Pyridine → 1,1-dimethylethyl 3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylate

HRID 1990280Notes

Reaction equation

HRID 1990280 reaction equation
ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:38])[CH2:33][O:34][CH:35]([F:37])[F:36])[CH:30]=3)[C:25](O)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=1.N1C=CC=CC=1>C(Cl)Cl.O.C(OCC)(=O)C>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([C:25]([NH:39][C:40]4[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=4)=[O:26])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:38])[CH2:33][O:34][CH:35]([F:37])[F:36])[CH:30]=3)=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1

Participants

8

Reactant 4

HCID 1049PyridineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 51358380tert-Butyl 3-amino-1H-pyrazole-1-carboxylateHCID 591271903-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoic acid

Product 1

HCID 591271291,1-dimethylethyl 3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylateYield 27.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.12 mL, 0.92 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoic acid (0.26 g, 0.61 mmol) in DCM (8 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (169 mg, 0.92 mmol) then pyridine (0.1 mL, 1.23 mmol) were added and stirred for a further 20 hours. The reaction mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 25-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (100 mg).

Workup

  1. stirringstirred for a further 20 hours
  2. additionwere added
  3. extractionThe aqueous layer was re-extracted into ethyl acetate (50 mL)
  4. washthe combined organics washed with water (50 mL), brine (50 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customThe crude oil was chromatographed on silica
  8. washeluting with 25-50% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-373154f058964959a78d9b8215ba456d
Source dataset
uspto-grants-2010_01
Patent number
US07642259B2

Reaction notes

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