Sodium ethoxide → 4H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

HRID 1178762Notes

Reaction equation

HRID 1178762 reaction equation
[O-]CC.[Na+].[N:5]1[N:6]2[CH2:17][CH2:16][CH2:15][C:7]2=[CH:8][C:9]=1[C:10]([O:12]CC)=[O:11].N1N2CCCC2=C(C(OCC)=O)C=1>C(O)C>[N:5]1[N:6]2[CH2:17][CH2:16][CH2:15][C:7]2=[CH:8][C:9]=1[C:10]([OH:12])=[O:11]

Participants

5

Reactant 3

HCID 2723922Sodium ethoxideHCID 12841166ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylateHCID 12841167Ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate

Product 1

HCID 113670964H,5H,6H-pyrrolo[1,2-b]pyrazole-2-carboxylic acidYield 48%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
18.5 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-530951d7f4034b02aa3eda4700be65c5
Source dataset
uspto-grants-2007_10
Patent number
US07276611B2

Reaction notes

Loading…