A kind of synthetic method of palbociclib intermediate

A synthetic method and intermediate technology, applied in the field of palbociclib intermediates, can solve the problems of complex steps, unsuitability for industrial production, and low product yield, and achieve simple operation, high product yield, and easy-to-obtain raw materials Effect

Active Publication Date: 2019-11-12
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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  • A kind of synthetic method of palbociclib intermediate
  • A kind of synthetic method of palbociclib intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1) Preparation of compound II

[0029] Dissolve 341.7 g of compound I into 1800 g of tetrahydrofuran in two steps, that is, the first time is 150 g of compound I+800 g of tetrahydrofuran, and the second is 191.7 g of compound I+1000 g of tetrahydrofuran.

[0030] 1800g of tetrahydrofuran was added to the reaction flask, 45g of magnesium scraps were put in, 1 iodine was added, 150g of the tetrahydrofuran solution of compound I was added dropwise to the Grignard flask under nitrogen protection, the temperature was raised to 30°C, and the remaining compounds were added after the reaction was initiated. The tetrahydrofuran solution of I was added dropwise to the Grignard reaction flask at a controlled temperature of 25-32°C, and continued stirring at this temperature for 2 hours after dropping. Control the temperature to -10-0°C, add 165g of trimethyl borate dropwise to the Grignard reaction flask, complete the dropwise addition and react for 30 minutes, control the materia...

Embodiment 2

[0035] 1) Preparation of compound II

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

[0037] 1500g of tetrahydrofuran was added to the reaction flask, 42g of magnesium scraps were put in, 1 iodine was added, 150g of the tetrahydrofuran solution of compound I was added dropwise to the Grignard flask under nitrogen protection, the temperature was raised to 30°C, and the remaining compounds were added after the reaction was initiated. The tetrahydrofuran solution of I was added dropwise to the Grignard reaction flask at a temperature of 25-32°C, and continued stirring at this temperature for 2.5 hours after dropping. Control the temperature to -10-0°C, add 163g of trimethyl borate into the Grignard reaction flask, dropwise and react for 35 minutes, control the material to 0-10°C, add it to 12kg o...

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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 palbociclib intermediate-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. Background technique [0002] 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, which was approved for marketing in 2015, 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 in the synthesis of palbociclib, and its currently commonly used synthetic method is The method disclosed in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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