Triethylamine → HCID 86706081, compound

Participants

Reaction Conditions

Reaction Steps

A solution of (E)-4-{2-[(R)-1-(tert-butoxycarbonyl-methyl-amino)-ethyl]-quinolin-7-yl}-2,2-dimethyl-but-3-enoic acid methyl ester (193 mg, 0.47 mmol) in 1,4-dioxane (10 mL) was treated with a solution of lithium hydroxide monohydrate (112 mg, 4.7 mmol) in water (5 mL). After stirring at 50° C. for 1 h, the volatiles were removed in vacuo. The residue was partitioned between water and diethyl ether. The aqueous layer was acidified to pH 2 by addition of hydrochloric acid then extracted with ethyl acetate (3×). The organics were combined and the volatiles were removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and was treated with 4-dimethylaminopyridine (57 mg, 0.47 mmol), 2-methyl-6-nitrobenzoic anhydride (275 mg, 0.80 mmol), and triethylamine (0.197 mL, 1.41 mmol). After stirring for 30 min (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (203 mg, 0.47 mmol) was added. After stirring for 16 h, the reaction was quenched by addition of a sodium bicarbonate solution (10 mL), the aqueous layer was extracted with dichloromethane (2×), the organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 3:1 to afford the title compound (260 mg, 68%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.97-1.05 (m, 6H), 1.29 (d, J=6.9 Hz, 3H), 1.44 (br s, 9H), 1.55 (s, 3H), 1.57 (s, 3H), 1.68 (d, J=6.9 Hz, 3H), 1.71-2.00 (m, 4H), 2.02-2.30 (m, 3H), 2.80 (br s, 3H), 3.56 (br s, 1H), 3.78-3.83 (m, 1H), 4.75-4.82 (m, 1H), 4.93-5.01 (m, 2H), 5.35-5.45 (m, 1H), 6.65-6.82 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.72-7.83 (m, 2H), 7.98 (s, 1H), 8.21 (d, J=8.5 Hz, 1H). LCMS (m/z) 814.1 [M+H], Tr=3.97 min.

Provenance & Evidence