2,2,2-Trifluoroethanol → HCID 53781901, compound

HRID 2288981Notes

Reaction equation

HRID 2288981 reaction equation
[H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22]3)=[N:18][C:17]=2[CH2:30]O)=[CH:12][CH:11]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[Na].FC(F)(F)CO>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]#[N:29])[CH2:25][CH2:26]3)=[N:18][C:17]=2[CH2:30][O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:12][CH:11]=1

Participants

8

Reactant 6

HCID 64092,2,2-TrifluoroethanolHCID 8471TriethylamineHCID 24758Sodium hydrideHCID 81560Methanesulfonic anhydrideHCID 54490302HCID 54490302, compoundHCID 867421422,2,2-Trifluoroethanol sodium salt

Product 1

HCID 53781901HCID 53781901, compoundYield 89%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A 5-l round bottom flask containing sodium hydride (60% dispersion, 180 g, 4.5 mole) and tetrahydrofuran (1.5 l) is cooled to 0° C. and 2,2,2-trifluoroethanol (516 mL, 7.2 mole) is added over 1 hour. A separate 12-l round bottom flask containing {4-[5-(4-fluorophenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl} acetonitrile (300 g, 0.90 mole), tetrahydrofuran (6.0 l) and triethylamine (500 mL, 3.6 mole) is cooled to -3° C. then methanesulfonic anhydride (360 g, 2.1 mole) is added in one portion. The resulting suspension is stirred for 30 minutes then the 2,2,2-trifluoroethanol sodium salt solution in the 5-l round bottom flask is added in one portion. The resulting slurry is warmed to room temperature, stirred for 1 hour, concentrated to a semi-solid and water (4.5 l) is added. The suspension is washed with methyl t-butylether (2×3 L). The combined organic extracts are washed with water (1.5 l), saturated aqueous sodium chloride (1.5 l), dried over sodium sulfate (100 g), filtered and concentrated to 1 l. To effect crystallization, heptane (4 l) is added. The resulting slurry is cooled to 0° C., the solids are collected by filtration and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoroethoxymethyl)-oxazol-2-yl]-piperidin-1-yl} acetonitrile (318 g, 0.801 mole). H NMR (400 MHz, CDCl3) d 1.99 (m, 2H), 2.20 (m, 2H), 2.54 (t, 2H), 2.90 (m, 3H), 3.60 (s, 2H), 4.00 (q, 2H), 4.70 (s, 2H), 7.16 (t, 2H), 7.73 (q, 2H).

Workup

  1. temperatureis cooled to -3° C.
  2. temperatureThe resulting slurry is warmed to room temperature
  3. stirringstirred for 1 hour
  4. concentrationconcentrated to a semi-solid and water (4.5 l)
  5. additionis added
  6. washThe suspension is washed with methyl t-butylether (2×3 L)
  7. washThe combined organic extracts are washed with water (1.5 l), saturated aqueous sodium chloride (1.5 l)
  8. dry with materialdried over sodium sulfate (100 g)
  9. filtrationfiltered
  10. concentrationconcentrated to 1 l
  11. customTo effect crystallization, heptane (4 l)
  12. additionis added
  13. temperatureThe resulting slurry is cooled to 0° C.
  14. filtrationthe solids are collected by filtration
  15. customdried to constant weight

Sources & evidence

ORD record
ord-a13c89bf5cb94b1aa538d34e38875e40
Source dataset
uspto-grants-2000_07
Patent number
US06090825

Reaction notes

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