Tetrahydrofuran → {2-[4-(5-Carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester

HRID 130695Notes

Reaction equation

HRID 130695 reaction equation
CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8].O1CCCC1.Cl[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=1>[Cl-].[Na+].O>[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:30]2[CH:38]=[CH:37][C:33]([C:34](=[O:35])[NH2:36])=[CH:32][N:31]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:8])[CH3:9]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 804566-ChloronicotinamideHCID 11831452tert-butyl N-(2-(4-hydroxyphenyl)ethyl)carbamateHCID 23665647Potassium tert-butoxide

Product 1

HCID 59730368{2-[4-(5-Carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl esterYield 46.2%

Reagents, catalysts & solvents 1

HCID 57417360Sodium chloride; waterSolvent

Procedure

Add potassium tert-butoxide (4.28 g, 36.2 mmol) to a stirred solution of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (6.40 g, 27.0 mmol) and anhydrous tetrahydrofuran (120 mL). Stir for 30 minutes under nitrogen at room temperature. Add 6-chloronicotinamide (4.27 g, 27.2 mmol) and heat to reflux for 18 h under nitrogen. Cool to room temperature, pour the reaction mixture into, brine (150 mL), and extract with diethyl ether (3×150 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 4.46 g (46%) of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester: mass spectrum (ion spray): m/z=358.1 (M+1); 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (dd, 1H), 8.02 (br s, 1H), 7.46 (br s, 1H), 7.23 (d, 2H), 7.06-7.02 (m, 3H), 6.92-6.89 (m, 1H), 3.17-3.12 (m, 2H), 2.69 (t, 2H), 1.35 (s, 9H).

Workup

  1. temperatureto reflux for 18 h under nitrogen
  2. temperatureCool to room temperature
  3. extractionextract with diethyl ether (3×150 mL)
  4. dry with materialDry the diethyl ether
  5. filtrationfilter
  6. concentrationconcentrate on a rotary evaporator
  7. customto give the crude product
  8. customThe crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform

Sources & evidence

ORD record
ord-9ddbd50215684758bbd547892508b6e1
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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