2-Piperidone → HCID 59321943, compound

HRID 220600Notes

Reaction equation

HRID 220600 reaction equation
[H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:39])[C:37]=4[CH3:38])[CH2:28][CH2:27]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:39][N:36]1[C:37]([CH3:38])=[C:33]([CH2:32][N:29]2[CH2:28][CH2:27][N:26]([C:21]3[C:20]([C:17]4[CH:16]=[CH:15][C:14]([CH2:13][N:3]5[CH2:8][CH2:7][CH2:6][CH2:5][C:4]5=[O:9])=[CH:19][CH:18]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:31][CH2:30]2)[CH:34]=[N:35]1

Participants

5

Reactant 3

HCID 126652-PiperidoneHCID 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 59321943HCID 59321943, compoundYield 73%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
5 °C

Procedure

Add sodium hydride (0.175 g of 60% weight suspension in mineral oil; 2.62 mmol) to a solution of piperidin-2-one (0.270 g; 2.73 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/DCM to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-piperidin-2-one (0.180 g; 73%). MS (ES+) m/z: 460 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the 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 a brown powder (164 mg, 66%). MS (ES): m/z=460 [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/DCM

Sources & evidence

ORD record
ord-43c545d0f637404a8d89c57e094cf652
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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