Water → 7-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

HRID 245708Notes

Reaction equation

HRID 245708 reaction equation
[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]4[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 86674652N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide

Product 1

HCID 866746537-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazineYield 25.1%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.382 mmol, 500 mg) in ethyl acetate (5 ml) at 0° C. was added phosphorus oxychloride (5.53 mmol, 0.515 ml). The reaction mixture was stirred at room temperature for two days and at 60° C. for one day. The reaction mixture was cooled to 0° C., an excess solid sodium hydrogencarbonate was added and the suspension was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes. Then the suspension was again cooled to 0° C., water was added and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane applying a gradient 0 to 10% methanol) to give 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (119 mg).

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. stirringthe suspension was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes
  3. temperatureThen the suspension was again cooled to 0° C.
  4. extractionextracted three times with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (sodium sulfate)
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (silica gel

Sources & evidence

ORD record
ord-06c0737fdb9d4361bad3102fce058795
Source dataset
uspto-grants-2014_02
Patent number
US08658794B2

Reaction notes

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