Preparation method of 2-ethylbutyl ((S)-(pentafluorophenoxy)(phenoxy)phosphoryl)-L-alanine ester_Industrial additives

Background and overview^[1]

2-Ethylbutyl ((S)-(pentafluorophenoxy)(phenoxy)phosphoryl)-L-alanine ester is a key intermediate of Remdesivir (GS-5734). Remdesivir: Remdesivir (GS-5734) was developed by Gilead Sciences in the United States. It is a nucleoside RNA-dependent RNA polymerase (RdRp) competitive inhibitor. Its triphosphate nucleotide product Remdesivir -TP can compete with RdRp for the substrate ATP and therefore can interfere with viral vRNA synthesis. RdRp is an RNA polymerase widely distributed in positive-stranded and double-stranded RNA viruses. Therefore, Remdesivir has a certain inhibitory effect on filoviruses (Ebola, etc.), arenaviruses (Lassa fever virus, etc.), coronaviruses (SARS, 2019-nCoV, etc.), and has a certain inhibitory effect on CoVs represented by MERS. Higher inhibitory activity.

Preparation^[1]

Dissolve phenyl dichlorophosphate (50g, 0.24mol) in 200mL tetrahydrofuran, add pentafluorophenol (43.6g, 0.24mol), add triethylamine (72.7g, 0.72mol) dropwise, and raise the temperature to 35°C Stir and react for 4 hours, add L-alanine-(2-ethylbutyl) ester hydrochloride (50.4g, 0.24mol) in batches, stir and react for 2 hours; filter after the reaction, and use saturated sodium chloride solution for the filtrate Wash twice, dry over anhydrous magnesium sulfate, concentrate under reduced pressure until thick, add a mixed solvent of ethyl acetate and n-hexane, raise the temperature to dissolve, cool to 0°C and crystallize for 2 hours, filter, and dry the solid in vacuum. Compound D, 2-ethylbutyl ((S)-(pentafluorophenoxy)(phenoxy)phosphoryl)-L-alanine ester, was obtained with a yield of 72% (purity 98.3%).