Carbamate → N-((3S)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamide

Participants

Reaction Steps

A solution of 6-(trifluoromethyl)quinazolin-4(3H)-one (84 mg, 0.39 mmol, prepared according to WO2005021500A), PCl5 (106 mg, 0.507 mmol) in dichloroethane was sealed in a microwave-safe tube and was microwaved for 3000 seconds reaching an internal temperature of 170° C. An additional portion of PCl5 (25 mg) was added and the mixture was again microwaved for 3000 seconds reaching an internal temperature of 170° C. The mixture was transferred to a flask, toluene was added, then was concentrated. The resulting 4-chloro-6-trifluoromethyl)quinazoline (used without further purification) was dissolved in acetonitrile (2 mL) and was added to a 0° C. cooled mixture of rel-N-[(3R,4R)-4-<allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]-2-aminoacetamide-bis-hydrochloride salt (139 mg, 0.309 mmol, prepared in similar fashion to rel-N-(2-{[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-trifluoromethyl)benzamide, substituting [(tert-butoxycarbonyl)amino]acetic acid for {[3-(trifluoromethyl)benzoyl]amino}acetic acid and the resulting tert-butyl rel-(2-{[(3R,4R)-4-allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)carbamate was deprotected under standard HCl/dioxane conditions), DBU (0.292 mL, 1.95 mmol) and acetonitrile (3.5 mL). The mixture was warmed to RT and after 150 min. was quenched with K2CO3 (1M solution) and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford the title compound (34 mg, 18%) as a white solid. 1H-NMR (DMSO-d6) δ−1.66 (m, 2M), 2.12 (m, 1H), 2.30 (m, 1H), 2.42 (m, 1H), 2.81 (m, 2H), 3.23 (m, 2H), 3.78 (m, 4H), 4.00 (m, 3H), 4.11 (m, 3H), 5.08 (d, 1H), 5.18 (d, 1H), 5.79 (m, 1H), 7.87 (d, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 8.51 (s, 1H), 8.78 (s, 1H), 9.01 (m, 1H). MS m/z=480 (M+1).

Provenance & Evidence