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Preparation method for intermediate of breast cancer treatment drug palbociclib

A technology for breast cancer and intermediates, applied in the field of medicine, can solve the problems of high isomer content, yield of only 80%, and undisclosed product purity, etc., and achieve the effect of high purity and simple post-processing

Inactive Publication Date: 2019-05-07
陈欣
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In CN107759596A, dichloromethane is used as the solvent, and the molar ratio of 5-bromo-2,4-dichloropyrimidine and cyclopentylamine is 1:1, and the reaction is carried out at 0-5°C for 2 hours, and after the reaction is completed, it is extracted and concentrated; the concentrate High-purity product was obtained through column chromatography, but the yield was only 80%
In J.Med.Chem.2014,57,3430-3449, N,N-diisopropylethylamine (DIPEA) is used as the base, dioxane is used as the reaction solvent, and 5-bromo-2,4-dichloro Under the condition that the molar ratio of pyrimidine to cyclopentylamine is 1:1.2, react at room temperature for 6 hours, extract and concentrate to obtain the crude product, and the yield is 100%. is 66%, the isomer content should be higher

Method used

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  • Preparation method for intermediate of breast cancer treatment drug palbociclib
  • Preparation method for intermediate of breast cancer treatment drug palbociclib

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 5-bromo-2,4-dichloropyrimidine (10mmol, 2.27g), metal ion additive 0.5mmol, dioxane 15ml into the parallel synthesizer, stir and disperse evenly, then add cyclopentylamine (12mmol, 1.02g), stirred at room temperature after the dropwise addition, and stopped stirring when the conversion rate of the substrate 5-bromo-2,4-dichloropyrimidine was detected by HPLC no longer changed, and the substrate 5-bromo-2,4-dichloropyrimidine was counted The conversion rate of chloropyrimidine and its product 5-bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine and its isomer impurity (5-bromo-4-chloro-N-cyclopentyl-2-pyrimidinamine, Abbreviated as the ratio of ISO), the results are shown in Table 1:

[0028] The influence of table 1 metal ion additive on reaction

[0029] additive

Conversion rate / %

Product / ISO

NA

96.5

84 / 13

Fe(NO 3 ) 3

93.8

82 / 12

Cu(NO 3 ) 2

98.6

86 / 12

Ni(NO 3 ) 2

90.4

78 / 12

Co(NO 3...

Embodiment 2

[0033] The present invention has further studied the influence of cobalt salt anion species and cobalt salt valence state on reaction, method is as follows:

[0034]Add 5-bromo-2,4-dichloropyrimidine (10mmol, 2.27g), cobalt salt 0.5mmol, dioxane 15ml into the parallel synthesizer, stir and disperse evenly, then add cyclopentylamine (12mmol, 1.02 g), stir at room temperature after the dropwise addition, stop stirring when the conversion rate of the substrate 5-bromo-2,4-dichloropyrimidine is no longer changed by HPLC, and count the substrate 5-bromo-2,4-dichloropyrimidine in the reaction system Conversion rate of pyrimidine and its product 5-bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine and its isomer impurity (5-bromo-4-chloro-N-cyclopentyl-2-pyrimidinamine, abbreviated is the ratio of ISO), the results are shown in Table 2:

[0035] Table 2 The impact of the cobalt salt type on the reaction

[0036] additive

[0037] The experimental results show that the trivalen...

Embodiment 3

[0039] Selected CoSO 4 As an additive, it is used to improve the chemical reaction selectivity of the 4-position chlorine in cyclopentylamine and 5-bromo-2,4-dichloropyrimidine. In order to improve the conversion rate of substrate 5-bromo-2,4-dichloropyrimidine, combined with the present According to reports in the prior art J.Med.Chem.2014,57,3430-3449, the present invention adds an organic base to improve the conversion rate of the substrate, and the method is as follows:

[0040] Add 5-bromo-2,4-dichloropyrimidine (10mmol, 2.27g), CoSO 4 ·7H 2 O 0.5mmol, organic base 10mmol, dioxane 15ml were stirred and dispersed evenly, then cyclopentylamine (12mmol, 1.02g) was added dropwise at room temperature, stirred at room temperature after the addition, and HPLC detected substrate 5-bromo-2, Stop stirring when the conversion rate of 4-dichloropyrimidine no longer changes, and count the conversion rate of substrate 5-bromo-2,4-dichloropyrimidine and its product 5-bromo-2-chloro-N-...

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to a preparation method for an intermediate of breast cancer treatment drug palbociclib. In the presence of an organicsolvent, the method provided by the invention adopts a divalent cobalt salt as the catalyst to catalyze the selective reaction of cyclopentylamine and 5-bromo-2, 4-dichloropyrimidine to produce the intermediate 5-bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine of the of breast cancer treatment drug palbociclib. The method improves the chemical reaction selectivity of cyclopentylamine and the 4-position chloro in 5-bromo-2, 4-dichloropyrimidine, the proportion of the product and the 2-position chloro for generation of isomer impurities is increased to 99:0.5. The product purity is improved, thepost-treatment is simple, and column chromatography isolation is not needed.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an intermediate of palbociclib, a drug for treating breast cancer. Background technique [0002] Palbociclib is a new type of highly effective oral anticancer drug developed by Pfizer. It is the world's first marketed CDK4 / 6 kinase inhibitor for the first-line treatment of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. The global breast cancer drug market can reach tens of billions of dollars each year, and palbociclib has a broad market prospect. [0003] 5-bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine is a key intermediate in the synthesis of Palbociclib, which is composed of 5-bromo-2,4-dichloropyrimidine and cyclopentylamine in It is condensed under alkaline conditions, and the reaction equation is shown in Scheme 1: [0004] [0005] The main difficulty of this ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
Inventor 刘瑶陈欣陈西成
Owner 陈欣
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