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Palbociclib intermediate synthesizing method

A synthesis method and a technology for intermediates, which are applied in the field of palbociclib intermediates, can solve the problems of complex steps, low product yield, unsuitable for industrialized production and the like, and achieve simple operation, high product yield and easy availability of raw materials. Effect

Active Publication Date: 2018-04-13
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the step of the back step reaction of this reaction is complicated, and the yield of product is low (total yield is less than 60%), is not suitable for suitability for suitability for industrialized production

Method used

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  • Palbociclib intermediate synthesizing method
  • Palbociclib intermediate synthesizing method

Examples

Experimental program
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Effect test

Embodiment 1

[0028] 1) Preparation of Compound II

[0029] 341.7g of compound I was dissolved in 1800g of tetrahydrofuran twice, that is, the first time was 150g of compound I+800g of tetrahydrofuran, and the second time was 191.7g of compound I+1000g of tetrahydrofuran.

[0030] Add 1800g of tetrahydrofuran to the reaction flask, put 45g of magnesium chips, and add 1 iodine tablet. Under the protection of nitrogen, add 150g of compound I in tetrahydrofuran solution dropwise into the Grignard flask, raise the temperature to 30°C, and remove the remaining compound after the reaction is initiated. The tetrahydrofuran solution of I was added dropwise into the Grignard reaction flask at a controlled temperature of 25-32° C., and continued to stir at this temperature for 2 hours after the drop was completed. Control the temperature at -10-0°C, add 165g of trimethyl borate dropwise into the Grignard reaction flask, and react for 30 minutes after the dropwise addition, control the material at 0-1...

Embodiment 2

[0035] 1) Preparation of Compound II

[0036] 341.7g of compound I was dissolved in 1500g of tetrahydrofuran twice, that is, the first time was 150g of compound I+600g of tetrahydrofuran, and the second time was 191.7g of compound I+900g of tetrahydrofuran.

[0037] Add 1500g of tetrahydrofuran into the reaction flask, put 42g of magnesium chips, add 1 iodine, add 150g of compound I tetrahydrofuran solution into the Grignard flask dropwise under the protection of nitrogen, raise the temperature to 30°C, and remove the remaining compound after the reaction is initiated. The tetrahydrofuran solution of I was added dropwise into the Grignard reaction flask at a controlled temperature of 25-32° C., and stirring was continued at this temperature for 2.5 hours after the drop was completed. Control the temperature at -10-0°C, add 163g of trimethyl borate dropwise into the Grignard reaction flask, and react for 35 minutes after the dropwise addition, control the material at 0-10°C, ad...

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Abstract

The invention discloses a palbociclib intermediate synthesizing method. According to the method, 2,4-dichloro-5-bromopyrimidine is utilized as a starting raw material; firstly, 5-position bromine is replaced by Grignard reaction; then, the starting material reacts with a boryl replacing reagent to generate aryl boric acid; then, the starting raw material couples with methyl 3-iodo crotonate through Suzuki reaction; then, pyrimidine ring subjects substitution reaction with cyclopentylamine under existence of organic alkali; finally, flupirtine exchange ring formation is performed to obtain palbociclib intermediate 2-chloro-8-cyclopentyl-5methyl-8H-pyrido(2,3-d)pyrimidine-7-one. Noble metal palladium on carbon in the palbociclib intermediate synthesizing method disclosed by the invention isfiltered while being heat to be recycled. The palbociclib intermediate synthesizing method has the advantages of simpleness in operation, easiness in obtaining raw materials, high product yield and suitability for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, an intermediate of palbociclib. Background technique [0002] Palbociclib (palbociclib) is the first CDK inhibitor successfully developed and marketed, combined with letrozole as an initial endocrine therapy-based regimen for the treatment of ER+ / HER2- postmenopausal advanced breast cancer. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon demonstration and description of clinical benefit in confirmatory trials. Pfizer Inc has been approved for marketing in 2015, which is a boon for advanced metastatic breast cancer and will have broad market prospects. [0003] 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one is a key intermediate for the synthesis of palbociclib, and its currently commonly used synthetic method i...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 吕红超朱义胜李彪
Owner SHANDONG BOYUAN PHARM CO LTD
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