反应详情

温度

-5 °C

To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).

1. customTo a flask equipped with a nitrogen inlet, addition funnel
2. customdid not exceed 5° C
3. additionwas slowly added
4. customto quench
5. customthe reaction
6. customThe layers were separated
7. extractionthe aqueous was re-extracted with MTBE (8 L)
8. washThe combined organic layers were washed with water (2×4 L) and brine (4 L)
9. dry with materialdried over sodium sulfate (NaSO4), and solvents
10. customremoved under reduced pressure
11. dissolutionThe residue was dissolved in heptane (2 L)
12. filtrationfiltered
13. washeluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L)
14. concentrationconcentrated under reduced pressure