Water → {4-[4-(1-Phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-phenyl}-acetonitrile hydrochloride

HRID 220577Notes

Reaction equation

HRID 220577 reaction equation
[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:1].[C:20]1([N:18]2[CH:19]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:3]4[C:2]([C:32]5[CH:33]=[CH:34][C:29]([CH2:28][C:26]#[N:27])=[CH:30][CH:31]=5)=[N:7][CH:6]=[CH:5][N:4]=4)[CH2:9][CH2:10]3)[CH:16]=[N:17]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 11430Potassium CarbonateHCID 27733424-(Cyanomethyl)benzeneboronic acidHCID 866416623'-chloro-4-(1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl

Product 1

HCID 68595177{4-[4-(1-Phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-yl]-phenyl}-acetonitrile hydrochlorideYield 58%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 31374DimethylacetamideSolvent

Procedure

Stir together 3′-chloro-4-(1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (177 mg, 0.50 mmol), 4-(cyanomethyl)benzene boronic acid (97 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.006 g, 0.003 mmol) and water (1 mL), in N,N-dimethylacetamide (2 mL) at room temperature under nitrogen, then heat at 120° C. for 3 hr. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 5:95 to 15:85 methanol:DCM). Dry in a vacuum oven over night, then further purify by low pH reverse phase HPLC. Form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 2 M ammonia in methanol and concentrate. Dissolve the solid in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a bright yellow solid (136 mg, 58%). MS (ES): m/z=436 [M+H]+.

Workup

  1. extractionextract with DCM (3×20 mL)
  2. concentrationconcentrate
  3. custompurify
  4. wash(silica gel chromatography, eluting with 5:95 to 15:85 methanol:DCM)
  5. customDry in a vacuum oven over night
  6. customfurther purify by low pH reverse phase HPLC
  7. washwashing with methanol
  8. washthen eluting with 2 M ammonia in methanol
  9. concentrationconcentrate
  10. dissolutionDissolve the solid in acetonitrile
  11. additionby adding 2 M aq HCl solution

Sources & evidence

ORD record
ord-14576f79947f43eca48b8de95ba39d29
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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