Palbociclib preparation method

A refining method and solid technology, applied in the direction of organic chemistry, etc., can solve the problems of high cost, unfriendly environment, affecting process amplification, etc., and achieve the effect of low manufacturing cost and cheap raw materials

Inactive Publication Date: 2015-09-16
上海百奇医药科技有限公司
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  • Abstract
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  • Application Information

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Problems solved by technology

[0008] The process route is mainly divided into 7 steps, and the purification in the third step depends on column chromatography, which affects the scale-up of the process; the cost of raw materials itself is relatively high, and the cost of raw materials consumed per kilogram of product is about 1100 yuan. The reagent of precious metal palladium needs to increase the cost of 5,000 yuan per kilogram, and the highly corrosive reagent bromine, which is not friendly to the environment, has been used many times in the process

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preparation example Construction

[0026] A preparation method of Palbociclib, comprising the steps of:

[0027] (1) Substitution step: dissolving 2,4-dichloropyrimidine in an organic solvent, adding cyclopentylamine dropwise under stirring for reaction, and recrystallizing to obtain solid A;

[0028] (2) Dehydration step: dissolving the obtained solid A and 2,2-diacetylacetic acid in an organic solvent, adding dicyclohexylcarbodiimide dropwise under stirring conditions, and recrystallizing to obtain solid B;

[0029] (3) Cyclization step: dissolving the obtained solid B in an organic solvent, reacting under the catalysis of boron trifluoride ether, and refining to obtain solid C;

[0030] (4) Step of introducing side chains: the obtained solid C is dissolved in toluene as the first phase, and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester is dissolved in toluene as the second phase Phase, the first phase is added dropwise during the stirring process of the second phase, after the react...

Embodiment 1

[0034] (1) Add 2 L of ethanol to a 5 L three-necked flask, then add 2,4-dichloropyrimidine (100 g, 0.67 mol), add cyclopentylamine (257 g, 3 mol) while stirring, and stir at room temperature for 3.5 hours. Add 4 L of water, continue stirring for 50 minutes, filter, collect the solid, and recrystallize with a 1:3 mixture of ethyl acetate and petroleum ether to obtain solid A (123 g, 89%). The main reaction equation of this step is:

[0035]

[0036] (2) Add 3L of dichloroethane to a 5L three-necked flask, add solid A (120g, 0.6mol) and 2,2-diacetylacetic acid (86g, 0.6mol) respectively, stir for 10 minutes and then add dicyclohexyl Carbodiimide (127g, 0.57mol), stirred at a constant temperature of 45°C for 4.5 hours, cooled to 10°C and continued stirring for 2 minutes, filtered. The filtrate was concentrated, 3L of water was added, and stirred for 1 hour. The solid was collected by filtration and recrystallized from a 1:2 mixture of ethyl acetate and petroleum ether to obt...

Embodiment 2

[0045] (1) Add 2 L of ethanol to a 5 L three-necked flask, then add 2,4-dichloropyrimidine (100 g, 0.67 mol), add cyclopentylamine (257 g, 3 mol) while stirring, and stir at room temperature for 5 hours. Add 4 L of water, continue stirring for 1 hour, filter, collect the solid, and recrystallize with a 1:4 mixture of ethyl acetate and petroleum ether to obtain solid A (119 g, 90%).

[0046] (2) Add 3L of dichloroethane into a 5L three-necked flask, add solid A (110g, 0.55mol) and 2,2-diacetylacetic acid (79g, 0.55mol) respectively, stir for 10 minutes and then add dicyclohexyl Carbodiimide (117 g, 0.57 mol) was stirred at a constant temperature of 50° C. for 4 hours, cooled to 10° C. and stirred for 3 minutes, and filtered. The filtrate was concentrated, 3L of water was added, and stirred for 1 hour. The solid was collected by filtration and recrystallized from a 1:1 mixture of ethyl acetate and petroleum ether to obtain solid B (155 g, 87%).

[0047] (3) Add 2L of toluene to ...

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Abstract

The present invention is a palbociclib preparation method, a solid A is obtained by substitution reaction of 2, 4-dichloro pyrimidine and cyclopentyl amine, a solid B is obtained by dehydration reaction of 2,2-diacetyl-acetic acid and the solid A, a solid C is obtained by cyclization reaction of the solid B, a solid D is obtained by reaction of the solid C and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, and palbociclib is obtained by salt-forming reaction of the solid D and ethylenehydrinsulfonic acid, the palbociclib preparation method comprises five steps, compared with the prior art, the steps are less, and comprise no step restricting enlargement of the process, the raw material is cheap, the use of expensive palladium reagents is avoided, manufacturing cost is lower; at the same time, use of bromine causing greater environmental pollution impact is avoided, and the preparation method meets the requirements of green and sustainable development.

Description

technical field [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for preparing Palbociclib with relatively low cost and relatively environment-friendly reagents. Background technique [0002] Palbociclib (transliterated as "palbociclib", "palbociclib", etc.) is a class of cell cycle-dependent kinase (CDK4 / 6) inhibitors developed by Pfizer. The molecular structural formula of one of the compounds is as follows: [0003] [0004] Palbociclib first entered people's field of vision at the 2012 San Antonio Breast Cancer Conference (SABCS), and once released, it attracted widespread attention from the industry. In April 2013, it was granted the "Breakthrough Therapy" qualification by the US FDA. 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 fact...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 柴腾
Owner 上海百奇医药科技有限公司
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