Diisopropylethylamine → 3-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

HRID 884783Notes

Reaction equation

HRID 884783 reaction equation
[Na].[CH3:2][O-].[Na+].C(O[C:8](=[O:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](OCCN2CCOCC2)[CH:10]=1)C.F[C:26](F)(F)[C:27]([OH:29])=O.[CH:32]1([NH:35][C:36](=[O:46])[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([NH:44][NH2:45])[CH:38]=2)[CH2:34][CH2:33]1.[CH:47]([N:50](C(C)C)CC)(C)C>O1CCOCC1.CO>[NH2:50][C:47]1[N:44]([C:39]2[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=2[CH3:43])[C:36]([NH:35][CH:32]2[CH2:34][CH2:33]2)=[O:46])[N:45]=[C:27]([O:29][CH3:2])[C:26]=1[C:8](=[O:24])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 5360545SodiumHCID 10942334Sodium MethoxideHCID 58089039Ethyl 3-{[2-(4-morpholinyl)ethyl]oxy}benzoateHCID 67024207N-cyclopropyl-3-hydrazinyl-4-methylbenzamide 2,2,2-trifluoroacetate

Product 1

HCID 248607173-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamideYield 19%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent2×

Procedure

Sodium (317 mg, 13.8 mmol) was added to methanol (10 ml) at 0° C. After all of the sodium was consumed, this solution of sodium methoxide was added to a stirred solution of 2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (3.12 g, 12.5 mmol) in dioxane (30 ml) at 0° C. The reaction was warmed to room temperature and then heated to 80° C. for 3 h. The dark red solution was cooled to room temperature and was added to a solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (4.00 g, 12.5 mmol) and diisopropylethylamine (2.18 ml, 12.5 mmol) in dioxane (15 ml). The mixture was heated to 85° C. for another 6 h. The solvent was removed in vacuo. The residue was diluted in saturated NaHCO3 solution and was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO2, gradient of 75 to 90% EtOAc/hexanes) and recrystallization from EtOAc to give the desired 3-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 3 as a white solid (950 mg, 19%). HPLC (4 minute 10-90 gradient) tR 2.33 min; MS m/z 391.2 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=3.4, 1 H), 7.91 (d, J=7.9, 1 H), 7.85 (s, 1 H), 7.61 (d, J=6.9, 2 H), 7.41-7.62 (m, 4 H), 7.00 (bs, 2 H), 3.66 (s, 3 H), 2.87 (m. 1 H), 2.20 (s, 3 H), 0.70 (m, 2 H), 0.85 (m, 2 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 188.1, 166.0, 159.5, 152.8, 140.1, 139.5, 135.5, 132.9, 131.1, 130.6, 128.1, 128.0, 127.4, 126.8, 91.0, 55.2, 23.0, 15.1, 5.6 ppm.

Workup

  1. customAfter all of the sodium was consumed
  2. temperatureheated to 80° C. for 3 h
  3. temperatureThe dark red solution was cooled to room temperature
  4. temperatureThe mixture was heated to 85° C. for another 6 h
  5. customThe solvent was removed in vacuo
  6. additionThe residue was diluted in saturated NaHCO3 solution
  7. extractionwas extracted three times with EtOAc
  8. dry with materialCombined organic layers were dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product was purified by flash chromatography (SiO2, gradient of 75 to 90% EtOAc/hexanes) and recrystallization from EtOAc

Sources & evidence

ORD record
ord-684a9c704f124e048d9d2f224a1f424d
Source dataset
uspto-grants-2012_08
Patent number
US08242117B2

Reaction notes

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