Hydrochloric Acid → 7-Bromo-5-methoxy-1H-indazole

HRID 913859Notes

Reaction equation

HRID 913859 reaction equation
Br.[Br:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH3:12])[C:4]=1[NH2:5].Cl.[N:14]([O-])=O.[Na+].C([O-])(=O)C.[Na+].CC(S)(C)C.CC(C)([O-])C.[K+]>O.C(O)C.CS(C)=O>[Br:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[C:4]=1[NH:5][N:14]=[CH:12]2

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 6387tert-Butyl mercaptanHCID 517045Sodium AcetateHCID 23665647Potassium tert-butoxideHCID 23668193Sodium NitriteHCID 67402403HCID 67402403, compound

Product 1

HCID 575462257-Bromo-5-methoxy-1H-indazole

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of 2-bromo-4-methoxy-6-methylaniline hydrobromide (18.5 g, 62.3 mmol) in hydrochloric acid (8 M, 56 mL, 448 mmol) at 0° C. was added a solution of sodium nitrite (4.51 g, 65.4 mmol) in water (ca. 14 mL) drop wise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (7.02 mL, 62.3 mmol) in ethanol (140 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (35 mL) and transferred to a solution of potassium tert-butoxide (55.9 g, 498 mmol) in dimethylsulfoxide (350 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Preparative HPLC gave 10.1 g (86%) as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 3.82 (s, 3H); Mass spec.: 226.95 (MH)+.

Workup

  1. additionThe resulting mixture was poured onto ice
  2. extractionthe resulting mixture was extracted into diethyl ether (2×)
  3. washThe ethereal was washed with water
  4. dry with materialbrine, dried over magnesium sulfate
  5. concentrationconcentrated
  6. dissolutionThe resulting residue was dissolved in dimethylsulfoxide (35 mL)
  7. custom(ca. 10° C.)
  8. customThe bath was removed
  9. stirringstirring
  10. waitcontinued for 30 min
  11. additionThe reaction mixture was poured onto ice/concentrated hydrochloric acid
  12. extractionThe resulting mixture was extracted with dichloromethane (2×)
  13. washwashed with water (3×)
  14. dry with materialbrine, dried over magnesium sulfate
  15. concentrationconcentrated
  16. customPreparative HPLC gave 10.1 g (86%) as a tan solid

Sources & evidence

ORD record
ord-07a28f609e5b4fbf91754055c5a25d24
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

Loading…