Sulfolane → Methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate

HRID 1476446Notes

Reaction equation

HRID 1476446 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH:14]=O)=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1

Participants

7

Reactant 4

HCID 31347SulfolaneHCID 521998p-Toluenesulfonic acid monohydrateHCID 5003444Sodium cyanoborohydrideHCID 71742648Methyl 6-bromo-3-formyl-1-isopropyl-1H-indazole-4-carboxylate

Product 1

HCID 67466747Methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of methyl 6-bromo-3-formyl-1-isopropyl-1H-indazole-4-carboxylate (4.5 g, 13.84 mmol) in DMF (31.5 mL) was added p-toluenesulfonic acid monohydrate (0.342 g, 1.8 mmol), p-toluenesulfonyl hydrazide (3.35 g, 18.0 mmol) followed by sulfolane (31.5 mL), and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (3.489 g, 55.0 mmol) was added portion wise over a period of 25 min. The resulting reaction mixture was stirred at 100° C. for 2 h and then at RT for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue (4.4 g) was purified by silica gel chromatography (eluent: 0-5% ethyl acetate: pet ether) to afford the title compound as an off white solid (2.95 g, 68%). 1H NMR (CDCl3, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.674 (s, 3H), 3.976 (s, 3H), 4.667-4.767 (m, 1H), 7.715 (d, J=1.6 Hz, 1H), 7.761 (d, J=1.6 Hz, 1H). LCMS (ES+): 98.63%, 313.06 [M+H] ion present.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customThe resulting reaction mixture
  3. stirringwas stirred at 100° C. for 2 h
  4. waitat RT for 6 h
  5. extractionextracted with ethyl acetate (4×300 mL)
  6. washThe combined organic layers were washed with water, brine
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude residue (4.4 g) was purified by silica gel chromatography (eluent: 0-5% ethyl acetate: pet ether)

Sources & evidence

ORD record
ord-16207fc8a6a043859eea413827a9a0ef
Source dataset
uspto-grants-2015_04
Patent number
US09018382B2

Reaction notes

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