Trimethylsilyl triflate → (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (285.0 mg, 0.536 mmol) in dichloromethane (15 mL) at 0° C. was treated with trimethylsilyl-trifluoromethanesulfonate (200 μL, 1.072 mmol). After stirring at 0° C. for 45 min, the reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid. To the white solid was added a solution of (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid (252.7 mg, 0.536 mmol) in anhydrous acetonitrile (10 mL) and the solution was cooled to 0° C. then treated with N,N-diisopropylethylamine (380 μL, 2.144 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (244.6 mg, 0.643 mmol). After stirring at room temperature for 20 h, the reaction was quenched with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:4 to provide the title compound (377.2 mg, 80%) as a 1:1 mixture of diastereosiomers and as a white foam. LCMS (m/z) 886.3/884.5 [M+H], Tr=4.14 min.

Provenance & Evidence