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

Temperature

0 °C

A cooled (0° C.) 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 (176.5 mg, 0.332 mmol) in dichloromethane (10 mL) was treated with trimethylsilyl-trifluoromethanesulfonate (120 μL, 0.664 mmol). After stirring at 0° C. for 70 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)-1-methyl-ethyl]-2-methyl-but-3-enoic acid [1,2,3]triazolo[4,5-b]pyridin-1-yl ester (200.0 mg, 0.332 mmol) in anhydrous acetonitrile (10 mL) and N,N-diisopropylethylamine (120 μL, 0.664 mmol). After stirring at room temperature for 19 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with ethyl acetate. The combined organics were washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The crude residue was combined with (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-methyl-but-3-enoylamino}-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester obtained in the previous step and purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:3 to afford the title compound (305.0 mg, 55%, over 3 steps) as a white solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 898.5/900.5 [M+H], Tr=4.16 min.

1. customthe reaction was quenched with a saturated solution of sodium bicarbonate
2. extractionThe aqueous layer was extracted with dichloromethane
3. filtrationThe combined organics were filtered through a phase separator
4. customthe volatiles were removed in vacuo

ORD record

ord-c52b3cdd88d449899b513a3ae94a169a

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145441B2