Overview of the preparation of 1-(6-nitropyridin-3-yl)piperazine
1-(6-nitropyridin-3-yl)piperazine is used as an intermediate for the breast cancer drug palbociclib. 1-(6-nitropyridin-3-yl)piperazine is a synthetic Key structural fragments of palbociclib.
1-(6-nitropyridin-3-yl)piperazine
Preparation of 1-(6-nitropyridin-3-yl)piperazine
Preparation of 1-(6-nitropyridin-3-yl)piperazine 1. Preparation of organically modified hectorite-loaded ionic liquid materials:
1) Preparation of vector:
50 mmol tetraethoxysilane was dissolved in 100 ml ethanol and the temperature was refluxed for 1-2 hours, then the temperature was lowered to 40-50°C and 60 ml of 10 wt% magnesium chloride aqueous solution was added dropwise. After the dropwise addition, the mixture was kept warm and stirred to form a uniform solution;
Add ammonia solution dropwise to the uniform solution to adjust the pH of the system to 11 to form a colloid, then cool to room temperature and stir for 16 hours, filter, wash with water, and vacuum dry at 90°C to obtain a silicon-magnesium complex; disperse all the silicon-magnesium complexes obtained in 100ml deionized water, then add 0.5g lithium chloride hydrate and 0.4g sodium hydroxide, stir at 40-50°C to form a uniform gel, place it in a polytetrafluoroethylene-lined stainless steel kettle, and perform a hydrothermal reaction at 160°C for 2 hours. , then cool to room temperature, filter, wash with water, and vacuum dry at 90°C to constant weight to obtain hectorite carrier (abbreviated as He);
2) Modification of carrier:
Place 1.0g of hectorite carrier in 50ml of purified water and stir to form a suspension, then add 0.8g of cetyltrimethylammonium bromide for reflux reaction for 2-3h, then cool to room temperature, filter, and reflux at 100°C Dry to constant weight, and then calcine at 600°C for 1 hour in an oxygen atmosphere to obtain organically modified hectorite (abbreviated as MH);
3) Preparation of ionic liquid:
Raise the temperature of 0.1 mol 1-butyl-3-methylimidazole chloride to 7 tetrahydrofuran 0°C and stir to dissolve, then add 0.04 mol cuprous iodide in batches under nitrogen conditions, and then keep warm and stir for 2-3 days. Cool to room temperature to obtain ionic liquid (abbreviated as IL);
4) Loading of ionic liquid:
Place 1.0g of organically modified hectorite in methanol and disperse it evenly by ultrasonic, then add 0.3g of ionic liquid for reflux reaction for 12 hours, and finally remove the methanol by distillation to obtain an organically modified hectorite-loaded ionic liquid material (abbreviated as MH@IL).
Preparation of 1-(6-nitropyridin-3-yl)piperazine 2. Preparation of 1-(6-nitropyridin-3-yl)piperazine:
1) Dissolve 5-bromo-2-nitropyridine (1mol, 203g) in 1.5L dimethyl sulfoxide, and then add the organically modified hectorite-loaded ionic liquid material MH@IL (40.6g , 20wt%), stir and disperse evenly to obtain the first mixed liquid;
2) Dissolve piperazine (129.2g, 1.5mol) in 800ml of dimethyl sulfoxide to form a piperazine solution, and then add the piperazine solution dropwise to the first mixed solution to perform a condensation reaction at 80°C;
3) After 5 hours, take the reaction solution for HPLC detection (the area percentage of 5-bromo-2-nitropyridine in the reaction solution is 0.08%, and the target product 1-(6-nitropyridin-3-yl)piperazine conjugate The content of pinacol borate is 99.68%, the double condensation by-product is 0.17%, and the balance is unknown impurities). Stop the reaction and use an organic microporous filter membrane with a pore size of 0.5 microns to remove the organically modified hectorite-loaded ionic liquid material. Get the filtrate;
4) Raise the temperature of the filtrate to 60-65°C, then add dropwise methylamine aqueous solution with a concentration of 3V%. Stop dropping when turbidity appears in the system, keep stirring for 20-30 minutes, and then continue to dropwise add methylamine with a concentration of 3V%. The methylamine aqueous solution was cooled to room temperature naturally until the concentration of 1-(6-nitropyridin-3-yl)piperazine in the solution no longer dropped, filtered, and vacuum dried at 45°C to obtain 197.4g solid, with a yield of 94.8%, HPLC The detected content is 99.92% (external standard method); LC-MS: m/z=209.1[M+H].
The organically modified hectorite-loaded ionic liquid material obtained by filtration was dried ultrasonically with acetone and then recycled for use. The yield of 1-(6-nitropyridin-3-yl)piperazine was 94.2%, and the content was 99.89%, which is equivalent to the catalytic effect of fresh preparation. Therefore, the catalytic material prepared in the present invention can be recycled and used to reduce the production cost of the condensation step.
