Diisopropylethylamine → (R)-3-{4-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

Bis(trichloromethyl)carbonate (triphosgene) (0.09 g, 0.31 mmol) was dissolved in DCM (2 mL) and cooled in an ice-bath under nitrogen. 3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyaniline (0.3 g, 0.93 mmol) was evaporated twice from toluene to remove any moisture and then dissolved in DCM (2 mL) and diisopropylethylamine (0.32 mL) was added. This solution was added to the cooled triphosgene solution and the mixture was stirred at 20° C. for 2.5 hours. (R)-3-{4-[(4-Cyclohexylphenylamino)methyl]benzoylamino}-2-hydroxypropionic acid methyl ester hydrochloride (0.37 g, 0.83 mmol) was evaporated twice from toluene and dissolved in DMF (3 mL) and diisopropylethylamine (0.141 mL, 0.83 mmol) was added. The solution was added to the isocyanate above and, with stirring, heated at 80° C under nitrogen for 2 hours. The reaction mixture was evaporated in vacuo and the residue was extracted with DCM (80 mL), aqueous citric acid (10%, 25 mL). The aqueous phase was extracted with DCM (30 mL). The combined organic phases were washed with aqueous citric acid (10%, 3×25 mL), dried with magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (58 g) using ethyl acetate and n-heptane (940 mL, 1:1 and 300 mL ethyl acetate) as eluent to afford 0.03 g of (R)-3-{4-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid methyl ester.

Provenance & Evidence