2-Methoxyethanol → 3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

HRID 251348Notes

Reaction equation

HRID 251348 reaction equation
[H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].C(O[C:11](=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OCCN2CCOCC2)[CH:13]=1)C.F[C:29](F)(F)[C:30](O)=O.[CH:35]1([NH:38][C:39](=[O:49])[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[C:42]([NH:47][NH2:48])[CH:41]=2)[CH2:37][CH2:36]1.[CH:50]([N:53](C(C)C)CC)(C)C>O1CCOCC1>[NH2:53][C:50]1[N:47]([C:42]2[CH:41]=[C:40]([CH:45]=[CH:44][C:43]=2[CH3:46])[C:39]([NH:38][CH:35]2[CH2:37][CH2:36]2)=[O:49])[N:48]=[CH:30][C:29]=1[C:11](=[O:27])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:3]2[O:7][CH2:6][CH2:5][O:4]2)[CH:17]=1

Participants

7

Reactant 5

HCID 80192-MethoxyethanolHCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 58089039Ethyl 3-{[2-(4-morpholinyl)ethyl]oxy}benzoateHCID 67024207N-cyclopropyl-3-hydrazinyl-4-methylbenzamide 2,2,2-trifluoroacetate

Product 1

HCID 113963403-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamideYield 17.3%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

Dry sodium hydride (21 mg, 0.84 mmol) was added to a solution of 2-methoxyethanol (0.63 ml, 8.0 mmol) in dioxane (2 ml) at 0° C. The mixture was stirred at room temperature for 30 min. 2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added, and the mixture was stirred at 85° C. for 4 h. The mixture was cooled to room temperature. N-Cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol), followed by diisopropylethylamine (0.14 ml, 0.80 mmol), was added and the reaction was heated to 85° C. for another 11 h. Solvents were 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 70 to 90% EtOAc/hexanes). The product was further purified by washing with a warm mixture of EtOAc and hexanes to give the desired 3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 5 as a white solid (60 mg, 17%). HPLC (4 minute 10-90 gradient) tR 2.17 min; MS m/z 435.2 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (s, 1 H), 7.89 (d, J=7.9, 1 H), 7.83 (s, 1 H), 7.64 (d, J=7.4, 2 H), 7.49 (d, J=7.7,2 H), 7.40-7.43 (m, 2 H), 6.99 (bs, 2 H), 4.12 (m, 2 H), 3.42 (m, 2 H), 3.12 (s, 3 H), 2.86 (m, 1 H), 2.07 (s, 3 H), 0.69 (m, 2 H), 0.56 (m, 2 H) ppm.

Workup

  1. stirringthe mixture was stirred at 85° C. for 4 h
  2. temperatureThe mixture was cooled to room temperature
  3. additionwas added
  4. temperaturethe reaction was heated to 85° C. for another 11 h
  5. customSolvents were 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 70 to 90% EtOAc/hexanes)
  12. customThe product was further purified
  13. washby washing with a warm mixture of EtOAc and hexanes

Sources & evidence

ORD record
ord-62d18b2ca45f46eda869ab26a83da28c
Source dataset
uspto-grants-2011_01
Patent number
US07863314B2

Reaction notes

Loading…