Hydrochloric Acid → Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate

HRID 1672146Notes

Reaction equation

HRID 1672146 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:11]2[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:7][CH:6]=1)=[O:4]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 3608067(2-Bromoethoxy)-tert-butyldimethylsilaneHCID 59802475Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate

Product 1

HCID 59802484Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylateYield 86%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Procedure

To a mixture of Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (115.7 mgs, 291 μmol) in 2 mL of DMSO under N2 was added NaH (95%, 2 equivalents, 582 μmol, 14.0 mgs), and the reaction mixture was stirred for 20 minutes. (2-bromoethoxy)-tert-butyldimethylsilane (1.5 equivalents, 436 μmol, 94 μL) was then along with KI (1.5 equivalents, 72.4 mgs), and the reaction was stirred at room temperature overnight. The crude product was acidified with 1 M HCl, diluted with water and extracted with dichloromethane. The extracted product was concentrated en vacuo then purified by automated flash chromatography (Biotage Horizon™, gradient elution, 5 to 40% Ethyl Acetate/Hexane) to give 136.0 mgs (86%) of Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate as a oily colorless solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 2 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. Chemical shifts were reported in ppm relative to the deuterated solvent used. Coupling constants were reported in hertz. Peak multiplicity was reported using the following abbreviations: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.05 Hz, 1H), 7.73 (d, J=8.05 Hz, 1H), 7.50 (d, J=8.42 Hz, 2H), 7.24 (d, J=8.42 Hz, 2H), 4.69 (t, J=6.40 Hz, 2H), 4.17 (s, 3H), 4.12 (s, 3H), 3.95 (t, J=6.40 Hz, 2H), 2.79 (m, 1H), 1.96 (m, 6H), 1.41-1.56 (m, 3H), 1.11-1.20 (m, 1H), 0.95 (s, 9H), 0.03 (s, 6H). MS m/z 557.23 (M+H), Rf 3.05 min., 100% purity.

Workup

  1. stirringalong with KI (1.5 equivalents, 72.4 mgs), and the reaction was stirred at room temperature overnight
  2. extractionextracted with dichloromethane
  3. concentrationThe extracted product was concentrated en vacuo
  4. customthen purified by automated flash chromatography (Biotage Horizon™, gradient elution, 5 to 40% Ethyl Acetate/Hexane)

Sources & evidence

ORD record
ord-837f41c87ac04fee91a84c2ec3c0f6cd
Source dataset
uspto-grants-2011_08
Patent number
US07998951B2

Reaction notes

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