Trimethyl orthoformate → 2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine

Participants

Reaction Steps

To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19 (90.8 g, 0.320 mol, 1.0 equiv.), 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 92.3 g, 0.460 mol, 1.45 equiv.) and sodium acetate (anhydrous powder, 37.7 g, 0.460 mol, 1.45 equiv.) in 1,2-dichloroethane (anhydrous, 1.8 L) was added trimethyl orthoformate (340 g, 3.20 mol, 10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours. Sodium triacetoxyborohydride (assay>90%, 101.3 g, 0.430 mol, 1.35 equiv.) was added and the reaction was stirred for 24 hours. LC/MS indicated that the reaction was complete. The reaction was quenched with water (4.4 L) and methylene chloride (4.4 L). The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated to give a yellow solid. The crude solid was then stirred in ethyl acetate (2.0 L) at 80° C. for 2 hours. The slurry was cooled to 30-40° C., filtered and rinsed with ethyl acetate (50 ml). The cake was dried in vacuum oven at 45° C. to give 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 as an off-white solid (110.2 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.52-2.55 (m, 4H), 2.89 (s, 3H), 3.12-3.14 (m, 4H), 3.73 (t, J=4.4 Hz, 4H), 3.81 (s, 2H), 3.86 (t, J=4.8 Hz, 4H), 7.59 (s, 1H). LCMS (ESI pos) m/e 432 (M+1).

Provenance & Evidence