Methyl iodide → HCID 66780292, compound

Participants

Reaction Steps

Sodium hydride (2.62 g, 65.4 mmol) was added portionwise to a suspension of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (3 g, 8.18 mmol) and 1,1′-thiocarbonyldiimidazole (4.37 g, 24.53 mmol) in Tetrahydrofuran (THF) (80 mL). The mixture was stirred at rt for 21 h, then quenched by the dropwise addition of water. The solvent was evaporated and the residue was suspended in water. The pH was adjusted to about 7 by the addition of 6 N HCl, while cooling in an ice bath. The yellow solid was collected by filtration, washed with water, then hexanes and dried. The solid obtained was suspended in Tetrahydrofuran (THF) (80 mL) and treated with iodomethane (0.562 mL, 9.00 mmol). After few hours minimal conversion was observed by LC/MS. Sodium carbonate (1.300 g, 12.27 mmol) and additional iodomethane (0.562 mL, 9.00 mmol) were added and stirring was continued overnight. LC/MS analysis showed that the reaction was still not complete. Additional sodium carbonate (1.300 g, 12.27 mmol) and iodomethane (0.562 mL, 9.00 mmol) were added and the mix was warmed at 45° C. for 4 h (an additional aliquot of sodium carbonate and iodomethane were added during this time). The reaction has stalled and only reached about 40% conversion. It was then cooled to rt, the solvent was evaporated and the residue was suspended in water. The pH was neutralized by the addition of 6 N HCl. The solid was collected, washed with water and dried. The dry solid obtained was suspended in N,N-Dimethylformamide (DMF) (35 mL). Potassium carbonate (3.96 g, 28.6 mmol) and iodomethane (1.534 mL, 24.53 mmol) were added and the mixture was stirred at 50° C. for 1.5 h. After cooling, it was poured into ice/water and the precipitate formed was collected, washed with water and dried to afford 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (2.27 g, 5.37 mmol, 65.6% yield) which was used in the next step without further purification. LC/MS (ES+): [M+H]+=422.9 (80% pure). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=7.83 Hz, 1H), 7.15 (t, J=7.83 Hz, 1H), 6.60 (d, J=7.33 Hz, 1H), 5.49 (s, 2H), 3.63-3.72 (m, 4H), 3.52 (d, J=4.55 Hz, 4H), 2.46 (s, 3H), 2.43 (s, 3H).

Provenance & Evidence