[4-(4-Methylpiperazino)phenyl]methanol

Synthesis

General procedure for the synthesis of 4-(4-methylpiperazine)benzyl alcohol from 1-BOC-4-(4-formylphenyl)piperazine: tert-butyl 4-(4-formylphenyl)-piperazine-1-carboxylate (1.3 g, 4.47 mmol) was dissolved in THF (50 mL), lithium aluminium hydroxide (LAH, 0.7 g, 17.87 mmol) was added with stirring and refluxing at 37 °C for for 14 hours. After completion of the reaction, the reaction was quenched with 14 N aqueous KOH (20 mL) at room temperature. The supernatant was separated, combined with the DCM wash solution and diluted with water (50 mL). The mixture was extracted with DCM (3 x 50 mL), the organic phases were combined and concentrated by rotary evaporator to give [4-(4-methylpiperazin-1-yl)phenyl]methanol (0.82 g, 89% yield). DMSO (0.56 mL, 7.96 mmol) was dissolved in DCM (50 mL), oxalyl chloride (0.7 mL, 7.96 mmol) was added and stirred at -78 °C for 0.5 h. The mixture was then dissolved in DCM (50 mL). A solution of [4-(4-methylpiperazin-1-yl)phenyl]methanol (0.82 g, 3.98 mmol) in DCM (20 mL) was added slowly and stirring was continued for 1.5 hours at -78 °C. Triethylamine (1.7 mL, 11.94 mmol) was added to gradually warm the reaction mixture to room temperature. After stirring for 4 h, the reaction was quenched with 1 N aqueous sodium bicarbonate (50 mL). The mixture was extracted with DCM (3 x 50 mL), the organic phases were combined and concentrated to give a residue, which was purified by column chromatography to give 4-(4-methylpiperazin-1-yl)benzaldehyde (0.5 g). Further, 5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one (120 mg, 41% yield) was converted to its hydrochloride salt (yellow solid). Characterization data: MS (m/z): 381.11; melting point 252.4-254.2 °C (dihydrochloride).

References

[1] Patent: US2008/188467, 2008, A1. Location in patent: Page/Page column 38-39
[2] Patent: US2013/281397, 2013, A1. Location in patent: Paragraph 0522; 0523