Acetic Acid → 3'-(4-Fluorophenyl)-4-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-ethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochloride

HRID 220501Notes

Reaction equation

HRID 220501 reaction equation
[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][CH:9]=O)[C:4]([CH3:11])=[N:3]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:50]>>[ClH:50].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:26][CH2:27][N:28]([CH2:9][CH2:8][C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])[CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:15][CH:14]=1

Participants

6

Reactant 5

HCID 176Acetic AcidHCID 6344DichloromethaneHCID 5049666Sodium triacetoxyborohydrideHCID 64868769(1,3,5-Trimethyl-1H-pyrazol-4-yl)-acetaldehydeHCID 673669592-(4-Fluorophenyl)-3-(piperazin-1-yl)pyrazine

Product 1

HCID 685942643'-(4-Fluorophenyl)-4-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-ethyl]-3,4,5,6-tetrahydro-2H-[1,2']bipyrazine hydrochlorideYield 5%

Procedure

Combine (1,3,5-trimethyl-1H-pyrazol-4-yl)-acetaldehyde (0.35 g, 2.27 mmol) and 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.71 g, 2.76 mmol) in DCM (10 mL) and stir at room temperature for 10 min. Add glacial acetic acid (0.21 mL, 3.44 mmol) followed by sodium triacetoxyborohydride (0.73 g, 3.44 mmol). Stir at room temperature for 2 hr. Concentrate, dissolve in methanol (5 mL) and load on a 10 g SCX column. Wash with methanol (2×50 mL). Elute with 2 M ammonia in methanol (2×30 mL). Concentrate the eluent and purify (silica gel chromatography, eluting with 45:45:10 hexanes:DCM:ethanol), to give the free base of the title compound (48 mg, 5%). Dissolve the free base (0.041 g, 0.104 mmol) in methanol and add a solution of ammonium chloride (0.006 g, 0.104 mmol) in a minimal volume of methanol. Shake for 18 hr. at room temperature and concentrate to give the title compound (50 mg, 95%). MS (ES): m/z=395 [M+H]+.

Workup

  1. concentrationConcentrate
  2. dissolutiondissolve in methanol (5 mL)
  3. washWash with methanol (2×50 mL)
  4. washElute with 2 M ammonia in methanol (2×30 mL)
  5. concentrationConcentrate the eluent
  6. custompurify
  7. wash(silica gel chromatography, eluting with 45:45:10 hexanes:DCM:ethanol)

Sources & evidence

ORD record
ord-da2f02fbfd7d4e56997e4f3c6b9bb55d
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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