反应详情

温度

18.5 °C

Sodium ethoxide solution, in denaturated ethanol (21 wt %, 12 ml, 38 mmol) is added to 6.9 g (38 mmol) of the crude mixture of esters, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate and ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate in 3A ethanol (containing 3, 7% water, 15 ml) and the mixture is stirred for 10 hours under a nitrogen atmosphere at 15-22° C. Consumption of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, is monitored by HPLC [Prodigy ODS3 4.6×150 mm column, 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02% trifluoroacetic acid, UV detection at 215 nm. Retention times under these conditions were: 2.6-2.7 min. for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer), 2.8-2.9 minutes for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the undesired, less polar isomer) and 0.86 minutes for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid]. The resulting mixture is evaporated under diminished pressure to a residue as a syrup. The syrup is mixed with ether (25 ml), and the resulting precipitate is collected on a filter. The hygroscopic filter cake is washed with diethyl ether (100 ml) and then dissolved in water (10 ml). The pH of the solution is adjusted to a value of 2 with 1N hydrochloric acid and the mixture extracted with ethyl acetate (3×25 ml). The combined organic extract is dried over magnesium sulfate and evaporated to give 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as an off-white solid (1.40 g, 48%), m.p. 140-145° C., which is characterized by NMR, mass spectrum, elemental analysis, and HPLC (Prodigy ODS3 4.6×150 mm column, with a 20 min gradient from 95:5 to 30:70 using water/acetonitrile with 0.02% trifluoroacetic acid and UV detection at 215 nm. The retention time for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid was 7.2 minutes) The product of the example is used directly in the next step (see example 13).

1. customConsumption of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate
2. customODS3 4.6×150 mm column, 10 minutes
3. custom2.6-2.7 min.
4. custom2.8-2.9 minutes
5. custom0.86 minutes
6. customThe resulting mixture is evaporated under diminished pressure to a residue as a syrup
7. additionThe syrup is mixed with ether (25 ml)
8. customthe resulting precipitate is collected on a filter
9. filtrationThe hygroscopic filter cake
10. washis washed with diethyl ether (100 ml)
11. dissolutiondissolved in water (10 ml)
12. extractionthe mixture extracted with ethyl acetate (3×25 ml)
13. extractionThe combined organic extract
14. dry with materialis dried over magnesium sulfate
15. customevaporated