Sodium hydride → HCID 86706874, compound

HRID 717895Notes

Reaction equation

HRID 717895 reaction equation
[H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[C:22]([C:24]2([OH:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=1.[Cl-].[NH4+]>O1CCCC1.O>[OH:28][C:24]1([C:22]2[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=[C:18]([O:3][CH:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]3)[CH:23]=2)[CH2:25][O:26][CH2:27]1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 86706873HCID 86706873, compound

Product 1

HCID 86706874HCID 86706874, compoundYield 33.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To sodium hydride (60% in mineral oil, 0.20 g, 4.9 mmol) in a dry flask was added tetrahydrofuran (20 mL), followed by tert-butyl 4-hydroxypiperidine-1-carboxylate (0.98 g, 4.9 mmol, Aldrich). After stirring for 1 hour at room temperature, a solution of 3-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]oxetan-3-ol (0.31 g, 1.2 mmol, from Step 1) in tetrahydrofuran (11 mL) was introduced. The reaction was stirred at ambient temperature for 2 hours, followed by heating to 65° C. overnight. The reaction was cooled to room temperature and water was added, followed by saturated ammonium chloride to adjust the pH to between 7 and 8. The product was extracted with two portions of DCM. The combined organic extracts were dried over sodium sulfate, decanted and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes, on a 40 g silica gel column to afford 0.17 g of desired product (yield 30%). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=1.3 Hz, 1H), 7.22-7.15 (m, 1H), 5.28 (tt, J=7.6, 3.7 Hz, 1H), 4.91 (d, J=7.6 Hz, 2H), 4.77 (d, J=6.9 Hz, 2H), 3.72 (ddd, J=12.5, 6.6, 3.9 Hz, 2H), 3.32 (ddd, J=13.8, 8.0, 3.7 Hz, 2H), 1.98 (ddt, J=13.6, 7.1, 3.6 Hz, 2H), 1.73 (ddt, J=16.5, 8.1, 3.9 Hz, 2H), 1.46 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −68.78 (s). LCMS (M+Na)+: 441.1.

Workup

  1. stirringThe reaction was stirred at ambient temperature for 2 hours
  2. temperatureby heating to 65° C. overnight
  3. temperatureThe reaction was cooled to room temperature
  4. extractionThe product was extracted with two portions of DCM
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. customdecanted
  7. concentrationconcentrated
  8. customThe product was purified by flash chromatography
  9. washeluting with a gradient from 0-20% EtOAc in hexanes, on a 40 g silica gel column

Sources & evidence

ORD record
ord-20325e40f29e460492b89aff85e9c935
Source dataset
uspto-grants-2015_11
Patent number
US09193733B2

Reaction notes

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