Thionyl Chloride → 6-Bromo-N'-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-methyl-1H-indazole-4-carbohydrazide

HRID 520553ノート

反応式

HRID 520553 の反応式
[Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.S(Cl)(Cl)=O.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH2:21]1.CCN(C(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:31][NH:30][C:28](=[O:29])[CH2:27][N:22]2[CH2:23][C@H:24]([CH3:26])[O:25][C@H:20]([CH3:19])[CH2:21]2)=[O:14])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1

参加物

6

反応物 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 304034132-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]acetohydrazideHCID 666914996-Bromo-1-methyl-1H-indazole-4-carboxylic acid

生成物 1

HCID 666916586-Bromo-N'-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-methyl-1H-indazole-4-carbohydrazide収率 60.7%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
100 °C

実験手順

6-Bromo-1-methyl-1H-indazole-4-carboxylic acid (480 mg, 1.882 mmol) was suspended in thionyl chloride (4.12 ml, 56.5 mmol) and heated to 100° C. for 30 mins. The thionyl chloride was removed in vacuo and excess azeotroped with dry diethyl ether to give a yellow solid. This was dissolved in dry tetrahydrofuran (THF) (15 ml) and 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetohydrazide (529 mg, 2.82 mmol) and DIPEA (1.315 ml, 7.53 mmol) were added. The reaction mixture was heated to 60° C. for 20 mins. Solvent was removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (15 ml). The layers were separated and the organic phase concentrated in vacuo to give a green solid which was purified by column chromatography, loading in dichloromethane and purified on Flashmaster II silica (Si) 20 g using a 0-100% ethyl acetate-cyclohexane+0-20% MeOH over 30 mins. The appropriate fractions were combined and evaporated in vacuo to afford the title compound as a yellow solid (485 mg). LCMS (Method A) Rt 0.49 min, MH+ 424.

後処理

  1. customThe thionyl chloride was removed in vacuo
  2. customexcess azeotroped with dry diethyl ether
  3. customto give a yellow solid
  4. temperatureThe reaction mixture was heated to 60° C. for 20 mins
  5. customSolvent was removed in vacuo
  6. customthe residue partitioned between dichloromethane (15 ml) and water (15 ml)
  7. customThe layers were separated
  8. concentrationthe organic phase concentrated in vacuo
  9. customto give a green solid which
  10. customwas purified by column chromatography, loading in dichloromethane
  11. custompurified on Flashmaster II silica (Si) 20 g
  12. customover 30 mins
  13. customevaporated in vacuo

出典と根拠

ORDレコード
ord-a46746390130409483b12ab4c932f047
出典データセット
uspto-grants-2016_05
特許番号
US09326987B2

反応ノート

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