Triethylamine → phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate

HRID 388493Notes

Reaction equation

HRID 388493 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N([CH2:32][CH3:33])CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>O1CCCC1>[CH2:18]([O:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:1]([C:16]([O:25][C:33]3[CH:32]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])[C:35](=[O:36])[O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:7]=2)=[CH:10][C:11]=1[F:26])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 57470855Benzyl[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate

Product 1

HCID 67135676phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of benzyl [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (1.25 g) in tetrahydrofuran (100 ml) were added triethylamine (1.48 ml) and phenyl chloroformate (1.11 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled away to give a crude product of phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate as a brown oil (ESI-MS (m/z): 616 [M+Na]+). This was dissolved in tetrahydrofuran (200 ml), 20% palladium hydroxide (497 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration. It was subsequently washed with tetrahydrofuran. The filtrate was concentrated to 20 ml to give a solution of phenyl N-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (ESI-MS (m/z): 482 [M+Na]+, 941 [2M+Na]+) in tetrahydrofuran. This was dissolved in N,N-dimethylformamide (50 ml). After then adding 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.58 g), benzotriazol -1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.13 g) and triethylamine (0.987 ml), the mixture was stirred at room temperature for 13.5 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine in that order and dried over anhydrous sodium sulfate. It was then concentrated and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:2, 1:1 and 1:2) to give the title compound as a colorless foam (940 mg, 40.0%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. distillationThe solvent was distilled away

Sources & evidence

ORD record
ord-969146bd802a45cc8031ed30865ae4b6
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

Loading…