Potassium Iodide → 4-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-3'-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl

HRID 220536Notes

Reaction equation

HRID 220536 reaction equation
Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][CH2:32][C:33]1[C:34]([CH3:39])=[N:35][NH:36][C:37]=1[CH3:38]>C(#N)C>[CH3:39][C:34]1[C:33]([CH2:32][CH2:31][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)=[N:15][CH:14]=[CH:13][N:12]=3)[CH2:21][CH2:20]2)=[C:37]([CH3:38])[NH:36][N:35]=1

Participants

6

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 5728794-(2-Bromoethyl)-3,5-dimethyl-1H-pyrazoleHCID 673669583'-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl dihydrochloride

Product 1

HCID 593218964-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-3'-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinylYield 0.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.200 g, 0.604 mmol) in acetonitrile (12 mL). Add potassium carbonate (0.334 g, 2.415 mmol), potassium iodide (0.005 g, 0.030 mmol), and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (0.135 g, 0.664 mmol). Heat reaction at reflux for 14 hr. under nitrogen. Cool to room temperature and filter over celite. Concentrate filtrate in vacuo and purify residue by flash chromatography eluting with DCM:acetone 6:4 to afford the freebase as a mixture. Purify by reverse phase chromatography (43 g C-18, CH3CN: 1% aqueous TFA 5 to 95% over 20 min.) to afford a mixture. Purify by flash chromatography eluting with chloroform:methanol 0-10% to afford 4-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 mg). Dissolve the free base (0.150 g, 0.394 mmol) in acetonitrile (1 mL) and add aqueous 1N HCl (0.433 mL, 0.433 mmol). Stir for 1 h at room temperature. Remove organics and lyophilize to afford the title compound (0.144 g, 77% yield). MS (m/z)=381 [M+H]+.

Workup

  1. temperatureHeat
  2. customreaction
  3. temperatureat reflux for 14 hr
  4. filtrationfilter over celite
  5. customConcentrate filtrate in vacuo and purify residue by flash chromatography
  6. washeluting with DCM:acetone 6:4
  7. customto afford the freebase as a mixture
  8. customPurify by reverse phase chromatography (43 g C-18, CH3CN: 1% aqueous TFA 5 to 95% over 20 min.)
  9. customto afford a mixture
  10. customPurify by flash chromatography
  11. washeluting with chloroform

Sources & evidence

ORD record
ord-40c3ac2c9dd342c6a727c635d73d2332
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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