Ethyl Acetate → 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide

HRID 354168Notes

Reaction equation

HRID 354168 reaction equation
[CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C.O>[CH:20]1([CH2:23][N:5]2[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:22][CH2:21]1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 81503BromomethylcyclopropaneHCID 178438045HCID 178438045, compound

Product 1

HCID 235031201-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO98/49166) (40.0 g, 217 mmol) in dry DMF (300 ml) was treated with cesium carbonate (77.8 g, 239 mmol). To this, in a single portion, was added cyclopropylmethyl bromide (22.9 ml, 239 mmol) and the resultant suspension stirred at RT for 6 h. After condensation in vacuo, the residue was partioned between ethyl acetate (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partioned between water (200 ml) and methylene chloride (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried over MgSO4, and condensed to a solid (40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, methylene chloride:methanol 98:2) crystallising from a mixture of methylene chloride (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (12 g, 50 mmol). Crystallisation of the mother liquors from acetonitrile gave the more polar component (Rf=0.19, methylene chloride:methanol 98:2) (10 g, 42 mmol) which was confirmed as the 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe experiements. The mother liquors contained further material as a mixture of regioisomers (20 g, 84 mmol).

Workup

  1. customAfter condensation in vacuo
  2. customthe insoluble material removed by filtration
  3. customremoved by filtration
  4. washCombined organics were washed with brine (100 ml)
  5. dry with materialdried over MgSO4, and condensed to a solid (40 g)
  6. customThe two regioisomers were separated by crystallisation of the crude mixture
  7. customThe more lipophilic component (Rf=0.27, methylene chloride:methanol 98:2) crystallising from a mixture of methylene chloride (50 ml) and diisopropylether (200 ml)

Sources & evidence

ORD record
ord-f9f29a74c9264947b7a513788e4dc4a5
Source dataset
uspto-grants-2004_06
Patent number
US06756373B1

Reaction notes

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