Water → HCID 67106005, compound

HRID 1958244Notes

Reaction equation

HRID 1958244 reaction equation
Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([NH:10][CH3:11])=[O:9].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>C1COCC1>[CH3:13][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[CH:12][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]

Participants

5

Reactant 3

HCID 962WaterHCID 531671-MethylpiperazineHCID 66661790HCID 66661790, compound

Product 1

HCID 67106005HCID 67106005, compoundYield 38.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-bromomethyl-2,N-dimethylbenzamide (4.94 g, 24 mmol) in anhydrous THF (75 mL) was added N-methylpiperazine (5.3 mL, 4.81 g, 48 mmol). A white precipitate was formed. Stirring continued overnight. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. Purification by column chromatography (Silica Gel 230-400 mesh; 0-5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent) to give 2,N-dimethyl-5-(4-methylpiperazin-1-ylmethyl)benzamide (2.4 g, 38%) of as a gummy material. n-Butyl lithium (9.1 mL, 14.64 mmol, 1.6 M solution in hexanes) was added to a solution of 2,N-dimethyl-5-(4-methylpiperazin-1-ylmethyl)benzamide (0.87 g, 3.33 mmol) in anhydrous THF (10 mL) dropwise at −10° C. over a period of 10 min under nitrogen. Color changed to orange-red. Stirring continued at 0° C. for 1 hour. The reaction mixture was cooled to −50° C. A solution of 4-(tert-butyldimethylsilanyloxy)-3,5-dimethylbenzonitrile (1.09 g, 4.16 mmol) in anhydrous THF (5 mL) was quickly added. Cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued at room temperature for 1 hour. The reaction mixture became dark colored. An aqueous ammonium chloride solution (20 mL) was added. The color changed to pale yellow. Ethyl acetate (50 mL) was added. The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). Removal of the solvent gave a yellow gummy material, which was used in next step without further purification. The above compound (1.87 g) was dissolved in anhydrous THF (10 mL). Tetrabutyl ammonium fluoride (6.8 mL, 1.0M solution in THF) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. and then at room temperature for 1 hour. Saturated aqueous ammonium chloride (30 mL) was added. The mixture was extracted with ethyl acetate (100 mL) and the organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, the crude product was purified by column chromatography (Silica Gel 230-400 mesh; 0-5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent) to give 2,6-dimethyl-4-[1-methylamino-7-(4-methylpiperazin-1-ylmethyl) isoquinolin-3-yl]phenol (0.487 g, 33%) as purple solid. To a solution of above compound (0.17 g, 0.43 mmol) in CH2Cl2 (10 mL) was added hydrogen chloride in ether (2.0 mL, 1.0 M solution) dropwise under nitrogen. A yellow precipitate was formed. The reaction mixture was stirred at room temperature for 11 hour. Solvent was removed under reduced pressure and dried under vacuum to give 2,6-dimethyl-4-(1-(methylamino)-7-((4-methylpiperazin-1-yl)methyl)isoquinolin-3-yl)phenol (0.178 g, 97%) as the trihydrochloride; MS (ES) m/z: 391.10 (M+1); MP 264-266° C.

Workup

  1. customA white precipitate was formed
  2. extractionthe mixture was extracted with ethyl acetate (200 mL)
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. customPurification by column chromatography (Silica Gel 230-400 mesh; 0-5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent)

Sources & evidence

ORD record
ord-76ddcb3d3dea40129e50860e1b040493
Source dataset
uspto-grants-2013_04
Patent number
US08410109B2

Reaction notes

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