4-Methylmorpholine → (S)-tert-Butyl 2-(4-(1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylate

HRID 571844Notes

Reaction equation

HRID 571844 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[F:21].[F:22][CH:23]([F:39])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O.CN(C=O)C>[F:39][CH:23]([F:22])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[CH:4][C:3]=3[F:21])=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68325451(S)-tert-Butyl 2-(4-amino-3-fluorophenyl)morpholine-4-carboxylateHCID 710867371-[3-(Difluoromethoxy)phenyl]-1H-pyrazole-4-carboxylic acid

Product 1

HCID 71086889(S)-tert-Butyl 2-(4-(1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxamido)-3-fluorophenyl)morpholine-4-carboxylateYield 59%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

(S)-tert-Butyl 2-(4-amino-3-fluorophenyl)morpholine-4-carboxylate (104 mg, 0.35 mmol), 1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxylic acid (107 mg, 0.42 mmol), HBTU (200 mg, 0.525 mmol) and N-methylmorpholine (106 mg, 115 μl, 1.05 mmol) were combined with DMF (4 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (20 g Silica gel, 70 to 50% ethyl acetate in heptane) to yield a white solid (110 mg, 59%). MS (ISP): 477.1 (100%, [M-tBu+H]+), 533.2 (30%, [M+H]+).

Workup

  1. customto give a light yellow solution
  2. extractionextracted with ethyl acetate twice
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by flash chromatography (20 g Silica gel, 70 to 50% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-9e4f941034f148d296dfb0378ac06992
Source dataset
uspto-grants-2015_05
Patent number
US09029370B2

Reaction notes

Loading…