N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl ester

Uses

N-[(S)-(2,3,4,5,6-Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-Methylethyl Ester is a reactant in the synthesis of phosphoramidate imidazo[2,1-f][1,2,4]triazine-4-amine adenosine prodrugs that can increase anti-HCV activity.

Synthesis

Phenyl dichlorophosphate (64.2 mL, 430 mmol) and dichloromethane (DCM, 1200 mL) were added to a reaction vial containing (S)-isopropyl 2-aminopropionic acid hydrochloride (72.0 g, 430 mmol). The reaction mixture was cooled to -70 to -78°C using a dry ice-acetone bath, followed by slow dropwise addition of triethylamine (120 mL, 859 mmol) over 30 min. The temperature was maintained at -70 to -78°C with stirring for 30 minutes, then the reaction mixture was allowed to slowly warm to room temperature and stirring was continued for 1 hour. Subsequently, the reaction mixture was cooled to 0-5°C in an ice bath and 100 mL of DCM solution containing 2,3,4,5,6-pentafluorophenol (79 g, 430 mmol) and triethylamine (59.9 mL, 430 mmol) was added slowly over a dropwise period of 30 minutes. The resulting mixture was stirred at -70 to -78°C for 30 minutes, then warmed to room temperature and stirred for 2 hours. Upon completion of the reaction, the solid was collected by filtration and the filter cake was washed with 200 mL of ethyl acetate. The filtrate and washings were combined and concentrated to a semi-solid state by vacuum distillation. This semi-solid was dissolved in 500 mL of ethyl acetate and washed sequentially with water and brine. The aqueous phase was back-extracted with 50 mL of ethyl acetate. The organic layers were combined, dried with anhydrous MgSO4 and concentrated to give 210 g of crude product in 100% yield.NMR analysis showed the crude product to be a 1:1 mixture of diastereoisomers. To obtain the target SS diastereoisomers, kinetic splitting was performed: the crude product was suspended in 500 mL of 20% ethyl acetate/hexane, and 20 mL of 20% ethyl acetate/hexane solution containing 5 g of pentafluorophenol, 10 mL of triethylamine, and 100 mg of dimethylaminopyridine was added. The reaction mixture was heated to 45-50°C kept for 30 minutes and then stirred overnight. The white solid was collected by filtration, washed with 200 mL of 20% ethyl acetate/hexane and 100 mL of hexane, and dried under vacuum at 40°C to give 98 g of white solid, which was shown to be predominantly SS diastereoisomer by NMR analysis. The filtrate and washings were combined and concentrated to give a semi-solid, mainly another diastereoisomer and impurities. This residue was dissolved in 150 mL of ethyl acetate and washed sequentially with 50 mL of 1N HCl, water and 5% K2CO3 solution. The organic layer was dried and concentrated, and the white residue was suspended in 100 mL of 20% ethyl acetate/hexane, the solid was collected by filtration, washed with 20% ethyl acetate/hexane and hexanes, and dried to give 22 g of white solid, which was shown to be predominantly the SS diastereoisomer by NMR analysis. The total product weight after splitting was 120 g in 61.6% yield.

References

[1] Patent: WO2017/223421, 2017, A1. Location in patent: Page/Page column 68; 69
[2] Patent: WO2016/30335, 2016, A1. Location in patent: Page/Page column 51
[3] Patent: CN107405356, 2017, A. Location in patent: Paragraph 0209; 0210; 0213; 0214; 0215; 0216; 0217
[4] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8311 - 8319
[5] Patent: WO2016/99982, 2016, A2. Location in patent: Page/Page column 55