Potassium Carbonate → 1-Methyl-1H-pyrazole-4-sulfonic acid (2-{4-[2-(4-methoxymethyl-phenyl)-pyridin-3-yl]-piperazin-1-yl}-ethyl)-methyl-amide hydrochloride

HRID 553515Notes

Reaction equation

HRID 553515 reaction equation
[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][CH2:35][CH2:36]OC.O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:1].[CH3:33][O:34][CH2:35][C:36]1[CH:2]=[CH:7][C:6]([C:2]2[C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]4[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=4)(=[O:19])=[O:18])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:5][CH:4]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 18180031Water 1,2-dimethoxyethaneHCID 866402101-Methyl-1H-pyrazole-4-sulfonic acid {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amide

Product 1

HCID 673690991-Methyl-1H-pyrazole-4-sulfonic acid (2-{4-[2-(4-methoxymethyl-phenyl)-pyridin-3-yl]-piperazin-1-yl}-ethyl)-methyl-amide hydrochloride

Reagents, catalysts & solvents 1

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst

Conditions

Temperature
80 °C

Procedure

Dissolve 1-methyl-1H-pyrazole-4-sulfonic acid {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amide (0.200 g, 0.501 mmol) in DME-H2O (6 mL; 3:1 v/v, previously degassed with nitrogen). Add 4-(methoxymethyl)boronic acid (0.125 g, 0.752 mmol), potassium carbonate (0.166 g, 1.203 mmol) and tetrakis(triphenylphosphine)-palladium (0.029 g, 0.025 mmol). Heat the reaction mixture at 80° C. for 8 hr. Cool to room temperature and concentrate to remove DME. Dilute with ethyl acetate and brine. Extract the aqueous layer with ethyl acetate. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify by silica gel chromatography eluting with dichloromethane:methanol 94:6 to 90:10 to afford the freebase of the title compound with minor impurities. Purify by SCX eluting sequentially with dichloromethane, dichloromethane:methanol 1:1, methanol, and 1N ammonia in methanol. Pass the pure free base through a silica gel plug eluting with dichloromethane:methanol 4:1 to afford the free base of the title compound.

Workup

  1. custom3:1 v/v, previously degassed with nitrogen)
  2. temperatureCool to room temperature
  3. concentrationconcentrate
  4. customto remove DME
  5. additionDilute with ethyl acetate and brine
  6. extractionExtract the aqueous layer with ethyl acetate
  7. dry with materialdry over sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate
  10. customPurify by silica gel chromatography
  11. washeluting with dichloromethane:methanol 94:6 to 90:10

Sources & evidence

ORD record
ord-1d4ffc618b6e43b18c15f41783fc240a
Source dataset
uspto-grants-2011_11
Patent number
US08048884B2

Reaction notes

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