Sodium hydride → 6-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester

HRID 1689787Notes

Reaction equation

HRID 1689787 reaction equation
[H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:23])[CH:8]=1)=[O:6].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]([CH3:33])[CH3:32].[NH4+].[Cl-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([O:22][CH2:25][C:26]4[C:27]([C:34]5[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=5[Cl:40])=[N:28][O:29][C:30]=4[CH:31]([CH3:33])[CH3:32])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[N:9]([CH3:23])[CH:8]=1)=[O:6]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 669061336-(4-Hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl esterHCID 669064404-Bromomethyl-3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazole

Product 1

HCID 593693356-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl esterYield 19.1%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Sodium hydride (60%, 93 mg, 1.2 equiv, 2.3 mmole) is added at room temperature under nitrogen atmosphere to a solution of 6-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (557 mg, 1.00 equiv, 1.93 mmole), tetra-n-butylammonium iodide (73 mg, 0.1 equiv, 193 μmoles) and 4-bromomethyl-3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazole (674 mg, 1 equiv, 1.93 mmole) in anhydrous tetrahydrofuran (6 mL). The reaction mixture is stirred for 6 h. Aqueous saturated NH4Cl is added and the resulting aqueous solution is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography (40 g silica) eluting with a gradient of ethyl acetate:hexane (10% to 100%) to provide the title compound as a white solid (205 mg, 19%). ES/MS m/z 556.0 (M+1)

Workup

  1. extractionthe resulting aqueous solution is extracted with ethyl acetate
  2. dry with materialdried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe residue is purified via flash chromatography (40 g silica)
  6. washeluting with a gradient of ethyl acetate

Sources & evidence

ORD record
ord-01957f90ae4249a1a4f782b406fa84ba
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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