Synthesis
General procedure for the synthesis of 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol from 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinecarboxylic acid: 1618 mL (1618 mmol) of a 1 mol/L lithium aluminum hydride solution in tetrahydrofuran was added to a 2 L four-necked flask equipped with stirring blades and a thermometer. Subsequently, 120 g (404 mmol) of 2-(4-methyl-2-phenyl-1-piperazine)-3-pyridinecarboxylic acid was dissolved in 1800 mL of tetrahydrofuran, the reaction temperature was maintained at about 25 °C and the solution was added slowly dropwise to the reaction flask over a period of 30 min. After the dropwise addition was completed, the reaction mixture was continued to be stirred at 25°C for 3 hours. Upon completion of the reaction, 70 mL of water was slowly added while the reaction solution was cooled with a water bath and the mixture was stirred. After that, the organic and aqueous layers were separated, and the organic layer was washed sequentially with 70 mL of 15 wt% aqueous sodium hydroxide solution and 200 mL of water. The organic layer was concentrated under reduced pressure to give a crude product of 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinemethanol. To the crude product was added 840 mL of isopropyl acetate, heated to 60°C to dissolve it completely, and then 840 mL of heptane was added slowly and dropwise at an internal temperature of not less than 50°C. The resulting solution was cooled to 5°C and the slurry was aged at that temperature for 2 hours. Subsequently, the solid was collected by vacuum filtration and the crystals obtained by filtration were washed with a mixture of 60 mL of isopropyl acetate and 60 mL of heptane. Finally, the white crystals were dried under reduced pressure at 40 °C for 5 h to obtain 102 g (363 mmol, yield: 89%) of 2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridine methanol with a purity of 99.53% and a water content of 320 ppm.
References
[1] Patent: US2002/35255, 2002, A1
[2] Organic Preparations and Procedures International, 2007, vol. 39, # 4, p. 399 - 402
[3] Patent: JP2017/39659, 2017, A. Location in patent: Paragraph 0048-0049
[4] Patent: JP2017/88565, 2017, A. Location in patent: Paragraph 0060; 0061
[5] Patent: JP2017/88564, 2017, A. Location in patent: Paragraph 0056; 0057
