Tetrabutylammonium Fluoride → 2-Chloro-4-[[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]-3-methyl-benzonitrile

HRID 245071

Reaction equation

HRID 245071 reaction equation
[Si]([O:8][C@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[NH2:14])(C(C)(C)C)(C)C.[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:14][C@H:10]2[C@@H:9]([OH:8])[CH2:13][O:12][CH2:11]2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]

Participants

4

Reactant 3

HCID 2724141Tetrabutylammonium FluorideHCID 445509712-Chloro-4-fluoro-3-methylbenzonitrileHCID 71151039(3R,4R)-4-(tert-Butyl(dimethyl)silyl)oxytetrahydrofuran-3-amine

Product 1

HCID 866937812-Chloro-4-[[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]-3-methyl-benzonitrileYield 19%

Procedure

The title compound is prepared by essentially following the procedure as described in Example 1 using (3R,4R)-4-(tert-butyl(dimethyl)silyl)oxytetrahydrofuran-3-amine (Preparation 36) and 2-chloro-4-fluoro-3-methyl-benzonitrile. The crude product is purified on silica gel using 40-70% EtOAc/hexanes. The isolated product is dissolved in THF to make a 0.5 M solution. TBAF (2.0 mL, 2 mmol, 1 M solution in THF) is added and stirred at room temperature for 16 h. The solution is concentrated in vacuo, EtOAc is added, and the solution is washed with water (2×). The organic portion is dried over magnesium sulfate, filtered, and concentrated. The residue is purified by reverse phase chromatography on silica-bound C18 using 15-95% acetonitrile/water+0.1% formic acid. Fractions containing the title compound are concentrated in vacuo to remove acetonitrile, then extracted with EtOAc. The organics are dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (134 mg, 19%). 1H-NMR (400 MHz, DMSO-d6) δ 7.53 (d, J=8.7 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.60-5.56 (m, 1H), 5.53 (d, J=4.9 Hz, 1H), 4.33-4.29 (m, 1H), 4.05-3.99 (m, 2H), 3.92 (dd, J=4.6, 9.6 Hz, 1H), 3.63 (dd, J=2.4, 9.5 Hz, 1H), 3.53-3.50 (m, 1H), 2.19 (s, 3H). LC-ES/MS m/z 253 (M+1).

Workup

  1. customThe title compound is prepared
  2. customThe crude product is purified on silica gel using 40-70% EtOAc/hexanes
  3. dissolutionThe isolated product is dissolved in THF
  4. concentrationThe solution is concentrated in vacuo, EtOAc
  5. additionis added
  6. washthe solution is washed with water (2×)
  7. dry with materialThe organic portion is dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue is purified by reverse phase chromatography on silica-bound
  11. additionFractions containing the title compound
  12. concentrationare concentrated in vacuo
  13. customto remove acetonitrile
  14. extractionextracted with EtOAc
  15. dry with materialThe organics are dried over magnesium sulfate
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-66841a548f8f47c7840f3f0679049773
Source dataset
uspto-grants-2014_02
Patent number
US08658693B2

Linked notes

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