Piperidine → N-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Participants

Reaction Conditions

Reaction Steps

Anhydrous toluene (2 mL) was added to a 50 mL round bottom flask previously evacuated and refilled with argon or nitrogen gas (3×). This was cooled to 0° C. in an ice-water bath for 5 min. Trimethylaluminum, 0.2 mL (1.8 equiv, 2.0M solution in hexanes) was added and the reaction was stirred at 0° C. for 15 min before piperidine (1.1 equiv, 0.25 mmol) was added to the above solution. It was allowed to stir at 0° C. for 10 min before warming to rt for 20 min. A 3 mL toluene solution of 100 mg (0.23 mmol, 1 equiv) of ethyl 4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate, 14, was added and the reaction mixture was heated at 100° C. until reaction was complete by TLC. The reaction mixture was cooled to 0° C. and quenched with 1N HCl. The reaction was adjusted to pH 9.0 with 1N NaOH and extracted with EtOAc (3×5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude oil which was purified via flash column chromatography MeOH/CH2Cl2 1:9 to provide the required product, 27, as a white solid (100 mg, 92%). 1H-NMR (CD2Cl2-d4) δ 8.49 (s, 1H), 8.05 (d, 1H), 7.62–7.59 (m, 1H), 7.23–7.26 (m, 2H), 7.12 (s, 1H), 3.59 (q, 2H), 3.52 (t, 2H), 3.23–3.10 (m, 3H), 2.94 (dd, 1H), 2.20–2.19 (m, 1H), 2.10–2.08 (m, 1H), 1.71–1.58 (m, 7H); LCMS RT=3.28 min; [M+H]+=473.3.

Provenance & Evidence