反应详情

To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added tert-butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (5, 15 g, 39.5 mmol), water (7.5 mL, 416 mmol) and dichloromethane (75 mL) at room temperature. The mixture was stirred at room temperature to generate a suspension. To the suspension was added a solution of 5 M hydrogen chloride (HCl) in isopropanol (55 mL, 275 mmol, 7.0 equiv) in 5 minutes. The resulting reaction mixture was then heated to gentle reflux and maintained at reflux for 3-4 hours. After the reaction was completed as monitored by HPLC, tert-butyl methyl ether (TBME, 45 mL) was added to the reaction suspension. The mixture was gradually cooled to room temperature, and stirred for an additional one hour. The solids were collected by filtration, washed with tert-butyl methyl ether (TBME, 45 mL) and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 13.6 g, 13.9 g theoretical, 98%) as an off-white to light yellow solid. For 6: 1H NMR (400 MHz, D2O) δ 8.96 (s, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.78 (d, J=3.8 Hz, 1H), 7.09 (d, J=3.7 Hz, 1H), 4.93 (d, J=12.8 Hz, 2H), 4.74 (d, J=12.5 Hz, 2H), 3.74 (s, 2H) ppm; 13C NMR (101 MHz, D2O) δ 151.35, 143.75, 143.33, 141.33, 132.03, 131.97, 115.90, 114.54, 113.85, 103.18, 59.72, 54.45 (2C), 27.02 ppm; C14H15Cl2N7 (C14H13N7 for free base, MW 279.30), LCMS (EI) m/e 280 (M++H).

1. customTo a 0.5-L flask equipped with a nitrogen inlet
2. customThe resulting reaction mixture
3. temperaturewas then heated
4. temperatureto gentle reflux
5. temperaturemaintained
6. temperatureat reflux for 3-4 hours
7. additionwas added to the reaction suspension
8. temperatureThe mixture was gradually cooled to room temperature
9. stirringstirred for an additional one hour
10. filtrationThe solids were collected by filtration
11. washwashed with tert-butyl methyl ether (TBME, 45 mL)
12. customdried under vacuum at 50° C. with nitrogen sweeping to constant weight