Pyrazole → HCID 59321844, compound

HRID 220598Notes

Reaction equation

HRID 220598 reaction equation
[H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl.Cl.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:37])[C:35]=4[CH3:36])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[CH3:37][N:34]1[C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:3]5[CH:7]=[CH:6][CH:5]=[N:4]5)=[CH:13][CH:14]=4)=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)[CH:32]=[N:33]1

Participants

5

Reactant 3

HCID 1048PyrazoleHCID 24758Sodium hydrideHCID 685941603'-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl dihydrochloride

Product 1

HCID 59321844HCID 59321844, compoundYield 61%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
5 °C

Procedure

Add sodium hydride (0.172 g of 60% weight suspension in mineral oil; 2.59 mmol) to a solution of pyrazole (0.183 g; 2.69 mmol) in DMF (5 mL). Cool the mixture to 5° C., stir for 30 min., remove the cooling bath, warm to room temperature and stir for 30 min. Add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.253 g; 0.540 mmol) in 6 mL of DMF and stir for 20 hr. at room temperature. Quench with a solution of 10% aq. acetic acid (9 mL), add methanol (minimal volume to achieve a homogeneous solution) and add to a 5 gm SCX column (Varian; pre-rinsed with MeOH). Elute the crude product with 2 M ammonia in methanol (18 mL) and concentrate. Purify via chromatography on silica gel eluting 0-10% methanol/dichlormethane to give 4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-pyrazol-1-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.140 g; 61%). MS (ES+) m/z: 429 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the pure free base. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 1 eq 2 M aq HCl solution. Add water and lyophilize to give the title compound as an off white powder (126 mg). MS (ES): m/z=429 [M+H]+.

Workup

  1. customremove the cooling bath
  2. temperaturewarm to room temperature
  3. stirringstir for 30 min
  4. customat room temperature
  5. customQuench with a solution of 10% aq. acetic acid (9 mL)
  6. additionadd methanol (minimal volume
  7. additionadd to a 5 gm SCX column (Varian; pre-rinsed with MeOH)
  8. washElute the crude product with 2 M ammonia in methanol (18 mL)
  9. concentrationconcentrate
  10. customPurify via chromatography on silica gel eluting 0-10% methanol/dichlormethane

Sources & evidence

ORD record
ord-c8df7e3a218944baa67b1e575a2fa6b7
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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