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Low-cost preparation method of palbociclib

A low-cost, high-compound technology, applied in the field of low-cost preparation of palbociclib, can solve the problems of rising cost of palbociclib, and achieve the effects of good quality, high yield, and simple post-treatment

Active Publication Date: 2021-11-23
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] But Route 2 uses [bis(diphenylphosphinoferrocene)]palladium dichloride (Pd(dppf) 2 Cl 2 ), its consumption is about 3% of compound 4, along with the rising day by day of palladium price, cause the continuous rising of palbociclib cost, according to the document process cost accounting, the price of palladium has become the main cost of this process, far exceeds raw material cost

Method used

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  • Low-cost preparation method of palbociclib
  • Low-cost preparation method of palbociclib
  • Low-cost preparation method of palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: 4-(6-((6-bromo-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-D]pyrimidine-2- Base) amino)-3-pyridyl)-1-piperazinecarboxylate tert-butyl ester (compound of formula 4) laboratory preparation

[0067] In a 5L reaction flask, add 167g (0.6mol) tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, 1600ml toluene, protect with nitrogen, and add 750ml 1mol / L sodium hexamethyldisilazide tetrahydrofuran solution, keep stirring at 20-30°C for 30 minutes. Disperse 171g (0.5mol) of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one in 600ml of toluene, slowly pour After adding the reaction solution, keep it at 30°C for 4 hours, TLC detects that 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one disappears It is the end point of the reaction (developing solvent: ethyl acetate / n-hexane=1 / 4). After the reaction is complete, slowly add a mixture of 340ml acetone and 170ml water, stir the mixture overnight, gradually pr...

Embodiment 2

[0068] Example 2: 4-(6-((6-bromo-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-D]pyrimidine-2- Base) amino)-3-pyridyl)-1-piperazinecarboxylate tert-butyl ester (compound of formula 4) laboratory preparation

[0069] In a 5L reaction flask, add 167g (0.6mol) tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, 1600ml toluene, protect with nitrogen, add dropwise 750ml1mol / L tetrahydrofuran solution of lithium hexamethyldisilazide, keep stirring at 20-30°C for 30 minutes. Disperse 171g (0.5mol) of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one in 600ml of toluene, slowly pour After adding the reaction solution, keep it at 30°C for 4 hours, TLC detects that 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one disappears It is the end point of the reaction (developing solvent: ethyl acetate / n-hexane=1 / 4). After the reaction is complete, slowly add a mixture of 340ml acetone and 170ml water, stir the mixture overnight, grad...

Embodiment 3

[0070] Example 3: 4-(6-((6-bromo-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyrido[2,3-D]pyrimidine-2- Base) amino)-3-pyridyl)-1-piperazinecarboxylic acid tert-butyl ester (formula 4 compound) industrial preparation

[0071] In a 2000L reactor, add 725kg of toluene, 84kg of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, protect it with nitrogen, and add 375L of 1mol / L hexa The tetrahydrofuran solution of sodium methyldisilazide was kept at 20-30° C. and stirred for 30 minutes. Disperse 86kg of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one in 270kg of toluene, slowly pour into the reaction solution, add After completion, keep the reaction at 30°C for 4h, TLC detects that 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-D]pyrimidin-7(8H)-one disappears as the end point of the reaction ( Developing solvent: ethyl acetate / n-hexane=1 / 4). After the reaction is complete, slowly add a mixture of 130kg acetone and 85kg water, stir the mixture ove...

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Abstract

The invention discloses a low-cost preparation method of palbociclib. The method comprises the steps: taking 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester as an initial raw material, taking large-steric-hindrance alkali as an acid-binding agent, carrying out nucleophilic substitution reaction with a compound represented by a formula 3, carrying out post-treatment, quenching and dealkalizing to obtain a large-particle compound represented by a formula 4; then taking n-butyl alcohol and water as solvents, taking diisopropylethylamine as an acid-binding agent and a protective agent, and under the action of a composite catalyst palladium chloride and cuprous iodide, carrying out a Herk alkylation reaction with n-butyl vinyl ether; and under the protection of an organic alkali, refining with an ester solvent to obtain a high-purity compound represented by a formula 5 with high yield, and hydrolyzing the compound represented by the formula 5 through a mixed solvent of n-butyl alcohol, anisole and water under an acidic condition to obtain a finished product of palbociclib. The method greatly reduces the usage amount of a palladium catalyst, and is simple and convenient to operate, less in environmental pollution, high in yield, high in product quality and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a low-cost preparation method of palbociclib. Background technique [0002] Palbociclib (palbociclib) is a new drug for the treatment of breast cancer developed by Pfizer of the United States. The product name is IBRANCE. It is an oral cyclin-dependent kinase (CDKs) 4 and 6 inhibitor. Cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. CDKs4 and 6 are key regulators of the cell cycle, which can trigger cell cycle progression. The indication of IBRANCE in the United States is combined with letrozole for the treatment of estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+ / HER2-) postmenopausal patients with advanced breast cancer, as an initial endocrine therapy-based regimen Treatment of metastatic disease. [0003] Palbociclib, Chinese name: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H- Pyrido[2...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 李太同苏曼张庆涛刘忠华呼修康
Owner SHANDONG BOYUAN PHARM CO LTD
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