反应详情

To a solution of tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 389.6 g, 0.765 mol) in dichloromethane (CH2Cl2, 7 L) was added a solution of hydrogen chloride (HCl) in dioxane (4 M, 1.15 L, 4.6 mol, 6.0 equiv) drop wise at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. When LCMS showed that all of the starting material had been consumed, the reaction mixture was transferred in portions to a 22 L separation funnel containing aqueous ammonium hydroxide (NH4OH, about 4% v/v, 2.5 L). Gas was evolved but the funnel stayed cool to the touch. Ice cubes were periodically added as a precaution. Once all of the reaction mixture was added, stirring was continued for about 15 min. The pH of the aqueous layer was found to be close to 11. The two layers were separated and the organic layer was washed with brine (2 L), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure to a minimum volume. Heptane (about 3 L) was added to the residue and the resulting suspension was concentrated to dryness under reduced pressure to give crude 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (16, 268.2 g, 313.3 g theoretical, 85.6% yield) as an orange oil which was used directly for the subsequent reaction without further purification. For crude 16: 1H NMR (300 MHz, CDCl3): δ 8.92 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.47 (d, 1H), 6.87 (d, 1H), 5.74 ( s, 2H), 4.36 (d, 2H), 3.95 (d, 2H), 3.77 (s, 2H), 3.62 (t, 2H), 1.9 (br. s, 1H), 0.99 (t, 2 H), 0.01 (s, 9H) ppm; C20H27N7OSi (MW, 409.56), LCMS (EI) m/e 410 (M++H).

1. customThe resulting reaction mixture
2. customhad been consumed
3. customthe reaction mixture was transferred in portions to a 22 L separation funnel
4. additioncontaining aqueous ammonium hydroxide (NH4OH, about 4% v/v, 2.5 L)
5. temperaturethe funnel stayed cool to the touch
6. additionIce cubes were periodically added as a precaution
7. additionOnce all of the reaction mixture was added
8. stirringstirring
9. waitwas continued for about 15 min
10. customto be close to 11
11. customThe two layers were separated
12. washthe organic layer was washed with brine (2 L)
13. dry with materialdried over anhydrous sodium sulfate (Na2SO4)
14. concentrationconcentrated under reduced pressure to a minimum volume
15. additionHeptane (about 3 L) was added to the residue
16. concentrationthe resulting suspension was concentrated to dryness under reduced pressure