Dichloromethane → 3'-(4-Fluoro-phenyl)-4-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-ylmethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochloride

HRID 220509Notes

Reaction equation

HRID 220509 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:31])([F:30])[CH2:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:47]>ClCCCl>[ClH:47].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:28][C:26]4[CH:25]=[N:24][N:23]([CH2:22][C:21]([F:31])([F:20])[F:30])[CH:27]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 5049666Sodium triacetoxyborohydride2×HCID 196195521-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbaldehyde2×HCID 673669592-(4-Fluorophenyl)-3-(piperazin-1-yl)pyrazine

Product 1

HCID 685967073'-(4-Fluoro-phenyl)-4-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-ylmethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochlorideYield 42%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 g, 0.581 mmol) in DCE (5 mL). Add 1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-4-carbaldehyde (0.124 g, 0.697 mmol) followed by sodium triacetoxyborohydride (0.185 g, 0.872 mmol) and stir at ambient temperature for 18 hr. Add 1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-4-carbaldehyde (0.062 g, 0.349 mmol) and stir at ambient temperature for 2 hr. Add sodium triacetoxyborohydride (0.092 g, 0.436 mmol) and stir at ambient temperature for 72 hr. Purify via SCX chromatography. Add resin-bound-isocyanate (0.796 g, 1.16 mmol) and DCM (8 mL) and shake at ambient temperature for 4 hr. Filter, concentrate and purify (silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate) to give the free base of the title compound (103 mg, 42%). Dissolve the free base (0.099 g, 0.237 mmol) in methanol and add a solution of ammonium chloride (0.013 g, 0.237 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (108 mg, 100%). MS (ES): m/z=421[M+H]+.

Workup

  1. customPurify via SCX chromatography
  2. filtrationFilter
  3. concentrationconcentrate
  4. custompurify (silica gel chromatography
  5. washeluting with 100:0 to 0:100 hexanes

Sources & evidence

ORD record
ord-b610ad9558964017984ff86048d02c93
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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