4-Methylmorpholine → (S)-5-(3-(Difluoromethoxy)phenyl)-1-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide hydrochloride

HRID 1520777Notes

Reaction equation

HRID 1520777 reaction equation
[F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[ClH:38].FC(F)O[C:42]1C=C(C2C=C(C(NC3C=CC([C@@H]4OCCNC4)=CC=3)=O)NN=2)C=C[CH:47]=1.Cl.N1CCO[C@@H](C2C=CC(NC(C3C=C(C4C=CC=CC=4)NN=3)=O)=CC=2)C1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCCCCCC.O.CN(C=O)C>[ClH:38].[F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]([CH2:42][CH3:47])[N:12]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1

Participants

9

Reactant 5

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 71087409(S)-3-(3-(Difluoromethoxy)phenyl)-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-5-carboxamide hydrochlorideHCID 71087839(5)-Tert-butyl 2-(4-(3-(3-(difluoromethoxy)phenyl)-1H-pyrazole-5-carboxamido)phenyl)morpholine-4-carboxylateHCID 178479716HCID 178479716, compound

Product 1

HCID 71087302(S)-5-(3-(Difluoromethoxy)phenyl)-1-ethyl-N-(4-(morpholin-2-yl)phenyl)-1H-pyrazole-3-carboxamide hydrochlorideYield 58%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8900HeptaneSolvent

Conditions

Temperature
60 °C

Procedure

(S)-Tert-butyl 2-(4-(3-(3-(difluoromethoxy)phenyl)-1H-pyrazole-5-carboxamido)phenyl)morpholine-4-carboxylate: In a 25 mL round-bottomed flask, 3-(3-(difluoromethoxy)phenyl)-1H-pyrazole-5-carboxylic acid (515 mg, 2.03 mmol, Eq: 1.1) (preparation described in example 40), (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (513 mg, 1.84 mmol, Eq: 1.00) (preparation described in example 1), N-Methylmorpholine (559 mg, 608 μl, 5.53 mmol, Eq: 3) and HBTU (1.05 g, 2.76 mmol, Eq: 1.5) were combined with DMF (2 ml) to give a yellow solution. The reaction mixture was stirred overnight at 60° C. The mixture was poured into water (10 ml) and extracted twice with EtOAc. The organic layers were washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a brown crude mixture. This mixture was diluted with Heptane, stirred for 15 minutes and the suspension was filtered. The resulting solid was washed several times with Heptane to afford the desired compound as a brown solid (550 mg, 58.0%).

Workup

  1. customto give a yellow solution
  2. extractionextracted twice with EtOAc
  3. washThe organic layers were washed with NaHCO3, brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give a brown crude mixture
  8. stirringstirred for 15 minutes
  9. filtrationthe suspension was filtered
  10. washThe resulting solid was washed several times with Heptane

Sources & evidence

ORD record
ord-adcece56e475470181442a1c7dfdd7dc
Source dataset
uspto-grants-2015_07
Patent number
US09073911B2

Reaction notes

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