Phosphorus oxide (P4O10) → 6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole

HRID 38856Notes

Reaction equation

HRID 38856 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][NH:24][C:25](=[O:35])[CH2:26][N:27]2[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]2)=O)[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.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].C([NH+](CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:35][C:25]([CH2:26][N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[N:24][N:23]=2)[CH:3]=1

Participants

5

Reactant 3

HCID 14812Phosphorus oxide (P4O10)HCID 21903323HCID 21903323, compoundHCID 666915176-Bromo-N'-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazide2×

Product 1

HCID 666957066-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazoleYield 73.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

6-Bromo-N′-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazide (950 mg, 1.683 mmol) was dried over phosphorus pentoxide in a desicator overnight. 6-bromo-N′-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]acetyl}-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbohydrazide (950 mg, 1.683 mmol) and methoxycarbonylsulfamoyl)triethylammonium hydroxide (602 mg, 2.52 mmol) were suspended in anhydrous tetrahydrofuran (20 ml) and heated to 75° C. for 2 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane (15 ml) and saturated sodium bicarbonate solution (15 ml). The layers were separated (hydrophobic frit), the aqueous washed with further dichloromethane (5 ml) and the combined organics concentrated in vacuo to give a yellow solid. This was purified by column chromatography, loading in dichloromethane onto a silica cartridge 50 g, using a 0-100% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (680 mg).

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue partitioned between dichloromethane (15 ml) and saturated sodium bicarbonate solution (15 ml)
  3. customThe layers were separated (hydrophobic frit)
  4. washthe aqueous washed with further dichloromethane (5 ml)
  5. concentrationthe combined organics concentrated in vacuo
  6. customto give a yellow solid
  7. customThis was purified by column chromatography, loading in dichloromethane onto a silica cartridge 50 g
  8. customover 40 mins
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-eeaadf81099f4a0b9123a753905be3c4
Source dataset
uspto-grants-2013_09
Patent number
US08524751B2

Reaction notes

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