Tetrabutylammonium Fluoride → HCID 178447112, compound

HRID 2178293Notes

Reaction equation

HRID 2178293 reaction equation
[Si]([C:8]1[C:13]([Cl:14])=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([C@:21]([O:26][Si](C)(C)C)([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH2:16]2)[N:11]=[C:10]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)[C:9]=1[F:40])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:14][C:13]1[C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([C@:21]([OH:26])([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH2:16]2)=[N:11][C:10]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)=[C:9]([F:40])[CH:8]=1

Participants

5

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 178447656HCID 178447656, compound

Product 1

HCID 178447112HCID 178447112, compoundYield 84.5%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-0be383d809404930b5f0968f3a03469f
Source dataset
uspto-grants-2015_06
Patent number
US09067932B2

Reaction notes

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