Description
L-alanine isopropyl ester hydrochloride is used as a key intermediate of sofosbuvir, a mature synthesis method is adopted at present, alanine is subjected to acyl chlorination by thionyl chloride and then reacts with isopropanol.
Uses
L-Alanine isopropyl ester hydrochloride is a reagent used in the synthesis of anti- hepatitis C virus prodrugs based on imidazotriazine and pyrrolotriazine molecules. Further, it reacts with (1R:2R)-2-Hydroxy-πnanone-3 to prepare isopropyl (1R,2R,5R)-2′-[(2-hydroxypinan-3-ylene)amino]propanoate.
Synthesis
To a reaction flask equipped with a mechanical stirrer, reflux condenser tube, thermometer and under nitrogen protection was added L-alanine (5.0 g, 56.1 mmol) and 11.1% w/w isopropanol HCl solution (73.8 g, 224.5 mmol). The reaction mixture was heated to reflux temperature (80-85 °C) and kept for 4 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) using a 7:3 ethanol-water mixture as eluent and ninhydrin as color developer. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove isopropanol and isopropyl acetate, and the residual solvent was removed by multiple azeotropic distillations to give the final product (R)-isopropyl (R)-2-aminopropionate hydrochloride in oil form (9.4 g, quantitative yield).
References
[1] Patent: WO2016/151542, 2016, A1. Location in patent: Page/Page column 19
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 20, p. 2622 - 2628
[3] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1197 - 1201
[4] Patent: WO2015/38596, 2015, A1. Location in patent: Page/Page column 237; 238
[5] Patent: WO2016/145142, 2016, A1. Location in patent: Page/Page column 287
