Hydrochloric Acid → 1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml) and 1.4N HCl in H2O (75 ml) was added to the solution. The mixture was stirred at 60° C. for 1 h. The mixture was concentrated to remove the solvents, followed by co-evaporation with toluene (×2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHCO3 aqueous solution while monitoring CO2 evolution. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used without further purification in the next step. The crude material was dissolved in CH2Cl2 (360 ml) and morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0° C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 min at 0° C. Saturated aqueous NaHCO3 solution was added to quench the reaction. After stirring for another 20 min, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester as a yellow solid (12 g, 50% yield). LCMS found 924.63 [M+H]+.

Provenance & Evidence