Hydrochloric Acid → 4-(4-bromo-2,5-difluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 2405362Notes

Reaction equation

HRID 2405362 reaction equation
[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17]2)=[O:11])=[C:4]([F:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH2:17]3)=[N:13][NH:12][C:10]2=[O:11])=[C:4]([F:27])[CH:3]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 71087602N-(4-bromo-2,5-difluorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide

Product 1

HCID 673553504-(4-bromo-2,5-difluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 31%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
115 °C

Procedure

To a round bottom flask were added N-(4-bromo-2,5-difluorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (1.80 g, 4.04 mmol) and potassium carbonate (1.955 g, 14.15 mmol) and water (200 mL). The resulting suspension was refluxed for 16 h at 115° C. The pH of the solution was lowered to ˜6 with 1N aq HCl and then partitioned with 150 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, then 0-25% isopropanol/ethyl acetate), and the desired fractions were combined and concentrated in vacuo to afford the title product as an off-white solid (400 mg, 31%). MS(ES)+ m/e 426.9, 428.8 M+H]+.

Workup

  1. custompartitioned with 150 mL of ethyl acetate
  2. extractionThe aqueous phase was extracted with ethyl acetate (3×)
  3. washthe combined organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-162bf31efba349fe9dd62bb006f3128f
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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