反应详情

温度

120 °C

A finely ground mixture of amino nitrile 10a (60 mg, 0.29 mmol) and chloroformamidine hydrochloride (132 mg, 1.16 mmol) was placed in a 10 mL pear-shaped flack, which was immersed in an oil bath and triturated continuously with a glass rod while being heated to 120° C. (internal temperature) under a gentle stream of N2 as described (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). After 20 min the reaction mixture was cooled to room temperature, the resulting glassy solid was dissolved in MeOH (0.75 mL), and the solution was diluted with CHCl3 (12 mL) and chilled at 0° C. for 1 h. The solid precipitate was collected, washed with CHCl3, and discarded. This solid consists mainly of by-products arising from the self-condensation of chloroformamidine, whereas the pooled filtrates contain the HCl salt of the desired product, along with a variable amount of the salt of what is presumed to an intermediate non-cyclized amidinonitrile of the type previously observed (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). To ensure complete ring closure, excess i-Pr2NH (0.5 mL) was added to the filtrate to neutralize the acid, the mixture was concentrated dryness on a rotary evaporator, and the solid residue was heated for 1.5 h at 70° C. under high vacuum (0.1 Torr). The crude product was then dissolved in boiling MeOH, and the solution treated with a little decolorizing carbon (Darco) and hot-filtered through a bed of Celite. When the filtrate became cool it was basified to pH 10 with ammonia, and the precipitate was collected. Recrystallization from MeOH—H2O afforded 8a as a white crystalline solid (32 mg, 44%): mp 220-222° C.; MS: m/z 251.4, calcd 251.3 (M+1); IR (KBr) v 3340, 3170, 1620, 1570, 1510, 1450, 1400 cm−1; 1H NMR (DMSO-d6) δ 3.92 (s, 2H, CH2), 5.84 (br s, 2H, 2-NH2), 7.13 (d, J=8.6 Hz, 1H, H-8), 7.16-7.35 (m, ca. 6H, H-7 and other aromatic protons), 7.89 (s, 1H, H-5). In contrast to the majority of the other diaminoquinazolines described below, the hydrogens on the 4-NH2 group apparently gave a signal at around δ 7.2 which was too broad to be observed. Anal. Calcd. for C15H15N4-0.3H2O: C, 70.46, H, 5.75, N, 22.16. Found: C, 70.20; H, 5.42; N, 22.28.

1. customwas immersed in an oil bath
2. customtriturated continuously with a glass rod
3. temperatureAfter 20 min the reaction mixture was cooled to room temperature
4. dissolutionthe resulting glassy solid was dissolved in MeOH (0.75 mL)
5. additionthe solution was diluted with CHCl3 (12 mL)
6. temperaturechilled at 0° C. for 1 h
7. customThe solid precipitate was collected
8. washwashed with CHCl3
9. customarising from the self-condensation of chloroformamidine, whereas the pooled filtrates