Dimethylformamide → 5-(1-Isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid ethyl ester

HRID 493984Notes

Reaction equation

HRID 493984 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[F:26][C:27]([F:38])([F:37])[CH2:28]OS(C(F)(F)F)(=O)=O.[CH3:39]N(C)C=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][C:27]([F:38])([F:37])[F:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:39]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonateHCID 670733165-(1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester

Product 1

HCID 670735255-(1-Isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid ethyl esterYield 78%

Conditions

Temperature
70 °C

Procedure

To a mixture of 5-(1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (intermediate, 4 g, 1.0 eq.) in dimethylformamide (40 mL) was added sodium hydride (dispersion in oil, 60% in mass, 533 mg, 1.1 eq.) in several portions. The solution was stirred 30 min at 70° C. Then 2,2,2-trifluoroethyltrifluoromethanesulfonate (3.37 g, 1.2 eq.) was added and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The organic layer was washed with water and brine, evaporated in vacuo and then purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 3.9 g (78%) of the desired product as off-white solid. MS (m/e): 413.5 (MH+, 100%)

Workup

  1. stirringthe reaction mixture was stirred at 70° C. overnight
  2. customThe reaction mixture was partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate
  3. washThe organic layer was washed with water and brine
  4. customevaporated in vacuo
  5. custompurified on silica eluting with dichloromethane/methanol/ammoniac
  6. customOne fraction was isolated
  7. customdried in vacuo

Sources & evidence

ORD record
ord-369327e0029746579f7bb67e3845805f
Source dataset
uspto-grants-2009_05
Patent number
US07538101B2

Reaction notes

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