4-Methylpiperazine-1-carbonyl chloride monohydrochloride → 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone

HRID 897606Notes

Reaction equation

HRID 897606 reaction equation
[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1>N1C=CC=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:39])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12

Participants

4

Reactant 2

HCID 30169344-Methylpiperazine-1-carbonyl chloride monohydrochloride2×HCID 223472623-(4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 697809204-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanoneYield 45%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.300 g, 0.780 mmol) in pyridine (5 mL) at 0° C. was treated with 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol). The reaction mixture was stirred for 5 min at 0° C., after which the ice bath was removed, and the reaction stirred at room temperature over night. An additional equivalent of 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol) was added and stirred for 2 h. Solvent was removed under reduced pressure. Dichloromethane (10 mL) and sodium bicarbonate (5 mL) saturated aqueous solution were added to the solid. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure to give 0.417 g of crude material. The crude product was purified by flash chromatography on silica gel eluting 8% methanol in dichloromethane, 15% methanol in dichloromethane, and then 20% methanol in dichloromethane as eluent to give 0.178 g (45%) of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone. A hot solution of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone (0.178 g, 0.347 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.081 g, 0.693 mmol) in ethyl acetate. Upon cooling of the solvent a precipitate formed, was filtered under nitrogen, and dried under high vacuum to give 0.124 g of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone bis-maleate.

Workup

  1. customafter which the ice bath was removed
  2. stirringthe reaction stirred at room temperature over night
  3. stirringstirred for 2 h
  4. customSolvent was removed under reduced pressure
  5. additionDichloromethane (10 mL) and sodium bicarbonate (5 mL) saturated aqueous solution were added to the solid
  6. customThe layers were separated
  7. extractionan Empore extraction cartridge
  8. customThe organic layer was removed under reduced pressure
  9. customto give 0.417 g of crude material
  10. customThe crude product was purified by flash chromatography on silica gel eluting 8% methanol in dichloromethane, 15% methanol in dichloromethane

Sources & evidence

ORD record
ord-161de3a24c3d4a3183224b29458e50a8
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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