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Preparation method and product of palbociclib

A solvent and intermediate technology, applied in the field of preparation of Palbociclib, can solve the problems of low yield of target products, unfavorable cost control, low environmental friendliness, etc., to improve the utilization rate of raw materials, reduce the difficulty of baking materials, reduce the The effect of product loss

Inactive Publication Date: 2019-02-15
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the preparation of palbociclib usually uses the intermediate II to synthesize palbociclib, and then purifies to obtain the target product. However, the loss rate of the target product reaches 20-30%, resulting in a partial yield of the final target product. Low
In addition, due to the nature of the product, the solubility of the solvent to it is too low, so a large amount of solvent is used during purification, which is not conducive to industrial scale-up production; a large amount of solvent is also not conducive to cost control, and the environmental friendliness is low; moreover, the currently used solvent Both are high boiling point solvents, it is extremely inconvenient to bake materials in industrial production

Method used

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  • Preparation method and product of palbociclib
  • Preparation method and product of palbociclib
  • Preparation method and product of palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation method of palbociclib has the following steps:

[0040] 1) Use inert gas N 2 Replace the reaction flask three times, add 1140g of tetrahydrofuran into the reaction flask, then add 93g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, cool to 0°C, add 280g of isopropyl Magnesium chloride, add dropwise within 1 hour, activate for 30 minutes; continue to add 6-bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-D]pyrimidine-7(8H) - 95g of ketone, the dropwise addition was completed within 1 hour, and the temperature was raised to 60°C for 30 minutes to react, until the end of the reaction, the acetic acid / THF mixture was added dropwise (the mass ratio of acetic acid to THF was 1:10), and the pH of the solution was adjusted to precipitate a solid. Cool down to 0°C, filter, take the filter cake and dry to obtain 139 g of intermediate I as a yellow solid powder, with a yield of 85.8%. The HPLC spectrum of the obtained palbociclib intermediate I is ...

Embodiment 2

[0044] The preparation method of palbociclib has the following steps:

[0045] 1) Use inert gas N 2 Replace the reaction flask three times, add 1140g of toluene into the reaction flask, then add 93g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, cool to 20°C, add 140g of isopropyl Magnesium chloride, added dropwise within 1 hour, activated for 30 minutes; continue to add 6-bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido[2,3-D]pyrimidine-7(8H )-ketone 95g, dropwise added within 1 hour; continue to dropwise add 140g isopropylmagnesium chloride, dropwisely completed within 1 hour, be warming up to 60 ℃ and react for 30 minutes, to the end of reaction, by dropwise adding acetic acid / tetrahydrofuran mixture ( The mass ratio of acetic acid to tetrahydrofuran is 1:10), adjust the pH of the solution to precipitate a solid, cool down to 0°C, filter, take the filter cake and dry to obtain 141 g of yellow solid powder intermediate I, with a yield of 87%. The HPLC spectrum ...

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Abstract

The invention discloses a preparation method of palbociclib. The preparation method comprises the following steps: 1) dissolving 4-(6-aminopyridine-3-yl)-piperazine-1-tertiary butyl carboxylate into asolvent A, adding an alkali reagent, activating at 0-20 DEG C, adding 6-bromine-2-chlorine-8-cyclopentyl-5-methyl-pyridino-[2,3-D]-pyrimidine-7(8H)-ketone, adjusting the solution to acid after a reaction is completed, cooling and filtering, taking filter cakes, and drying the filter cakes to obtain an intermediate I; 2) in the presence of an inert atmosphere, dissolving the intermediate I and butyl vinyl ether into a solvent B, catalyzing with a catalyst at 95-105 DEG C, cooling and separating a crystal after the reaction is completed, filtering, and taking the filter cakes, and drying the filter cakes to obtain an intermediate II; 3) dissolving the intermediate II into a solvent C, adding an acid, adjusting the solution to acid after the reaction is completed, filtering, and taking and centrifuging filtrate to obtain a target product, namely palbociclib. By adjusting reaction parameters and optimizing preparation process procedures, the preparation method is high in product yield, good in purity, simple and mild in process conditions and applicable to industrial large-scale production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of palbociclib and a product thereof. Background technique [0002] The global incidence of breast cancer has been on the rise since the late 1970s. In the United States, 1 in 8 women will develop breast cancer in her lifetime. China is not a country with a high incidence of breast cancer, but in recent years, the growth rate of the incidence of breast cancer in my country is 1 to 2 percentage points higher than that of countries with a high incidence. According to the incidence data of breast cancer released by the National Cancer Center and the Bureau of Disease Control and Prevention of the Ministry of Health, the incidence of breast cancer in the national tumor registration area ranks first among female malignant tumors. [0003] Palbociclib (also known as palbociclib) is a new cell cycle CDK inhibitor developed by Pfizer. It was first approved ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 温建东彭磊何伟杨志坤范军杨欢
Owner CHONGQING SANSHENG IND CO LTD
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