1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide

HRID 884801Notes

Reaction equation

HRID 884801 reaction equation
[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 69828Cyclopropylamine2×HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11153934HCID 11153934, compound

Product 1

HCID 114852003-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamideYield 66.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9 L) was added EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306, 2.14 equiv) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv) and the solution was stirred for 20 minutes at room temperature. Then it was cooled to 15-20° C. and cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv) was added and stirred at room temperature. The reaction was monitored by TLC. After 14 hours, since the reaction was not complete and additional cyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirring was continued for two hours. DMF was removed under reduced pressure at 50-55° C. To the residue EtOAc (1 L) and water (500 ml) were added and the mixture was stirred for 10 minutes. The mixture was extracted and the organic layer was collected. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layer was washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue EtOAc/dichloromethane/hexane (50 ml/50 ml/50 ml) was added, the mixture was stirred for 10 minutes, and filtered to provide the product (34.1 g, 65.7%) as an off white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 50/50, 30 min elution) tR 5.53 min, 99.3% purity; MS m/z 360 [M]+; 1H NMR (DMSO-d6, 400 MHz) is consistent with Example 4.

Workup

  1. temperatureThen it was cooled to 15-20° C.
  2. stirringstirred at room temperature
  3. waitAfter 14 hours
  4. stirringstirring
  5. waitwas continued for two hours
  6. customDMF was removed under reduced pressure at 50-55° C
  7. additionTo the residue EtOAc (1 L) and water (500 ml) were added
  8. stirringthe mixture was stirred for 10 minutes
  9. extractionThe mixture was extracted
  10. customthe organic layer was collected
  11. extractionThe aqueous layer was extracted with EtOAc (2×250 ml)
  12. washThe combined organic layer was washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml)
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationconcentrated
  15. additionTo the residue EtOAc/dichloromethane/hexane (50 ml/50 ml/50 ml) was added
  16. stirringthe mixture was stirred for 10 minutes
  17. filtrationfiltered

Sources & evidence

ORD record
ord-ea691d1f007341f4b2d3acbdd5487c35
Source dataset
uspto-grants-2012_08
Patent number
US08242117B2

Reaction notes

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