Triethylamine → [4-(4-{[1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester

HRID 2066193Notes

Reaction equation

HRID 2066193 reaction equation
[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44]([C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1)=[O:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:49]([C:46]4([C:44](=[O:45])[NH:43][C:37]5[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=5[F:35])[CH2:48][CH2:47]4)=[O:50])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 190968281-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acidHCID 67136032[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester

Product 1

HCID 59596952[4-(4-{[1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl esterYield 19.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (400 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acid (241 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (116.2 mg).

Workup

  1. customLiquid-liquid separation
  2. additionafter addition of ethyl acetate and water to the reaction mixture
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was removed
  6. customthe residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1)

Sources & evidence

ORD record
ord-26472abf8146462f89d1365f8cfd38ee
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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