反应详情

A suspension of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (40.0 g, 217 mmol, prepared using procedure in WO9849166) 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 (32.2 g, 239 mmol) and the resultant suspension stirred at 20° C. for 6 h. After concentrating in vacuo, the residue was partitioned between EtOAc (200 ml) and water (200 ml), and the insoluble material removed by filtration. The solid was partitioned between water (200 ml) and DCM (200 ml), and undissolved solid removed by filtration. Combined organics were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuo to a solid (˜40 g). The two regioisomers were separated by crystallisation of the crude mixture. The more lipophilic component (Rf=0.27, DCM:MeOH 98:2) crystallised from a mixture of DCM (50 ml) and diisopropylether (200 ml) to give 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (11.9 g, 50.0 mmol, 23%). Crystallisation of the mother liquors from MeCN gave the more polar component (Rf=0.19, DCM:MeOH 98:2) (10.0 g, 42.0 mmol) which was confirmed as 1-(cyclopropylmethyl)-5-ethyl-4-nitro-1H-pyrazole-3-carboxamide by nOe studies. The mother liquors contained further material as a mixture of regioisomers (20.0 g, 84.0 mmol). 1-(cyclopropylmethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide:

1. concentrationAfter concentrating in vacuo
2. customthe residue was partitioned between EtOAc (200 ml) and water (200 ml)
3. customthe insoluble material removed by filtration
4. customThe solid was partitioned between water (200 ml) and DCM (200 ml), and undissolved solid
5. customremoved by filtration
6. washCombined organics were washed with brine (100 ml)
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated in vacuo to a solid (˜40 g)
10. customThe two regioisomers were separated by crystallisation of the crude mixture
11. customThe more lipophilic component (Rf=0.27, DCM:MeOH 98:2) crystallised from a mixture of DCM (50 ml) and diisopropylether (200 ml)