Tetrabutylammonium Fluoride → HCID 178447112, compound

Participants

Reaction Steps

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.

Provenance & Evidence