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Method for preparing CDK46 kinase inhibitor Palbociclib

A technology of kinase inhibition and cyclopentyl group, applied in the field of drug synthesis, can solve the problems of long reaction time, low overall yield, unfavorable health of workers, etc., and achieve the effects of mild reaction conditions and high overall yield

Active Publication Date: 2016-10-12
刘淑兰 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method provides a new way for preparing palbociclib, the overall yield of this method is still low, which is mainly due to the third step and N-[5-(1-piperazinyl)-2-pyridine Base] guanidine condensation yield is low, reaction time is long, and this method dehydrogenation reaction has used hypertoxic sodium selenate in addition, is not suitable for large-scale production, and is unfavorable for the health of laborers

Method used

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  • Method for preparing CDK46 kinase inhibitor Palbociclib
  • Method for preparing CDK46 kinase inhibitor Palbociclib
  • Method for preparing CDK46 kinase inhibitor Palbociclib

Examples

Experimental program
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Effect test

Embodiment 1

[0030] A method for preparing CDK46 kinase inhibitor palbociclib, the method comprising the following steps:

[0031] 1) Under nitrogen protection, the compound N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6- Bromopyrido[2,3-d]pyrimidin-7(8H)-one 48.4g (100mmol) in the presence of cuprous bromide 5.7g (40mmol) and potassium tert-butoxide 28g (250mmol) with trimethylsilyl Acetylene 16.7g (170mmol) was reacted in THF at 55°C for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the compound N-cyclopentyl-5-methanone represented by formula (II) Base-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one 34.4g, yield It is 80.2%, and the purity is 99.90% (HPLC area normalization method).

[0032] 2) The compound N-cyclopentyl-5-methyl-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl) represented by the formula (II) obtained in step ...

Embodiment 2

[0035] A method for preparing CDK46 kinase inhibitor palbociclib, the method comprising the following steps:

[0036] 1) Under nitrogen protection, the compound N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6- Bromopyrido[2,3-d]pyrimidin-7(8H)-one 48.4g (100mmol) in the presence of cuprous bromide 5.7g (40mmol) and potassium tert-butoxide 28g (200mmol) with trimethylsilyl Acetylene 17.7g (180mmol) was reacted in THF at 65°C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the compound N-cyclopentyl-5-methanone represented by formula (II) Base-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one 34.2g, yield It is 79.7%, and the purity is 99.90% (HPLC area normalization method).

[0037] 2) The compound N-cyclopentyl-5-methyl-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl) represented by the formula (II) obtained in step ...

Embodiment 3

[0039] A method for preparing CDK46 kinase inhibitor palbociclib, the method comprising the following steps:

[0040]1) Under nitrogen protection, the compound N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6- Bromopyrido[2,3-d]pyrimidin-7(8H)-one 48.4g (100mmol) in the presence of cuprous bromide 7.2g (50mmol) and potassium tert-butoxide 33.7g (300mmol) with trimethylsilane 14.7g (150mmol) of acetylene was reacted in THF at 60°C for 3 hours. After the reaction, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the compound N-cyclopentyl-5- Methyl-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one 33.9g, received The yield was 78.9%, and the purity was 99.90% (HPLC area normalization method).

[0041] 2) The compound N-cyclopentyl-5-methyl-6-ethynyl-2-[[5-(1-piperazinyl)-2-pyridyl) represented by the formula (II) obtained in step 1) ]Amino]pyrido[2,3-d]pyrimidi...

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Abstract

The invention discloses a method for preparing the CDK46 kinase inhibitor Palbociclib. The method includes the following steps that 1, the compound N-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-6- bromopyridine -[2,3-d]-pyrimidine-7(8H)-ketone shown in the formula (I) reacts with trimethylsilylacetylene in the presence of cuprous bromide and potassium tert-butoxide to generate the compound N-cyclopentyl-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyridino-[2,3-d] pyrimidine-7(8H)-ketone shown in the formula (II); 2, the compound N-cyclopentyl-5-methyl-6-acetenyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyridino-[2,3-d] pyrimidine-7(8H)-ketone shown in the formula (II) and obtained in the step 1 is hydrolyzed in an acid water solution to obtain Palbociclib. By means of the method, a new way for preparing Palbociclib is developed, conditions are mild, and the yield is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing CDK46 kinase inhibitor palbociclib. Background technique [0002] Palbociclib, the world's first CDK4 / 6 kinase inhibitor developed by Pfizer, is used for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer first-line treatment. The chemical name of palbociclib is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2, 3-d] pyrimidin-7(8H)-one, the specific structure is as follows: [0003] [0004] WO2008032157 discloses a synthetic method of palbociclib, which uses 2,4-dichloro-5-bromo and cyclopentylamine as starting materials to obtain the target product through seven steps. The specific synthetic route is as follows: [0005] [0006] This synthesis method route is long, and wherein the 5th step reaction exists the competitive reaction of Cl and B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王传秀
Owner 刘淑兰
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