反应详情

3-(4-(tert-butyldimethylsilyl)-5-chloro-3-fluoro-6-((S)-3-((R)-3-methyl-2-(trimethylsilyloxy)butan-2-yl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (125 g, 206.5 mmol) was dissolved in THF (450 mL) at ambient temperature. Tetrabutylammonium fluoride (433.6 mL of 1 M THF solution, 433.6 mmol) was added dropwise via cannula to the yellow solution. The internal temperature increased from 21.3° C. to 27.7° C. The reaction was stirred for 48 hours. The mixture was then diluted with ethyl acetate (1.5 L) and washed with a 1:1 mixture of saturated aqueous sodium bicarbonate and water (3×600 ml). The combined aqueous phases were back-extracted with ethyl acetate (2×600 ml). The combined organic phases were then washed with brine (600 ml), dried over MgSO4, filtered and partially concentrated in vacuo until the title product began to precipitate. A few drops of methanol were added and the mixture stirred at ambient temperature overnight. The product was then was filtered, rinsed with a minimum of ethyl acetate and petroleum ether to give an off-white solid which was dried under vacuum overnight (40° C. and 1.5 mbar). This afforded the title compound as a white solid (73.1 g, 84%); mp (DSC) onset 215.3° C., peak 218.1° C.; 1H NMR (400.0 MHz, DMSO) 0.91 (d, 3H), 0.94 (d, 3H), 1.10 (s, 3H), 1.83 (b quint, 2H), 2.72 (t, 1H), 2.80-2.94 (m, 3H), 3.14-3.17 (m, 1H), 3.62 (d, 1H), 3.88 (d, 1H), 4.14 (s, 1H), 7.37 (dd, 1H), 8.16 (d, 1H), 8.65 (dd, 1H), 8.86 (dd, 1H), 14.12 (bs, 1H); 19F NMR (decoupled) −127.9; MS ES(+) 419.1 (M+1); ee>98% (Minigram SFC, ODH 250×10 mm, 20% MeOH (0.1% TEA), 5 mg/ml.

1. temperatureThe internal temperature increased from 21.3° C. to 27.7° C
2. washwashed with a 1:1 mixture of saturated aqueous sodium bicarbonate and water (3×600 ml)
3. extractionThe combined aqueous phases were back-extracted with ethyl acetate (2×600 ml)
4. washThe combined organic phases were then washed with brine (600 ml)
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationpartially concentrated in vacuo until the title product
8. customto precipitate
9. additionA few drops of methanol were added
10. stirringthe mixture stirred at ambient temperature overnight
11. filtrationThe product was then was filtered
12. washrinsed with a minimum of ethyl acetate and petroleum ether
13. customto give an off-white solid which
14. customwas dried under vacuum overnight (40° C. and 1.5 mbar)