Acetic Anhydride → Ethyl 1-acetyl-1H-indazole-5-carboxylate

HRID 2297095Notes

Reaction equation

HRID 2297095 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5])[CH3:2].[C:15]([O-])(=[O:17])[CH3:16].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.CCCCCON=O>C(Cl)(Cl)Cl>[C:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=2)[CH:9]=[N:10]1)(=[O:17])[CH3:16]

Participants

7

Reactant 5

HCID 7918Acetic AnhydrideHCID 10026Pentyl nitriteHCID 2855718-Crown-6HCID 517044Potassium AcetateHCID 1501980Ethyl 1H-indazole-5-carboxylate

Product 1

HCID 1519478Ethyl 1-acetyl-1H-indazole-5-carboxylateYield 82%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

5-Ethoxycarbonylindazole. A mixture of the product prepared according to Example E-19 Part B (250.55 g, 1.4 mol), potassium acetate (143.3 g, 1.46 mol), acetic anhydride (285.9 g, 2.8 mol) and chloroform (ethanol-free; 2700 mL) was stirred at room temperature. The temperature rose to 40° C., then started to decline, at which time no starting material was detected by TLC. A mixture of 18-crown-6 (75 g, 280 mmol) and n-amyl nitrite (364.5 g, 3.1 mol) was added and the mixture was heated at reflux overnight. The cooled mixture was washed with saturated aqueous sodium bicarbonate, then with water, and was dried (MgSO4), filtered and concentrated. The residue was combined with that from another batch (711.3 g) and distilled through a 10 cm vigreaux column under vacuum to provide 1-Acetyl-5-ethoxycarbonyl-indazole (576 g, 82%), bp 115-165 ° C. (1.0 Torr). This intermediate was combined with hydrochloric acid (6N; 2000 mL) and ethanol (2000 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the solid was combined with water. The pH of the mixture was adjusted to 8 with aqueous ammonia, and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated to provide a solid (460 g). This was recrystallized from acetonitrile (1000 mL), and the crystals were washed with ethanol, then hexane, and dried to provide the title product (281 g, 60%) as a tan solid, mp 122-124° C.: 1H NMR (CDCl3) d 10.23 (bs, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.53 (d, 1H), 4.42 (q, 2H), 1.42 (t, 3H); High resolution mass spectrum (NH3-CI) calculated (M+H+) 191.0821, found 191.0838.

Workup

  1. additionA mixture of the product
  2. customprepared
  3. customrose to 40° C.
  4. additionwas added
  5. temperaturethe mixture was heated
  6. temperatureat reflux overnight
  7. washThe cooled mixture was washed with saturated aqueous sodium bicarbonate
  8. dry with materialwith water, and was dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. distillationdistilled through a 10 cm vigreaux column under vacuum

Sources & evidence

ORD record
ord-6700130bb16547679f08c37701f7a359
Source dataset
uspto-grants-2002_12
Patent number
US06489333B2

Reaction notes

Loading…