Pyridine → N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

HRID 1178765Notes

Reaction equation

HRID 1178765 reaction equation
[N:1]1[N:2]2[CH2:11][CH2:10][CH2:9][C:3]2=[CH:4][C:5]=1[C:6](O)=[O:7].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)(=O)C(Cl)=O.ClCCl.CN(C)C=O.O.C(#N)C>[CH3:16][O:15][N:14]([CH3:13])[C:6]([C:5]1[CH:4]=[C:3]2[CH2:9][CH2:10][CH2:11][N:2]2[N:1]=1)=[O:7]

Participants

9

Reactant 4

HCID 1049PyridineHCID 6422Trifluoroacetic acidHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 113670964H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

Product 1

HCID 11356033N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×HCID 65578Oxalyl chlorideSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
18.5 °C

Procedure

5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 3.8 g, 25 mmol) is slurried in 40 ml of 2M oxalyl chloride in dichloromethane, and to the slurry are added a few drops of dimethylformamide. The resulting mixture is stirred under a nitrogen atmosphere at 15-22° C. for 10-12 hours. The resulting acid chloride as a dark solution is evaporated to a dry residue. The residue is dissolved in toluene (50 ml) and evaporated once more to give the crude acid chloride. To a stirred mixture of the crude acid chloride in dichloromethane (100 ml) and N,O-dimethylhydroxylamine hydrochloride (2.7 g, 27.5 mmol) at 0-5° C. is added pyridine (4.7 g, 3.2 ml, 60 mmol) dropwise under a nitrogen atmosphere while maintaining the temperature about 0-5° C. The resulting stirred mixture is allowed to warm to 15-20° C. over a period of 4 hours and the reaction is monitored for completion by HPLC (Prodigy ODS3 4.6×150 mm column, using a 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02% trifluoroacetic acid and UV detection at 254 nm. The retention time of the amide was 1.1 min). The mixture is washed with water (50 ml), concentrated, and purified on a short column of silica gel using elution with chloroform to give upon evaporation of volatiles N-Methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide, 4.1 g, 86%) as a light-brown crystalline solid, m.p. 45-50° C., which is characterized by NMR, mass spectrum, and elemental analysis.

Workup

  1. customThe resulting acid chloride as a dark solution is evaporated to a dry residue
  2. dissolutionThe residue is dissolved in toluene (50 ml)
  3. customevaporated once more
  4. customto give the crude acid chloride
  5. temperaturewhile maintaining the temperature about 0-5° C
  6. stirringThe resulting stirred mixture
  7. temperatureto warm to 15-20° C. over a period of 4 hours
  8. washThe mixture is washed with water (50 ml)
  9. concentrationconcentrated
  10. custompurified on a short column of silica gel using elution with chloroform

Sources & evidence

ORD record
ord-3be1bbb31b7a41c2bf9324b07e24678a
Source dataset
uspto-grants-2007_10
Patent number
US07276611B2

Reaction notes

Loading…