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

HRID 1959505ノート

反応式

HRID 1959505 の反応式
[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

参加物

7

反応物 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

生成物 1

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

試薬・触媒・溶媒 1

HCID 312751,4-Dioxane溶媒

実験手順

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, 1H), 7.89 (d, J=7.9, 1 H) 7.83 (s, 1H), 7.64 (d, J=7.4, 2H), 7.49 (d, J=7.7, 2H), 7.40-7.43 (m, 2H), 6.99 (bs, 2H), 4.12 (m, 2H), 3.42 (m, 2H), 3.12 (s, 3H), 2.86 (m, 1H), 2.07 (s, 3H), 0.69 (m, 2H), 0.56 (m, 2H) ppm.

後処理

  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

出典と根拠

ORDレコード
ord-a60c3ddcab104beca952e29ffac98ba2
出典データセット
uspto-grants-2013_04
特許番号
US08410160B2

反応ノート

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