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Method for preparing Palbociclib

A compound and crude product technology, applied in the field of medicine, can solve problems such as being unsuitable for industrial production, cumbersome steps, increase production costs, etc., and achieve the effects of reducing adverse reactions and treatment costs, mild reaction conditions, and low production costs.

Active Publication Date: 2018-02-23
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The preparation method of the prior art has cumbersome steps and many side reactions, and is not suitable for industrial production; or the yield is low, raw materials are wasted, and production costs are increased
In addition, in some cases, due to improper control of the production process, the purity of the drug did not meet the requirements
The prior art does not disclose a special purification method for this, so it is necessary to further purify such unqualified products or crude products to improve the yield and purity of the product

Method used

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  • Method for preparing Palbociclib
  • Method for preparing Palbociclib
  • Method for preparing Palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, the preparation of palbociclib

[0038] , the synthesis of palbociclib crude product

[0039] (1) Add 18.62g of compound 4, 22.03g of compound 5, and 13.33g of aluminum trichloride into a three-neck flask, add 250ml of ethanol, stir at room temperature for 4h, add 4g of sodium hydroxide, stir at room temperature for 3h, and adjust the pH with 2M dilute hydrochloric acid to 5, stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 29.07g of compound 3 with a yield of 84.81% and a purity of 99.90%.

[0040] (2) Mix 17.12g of compound 3 with 200ml of isopropanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 3.40g of sodium ethoxide, stir for 30min, then add 6.46g of compound 2 for reflux reaction After 3 hours, it was cooled to room temperature, filtered, washed with deionized water, and dried in ...

Embodiment 8

[0048] Embodiment 8, the preparation of palbociclib

[0049] , the synthesis of palbociclib crude product

[0050](1) Add 20.18g of compound 4, 22.03g of compound 5, and 20.00g of aluminum trichloride into a three-neck flask, add 200ml of ethanol, stir at room temperature for 4 hours, add 8.00g of sodium hydroxide, stir at room temperature for 3 hours, and adjust with 2M dilute hydrochloric acid The pH was 5, stirred for 30 minutes, then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.90 g of compound 3 with a yield of 84.33% and a purity of 99.91%.

[0051] (2) Mix 17.12g of compound 3 with 200ml of isopropanol, add 3.83g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 6.81g of sodium ethoxide, stir for 30min, then add 6.46g of compound 2 for reflux reaction 3h, lowered to normal temperature, filtered, washed with deionized water, and dried in vacu...

Embodiment 15

[0060] Embodiment 15, the preparation of palbociclib

[0061] , the synthesis of palbociclib crude product

[0062] (1) Add 19.55g of compound 4, 22.03g of compound 5, and 16.00g of aluminum trichloride into a three-neck flask, add 250ml of ethanol, stir at room temperature for 4 hours, add 4g of sodium hydroxide, stir at room temperature for 3 hours, and adjust the pH with 2M dilute hydrochloric acid to 5, stirred for 30 minutes and then raised to 60°C, cooled to room temperature after the solid was completely dissolved, filtered under reduced pressure, and dried to obtain 28.99g of compound 3 with a yield of 84.57% and a purity of 99.89%.

[0063] (2) Mix 17.12g of compound 3 with 200ml of isopropanol, add 4.26g of cyclopentylamine, control the temperature at 20-60°C, heat to reflux for 4h, add 6.81g of sodium ethoxide, stir for 30min, then add 6.46g of compound 2 for reflux reaction After 3 hours, it was cooled to room temperature, filtered, washed with deionized water, an...

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Abstract

The invention discloses a method for preparing Palbociclib. The method comprises the steps of Palbociclib crude product synthesizing and Palbociclib refining, wherein the refining comprises the steps:(a) adding a Palbociclib crude product into a mixed organic solvent of tert-butyl alcohol and glycol dimethyl ether, heating the temperature of the mixture to 70 DEG C to 80 DEG C at the speed of 15DEG C / h to 20 DEG C / h, carrying out temperature-controlled stirring until dissolved clarification is achieved, adding silica gel with the particle size of 200 meshes, carrying out heat-preserved decoloring, carrying out thermal filtration, and collecting filtrate; (b) cooling the temperature of the filtrate to 20 DEG C to 25 DEG C at the speed of 20 DEG C / h, adding Palbociclib seed crystals into the filtrate, and carrying out temperature-controlled stirring for 25 to 30 minutes; (c) cooling the temperature of the filtrate to 5 DEG C to 10 DEG C at the speed of 10 DEG C / h, and carrying out temperature-controlled stirring for grain growing; and (d) carrying out suction filtration, collecting crystals, carrying out washing with a small volume of methyl tert-butyl ether, and carrying out vacuum drying, thereby obtaining refined Palbociclib. By the method disclosed by the invention, the purity of the obtained Palbociclib can reach 99.96% or more, the quality of the product is remarkably improved, and the operation is simple and convenient, so that the method is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an antineoplastic drug palbociclib. Background technique [0002] Palbociclib (Palbociclib) is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, which was granted the "Breakthrough Therapy" qualification by the US FDA in April 2013. Due to its good clinical performance in Phase III, Pfizer submitted a marketing application to the US FDA in August 2014 and obtained priority review qualifications for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative ( First-line treatment of HER2-) advanced breast cancer. The successful research of this drug will provide another important new option for patients with metastatic breast cancer. [0003] The chemical name of palbociclib (Palbociclib, I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl] Amino]pyrido[2,3-d]pyrimidin-7(8H)-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘振腾孙逸威侯善波孙运贝王亚飞
Owner SHANDONG YUXIN PHARMA CO LTD