Acetonitrile → 3-carbamoyl-1H-indazole-5-carboxylic acid

HRID 711056Notes

Reaction equation

HRID 711056 reaction equation
[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2].OO.NC(N)=[O:20].C(#N)C.ClCCl>CO.[OH-].[Na+].O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)(=[O:20])[NH2:2]

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 6344DichloromethaneHCID 31294Carbamide PeroxideHCID 44632177Methyl 3-cyano-1H-indazole-5-carboxylate

Product 1

HCID 674916123-carbamoyl-1H-indazole-5-carboxylic acidYield 77.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 14798Sodium HydroxideSolvent

Conditions

Temperature
10 °C

Procedure

A suspension of methyl 3-cyano-1H-indazole-5-carboxylate (50.0 g, 249 mmol) in methanol (1 L) was cooled to 10° C. A solution of urea hydrogen peroxide (241 g, 2.49 mol) in sodium hydroxide (1 L of 2.5 N) and water (100 mL) was added dropwise, maintaining an internal temperature below 25° C. When the addition was complete, the ice bath was removed and the reaction was allowed to stir at room temperature for 16 hours. A small amount of unreacted starting material was observed by HPLC. The reaction was cooled to 15° C. and additional urea hydrogen peroxide (50 g) was added portionwise. Vigorous bubbling was noted. The reaction was allowed to stir for another 2 hours. The crude reaction was filtered to remove the solids present and the filtrate was concentrated to remove the methanol. The remaining solution was cooled in an ice bath and 6 N hydrochloric acid (420 mL) was added dropwise to adjust the pH to 4. The solution was stirred for 20 minutes and the resulting tan solid was collected by filtration and dried to give 57.2 g of crude product. To the crude was added acetonitrile (700 mL) and dichloromethane (700 mL) and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 1:1 acetonitrile:dichloromethane (400 mL) and dried to give the title compound (39.5 g, 77%) as a tan solid. +ESI (M+H) 206.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.81 (s, 1H), 12.85 (br. s., 1H), 8.82 (d, J=0.8 Hz, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.79-7.85 (m, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.44 (s, 1H).

Workup

  1. temperaturemaintaining an internal temperature below 25° C
  2. additionWhen the addition
  3. customthe ice bath was removed
  4. temperatureThe reaction was cooled to 15° C.
  5. additionadditional urea hydrogen peroxide (50 g) was added portionwise
  6. customVigorous bubbling
  7. stirringto stir for another 2 hours
  8. customThe crude reaction
  9. filtrationwas filtered
  10. customto remove the solids present
  11. concentrationthe filtrate was concentrated
  12. customto remove the methanol
  13. temperatureThe remaining solution was cooled in an ice bath
  14. addition6 N hydrochloric acid (420 mL) was added dropwise
  15. stirringThe solution was stirred for 20 minutes
  16. filtrationthe resulting tan solid was collected by filtration
  17. customdried
  18. customto give 57.2 g of crude product
  19. stirringthe mixture was stirred at room temperature for 1 hour
  20. filtrationThe solid was collected by filtration
  21. washwashed with 1:1 acetonitrile
  22. dry with materialdichloromethane (400 mL) and dried

Sources & evidence

ORD record
ord-f0c10a211f9141128e753a30c72cb6ef
Source dataset
uspto-grants-2015_11
Patent number
US09181252B2

Reaction notes

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