Sodium hydride → 5-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid methyl ester

HRID 1689786Notes

Reaction equation

HRID 1689786 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].Br[CH2:25][C:26]1[C:27]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:25][C:26]3[C:27]([C:34]4[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:40])=[N:28][O:29][C:30]=3[CH:31]3[CH2:33][CH2:32]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)=[O:4]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 593693284-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazoleHCID 669063285-(4-Hydroxy-piperidin-1-yl)-biphenyl-2-carboxylic acid methyl ester

Product 1

HCID 593693415-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid methyl esterYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 5-(4-hydroxy-piperidin-1-yl)-biphenyl-2-carboxylic acid methyl ester (318 mg, 1.02 mmol), 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (375 mg, 1.08 mmol), and sodium hydride (52 mg, 1.30 mmol) in dimethylformamide (4 mL) is stirred at room temperature for 2.5 h. The mixture is partitioned between saturated aqueous ammonium chloride and ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The ethyl acetate layers are washed with brine (3×), dried (MgSO4), and concentrated under reduced pressure. The crude material is purified on silica (40 g) eluting with a gradient of ethyl acetate in heptane (0-60%) to provide the title compound (245 mg, 42%) as a glassy film. LC-ES/MS m/z 579.2 (M+1).

Workup

  1. customThe mixture is partitioned between saturated aqueous ammonium chloride and ethyl acetate
  2. customThe layers are separated
  3. extractionthe aqueous layer is extracted with ethyl acetate (3×)
  4. washThe ethyl acetate layers are washed with brine (3×)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe crude material is purified on silica (40 g)
  8. washeluting with a gradient of ethyl acetate in heptane (0-60%)

Sources & evidence

ORD record
ord-15e48e01bd014b2e9a5c07328421193a
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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