Ammonium Chloride → 6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester

HRID 1689789Notes

Reaction equation

HRID 1689789 reaction equation
C1OCCOCCOCCOCCOCCOC1.[K].[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]3)=[CH:30][CH:31]=2)[N:26]([CH3:40])[CH:25]=1)=[O:23].Br[CH2:42][C:43]1[C:44]([C:51]2[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1.[NH4+].[Cl-]>C(O)(C)(C)C.O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[CH2:38][CH2:37][CH:36]([O:39][CH2:42][C:43]4[C:44]([C:51]5[C:52]([Cl:58])=[CH:53][CH:54]=[CH:55][C:56]=5[Cl:57])=[N:45][O:46][C:47]=4[CH:48]4[CH2:50][CH2:49]4)[CH2:35][CH2:34]3)=[CH:30][CH:31]=2)[N:26]([CH3:40])[CH:25]=1)=[O:23]

Participants

8

Reactant 5

HCID 25517Ammonium ChlorideHCID 2855718-Crown-6HCID 5462222PotassiumHCID 593693284-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazoleHCID 669061336-(4-Hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester

Product 1

HCID 593693306-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl esterYield 34%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

Tetrahydrofuran (4 mL) is added at room temperature to a mixture of 18-crown-6 (306 mg, 1.14 mmole), tert-butyl alcohol, potassium derivative (134 mg, 1.14 mmole) and 6-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (300 mg, 1.040 mmole). The mixture is stirred for 15 minutes and then 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (361 mg, 1.04 mmole) is added. After 1.5 h, a saturated solution of NH4Cl is added and extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is purified via flash chromatography (12 g silica) eluting with a gradient of hexane:ethyl acetate from 20% to 100% to provide the title compound (196 mg, 34%) as a white solid. ES/MS m/z 554.0 (M+1)

Workup

  1. waitAfter 1.5 h
  2. extractionextracted with ethyl acetate
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. customthe solvent is removed under reduced pressure
  6. customThe residue is purified via flash chromatography (12 g silica)
  7. washeluting with a gradient of hexane

Sources & evidence

ORD record
ord-c4f1bc8d2390402da7606df4300bab09
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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