Carbamate → Apd-668

Participants

Reaction Conditions

Reaction Steps

Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0 g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57 g, 0.356 mol), was added at room temperature. The reactor was cooled to 12° C. and sodium tert-butoxide (37.09 g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34° C. due to an exotherm. Then the internal temperature was brought down to 23-25° C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H), 5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH3—CH—CH3), 3.91 (m, 2H, —CH2—), 3.37 (m, 2H, —CH2—), 3.12 (s, 3H, —SO2CH3), 2.09 (m, 2H, —CH2—), 1.87 (m, 2H, —CH2—), 1.27 (d, 6H, J=8 Hz, CH3—CH—CH3); mass spec. (electrospray) m/z 478 (M+H).

Provenance & Evidence