HCID 66661434, compound → HCID 135523828, compound

Temperature

-50 °C

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.

1. temperatureCooling bath
2. customwas removed
3. temperatureto warm to room temperature
4. stirringStirring
5. waitwas continued at room temperature for 1 hour
6. additionAn aqueous ammonium chloride solution (20 mL) was added
7. additionEthyl acetate (50 mL) was added
8. customThe organic layer was separated
9. washwashed with water (10 mL)
10. dry with materialdried (Na2SO4)
11. customRemoval of the solvent
12. customgave a yellow gummy material, which
13. customwas used in next step without further purification
14. dissolutionThe above compound (1.87 g) was dissolved in anhydrous THF (10 mL)
15. additionTetrabutyl ammonium fluoride (6.8 mL, 1.0M solution in THF) was added at 0° C
16. stirringThe reaction mixture was stirred at 0° C. for 30 min.
17. waitat room temperature for 1 hour
18. additionSaturated aqueous ammonium chloride (30 mL) was added
19. extractionThe mixture was extracted with ethyl acetate (100 mL)
20. customthe organic layer was separated
21. dry with materialdried over anhydrous Na2SO4
22. customThe solvent was removed under reduced pressure
23. customthe crude product was purified by column chromatography (Silica Gel 230-400 mesh; 0-5% methanol (containing 7.0 M ammonia) in CH2Cl2 as eluent)

ORD record

ord-42270e18b4da4c9f804f843f97e8be3a

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410109B2