Ethanone, 1-(4-chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]- → (S)-N-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide

Participants

Reaction Steps

To a solution of 1-(3,4-dichlorophenyl)-2-hydroxyethanone (11.86 g, 57.843 mmol, CASRN 113337-38-5), imidazole (5.91 g, 86.764 mmol), and DMAP (0.71 g, 5.7843 mmol) in DMF (100 mL) cooled to 0° C. was added slowly tert-butylchlorodimethylsilane (10.898 g, 72.304 mmol) and the reaction was stirred at RT for 18 h. Water was added and the mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The crude residue was purified by passage through a SiO2 plug eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 12.15 g (82.0%) of 2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethanone (84). Conversion of 84 to (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (85) was carried out in accord with the procedure in steps 3 to 5 of example 10 except in step 3,2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62) was replaced with 84. The title compound was prepared from 85 in accord with the procedure in steps 6 and 7 of example 10 except in step 6, 72 was used in place of 26 and 85 was used in place of 68 to afford 136 mg (56%) of I-16: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.42 (m, 2H), 7.18 (d, 1H), 5.32 (m, 1H), 4.95 (m, 1H), 4.81 (d, 1H), 4.38 (s, 2H), 4.10 (m, 1H), 3.92 (m, 1H), 3.83 (m, 1H), 3.75-3.60 (m, 2H), 2.67 (t, 2H), 2.55 (bs, 1H), 1.22 (d, 6H); LCMS (ACPI-pos) m/z 426.4 (M+H)+.

Provenance & Evidence