Hydrochloric Acid → 1,1-dimethylethyl (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate

HRID 525247Notes

Reaction equation

HRID 525247 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[O:10])=[C:4]([F:28])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.Cl>C(OCC)(=O)C.C(O)CC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:11][N:12]=[C:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[C:4]([F:28])[CH:3]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 90495Di-tert-butyl dicarbonateHCID 866748271,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate

Product 1

HCID 673758561,1-dimethylethyl (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylateYield 41.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 10311-PropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

Into a 250 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate (4.35 mmol). Added to the flask was K2CO3 (21.71 mmol), water (100 mL), and 1-propanol (10.00 mL). The solution was stirred at reflux (140° C.) for 16 h and then cooled to room temperature and filtered to remove an undetermined solid. The filtrate was concentrated in vacuo. Added to the white solid was 1N aq NaOH (10 mL) followed by the addition of Boc2O (4.35 mmol). The solution was stirred at room temperature overnight. The solution was diluted with 100 mL ethyl acetate and brought to a pH=7 with the addition of 1N aq HCl. The organic layer was separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel purification (100% dichloromethane, 0-100% ethyl acetate, and 0-10% methanol:ethyl acetate) provided the title product (790 mg, 39%). MS(ES)+ m/e 442.0, 443.0 [M+H]+.

Workup

  1. customInto a 250 mL round bottom flask was placed
  2. additionAdded to the flask
  3. temperaturecooled to room temperature
  4. filtrationfiltered
  5. customto remove an undetermined solid
  6. concentrationThe filtrate was concentrated in vacuo
  7. additionAdded to the white solid
  8. stirringThe solution was stirred at room temperature overnight
  9. customThe organic layer was separated
  10. washthe aqueous layer was washed twice with ethyl acetate
  11. dry with materialThe combined organic layers were dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customSilica gel purification (100% dichloromethane, 0-100% ethyl acetate, and 0-10% methanol:ethyl acetate)

Sources & evidence

ORD record
ord-53d6a2e00abe438b906cd6d6d8aeda1c
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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