furthermore,a ne nantioselective synthesis of escitalopram was studied by using this methodology (Scheme 2). It should be noted that most reported syntheses of escitalopram rely on chemical or enzymatic resolution [14] of [b] ee [%] [c] 14 -FC 6…”