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

HRID 38855Notes

Reaction equation

HRID 38855 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:21](O)=[O:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.S(Cl)(Cl)=O.[CH3:28][C@H:29]1[O:34][C@@H:33]([CH3:35])[CH2:32][N:31]([CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH2:30]1.CCN(C(C)C)C(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH:40][NH:39][C:37](=[O:38])[CH2:36][N:31]2[CH2:32][C@H:33]([CH3:35])[O:34][C@H:29]([CH3:28])[CH2:30]2)=[O:22])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])[C:9]=2[CH:10]=1

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 304034132-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]acetohydrazideHCID 666917216-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carboxylic acid

Product 1

HCID 666915176-Bromo-N'-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazideYield 44.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

6-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carboxylic acid (1.5 g, 3.80 mmol) was suspended in thionyl chloride (8.31 ml, 114 mmol) and heated to 100° C. for 30 mins. The thionyl chloride was removed in vacuo and excess aziotroped with dry diethyl ether to give a yellow solid. This was dissolved in dry tetrahydrofuran (40 ml) and 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetohydrazide (1.066 g, 5.69 mmol) and DIPEA (2.65 ml, 15.18 mmol) added. The reaction mixture was heated to 60° C. for 20 mins. The solvent was removed in vacuo and the residue partitioned between dichloromethane (50 ml) and water (50 ml). The layers were separated and the organic concentrated in vacuo to give a yellow foam. This was purified by column chromatography, loading in dichloromethane onto a silica cartridge (50 g), eluting with 0-100% ethyl acetate-cyclohexane over 30 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (950 mg).

Workup

  1. customThe thionyl chloride was removed in vacuo and excess aziotroped with dry diethyl ether
  2. customto give a yellow solid
  3. temperatureThe reaction mixture was heated to 60° C. for 20 mins
  4. customThe solvent was removed in vacuo
  5. customthe residue partitioned between dichloromethane (50 ml) and water (50 ml)
  6. customThe layers were separated
  7. concentrationthe organic concentrated in vacuo
  8. customto give a yellow foam
  9. customThis was purified by column chromatography, loading in dichloromethane onto a silica cartridge (50 g)
  10. washeluting with 0-100% ethyl acetate-cyclohexane over 30 mins
  11. customevaporated in vacuo

Sources & evidence

ORD record
ord-2a1d197fc0ca4502b196bb1cf17b0230
Source dataset
uspto-grants-2013_09
Patent number
US08524751B2

Reaction notes

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