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Water → 6-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinic acid methyl ester

HRID 8101
Notes
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Reaction equation

HRID 8101 reaction equation
[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[N:30][CH:29]=1.O>CN(C)C=O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[NH:12][CH:11]=[C:10]3[CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:21])[CH3:20])=[N:30][CH:29]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 254249Methyl 6-chloropyridine-3-carboxylateHCID 69519112[2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester

Product 1

HCID 695167856-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinic acid methyl esterYield 58%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (104 mg, 0.342 mmol) in dimethylformamide (10 mL) is added sodium hydride (10 mg, 0.410 mmol). The mixture is stirred at ambient temperature for 30 minutes under nitrogen. 6-Chloro-nicotinic acid methyl ester (99 mg, 0.581 mmol) is added and the mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen. The mixture is then heated an additional 5 hours at eighty-five degrees Celsius. Water (100 ml) is added to quench the reaction and the mixture is extracted three times with 50 mL of ethyl acetate. The organic layers are combined and washed twice with 50 mL of 1.00 N sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in dichloromethane and purified using silica gel chromatography (6% 2M ammonia in methanol, 94% dichloromethane used as mobile phase) to give 87 mg (58%) of 6-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinic acid methyl ester. FDMS m/e=440 (M++1).

Workup

  1. temperaturethe mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen
  2. temperatureThe mixture is then heated an additional 5 hours at eighty-five degrees Celsius
  3. customto quench
  4. customthe reaction
  5. extractionthe mixture is extracted three times with 50 mL of ethyl acetate
  6. washwashed twice with 50 mL of 1.00 N sodium hydroxide
  7. dry with materialThe organic layer is dried with sodium sulfate
  8. filtrationfiltered
  9. customthe solvent evaporated
  10. dissolutionThe residue is dissolved in dichloromethane
  11. custompurified

Sources & evidence

ORD record
ord-cf0e1cb12fbf4ee49772ed33ad4ad6b7
Source dataset
uspto-grants-2006_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07087635B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes