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Preparation method for selective kinases inhibitor Palbociclib

The technology of a kinase inhibitor and a reducing agent is applied in the field of pharmaceutical preparation, which can solve the problems of difficulty in purchasing raw material compounds and intermediate products, and achieve the effects of low cost, simple reaction mechanism and stable yield.

Active Publication Date: 2015-12-16
JIANGSU ZHONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention provides a new method for preparing Palbociclib, which solves the problem that raw material compounds and intermediate products are difficult to purchase in the prior art

Method used

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  • Preparation method for selective kinases inhibitor Palbociclib
  • Preparation method for selective kinases inhibitor Palbociclib
  • Preparation method for selective kinases inhibitor Palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of Intermediate 2

[0027] Add 20.8g (0.1mol) of compound I and 208mL of tetrahydrofuran into a 1L reaction flask. After stirring to dissolve, the system cools down to -78°C. After the temperature stabilizes, add 62.5mL of n-butyllithium-n-hexane (concentration: 15%) dropwise. . After dropping, keep stirring at this temperature for 10 min, and at the same time add dropwise a solution of 12.9 g (0.125 mol) of N-methoxy-N-methylacetamide and 129 mL of tetrahydrofuran. After dropping, stir at -78°C for 1 hour, then the system naturally warms up to 0°C, add 100mL of saturated ammonium chloride solution, stir for 30min, extract with 3X300mL ethyl acetate, combine the organic layer, wash the organic layer with 3X300mL saturated salt water, and anhydrous magnesium sulfate After drying, filtering and concentrating, 15.8 g of crude yellow solid was obtained, yield: 91.9%, which was directly used in the next step.

[0028] Synthesis of intermediate 3

[0029] 10.3g (...

Embodiment 2

[0039] Synthesis of Intermediate 2

[0040] Add 20.8g (0.1mol) of compound I and 208mL tetrahydrofuran into a 1L reaction flask. After stirring to dissolve, the system cools down to -78°C. After the temperature stabilizes, 11.2g (0.1mol) of potassium tert-butoxide is added in batches. After the addition, keep stirring at this temperature for 30 min, and at the same time add dropwise a solution of 12.9 g (0.125 mol) of N-methoxy-N-methylacetamide and 129 mL of tetrahydrofuran. After dropping, stir at -78°C for 1 hour, then the system naturally warms up to -10°C, add 20mL of water dropwise, then slowly drop in 20mL of 1N hydrochloric acid, add 40mL of saturated sodium bicarbonate solution, stir for 30min, then use 3X300mL ethyl acetate Extract and combine the organic layers. The organic layer was washed with 3×300 mL saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 14.5 g of yellow solid crude product, yield: 84.3%, which was directly...

Embodiment 3

[0052] Synthesis of Intermediate 2

[0053] 20.8g (0.1mol) of compound I and 208mL of tetrahydrofuran were added to a 1L reaction flask, stirred to dissolve, and then 5.4g (0.1mol) of sodium methoxide was added, and the temperature of the system was raised to 60°C. After the addition, keep stirring at this temperature for 1.5 h, and at the same time add dropwise a solution of 12.9 g (0.125 mol) of N-methoxy-N-methylacetamide and 129 mL of tetrahydrofuran. After dropping, stir at 60°C for 2 hours and monitor the system. The reaction of the raw materials is complete. Add 200mL of water and 200mL of ethyl acetate after distilling off the solvent, beat for 10min and then separate into layers. Concentrate to obtain 12.2 g of yellow solid crude product, yield: 70.9%, which is directly used in the next step.

[0054] Synthesis of intermediate 3

[0055] 10.3g (0.06mol) of intermediate 2, 8.6g (0.066mol) of ethyl acetoacetate, 16.2g (0.3mol) of sodium methoxide and 103mL of methanol...

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Abstract

The invention provides a novel preparation method for a selective kinases inhibitor Palbociclib for cyclin-dependent kinases CDK4 and CDK6, and belongs to the technical field of medicament preparation. The preparation method comprises taking 4-amino-5-bromo-2-chloropyrimidine as an initial raw material, performing acetylation with N-methoxy-N-methylacetamide to obtain an intermediate 2, performing Friedlaender reaction on the intermediate and a raw material ethyl acetoacetate to obtain an intermediate 3, and performing amino substitution on the intermediate 3 and a halogenated cyclopentane to obtain an intermediate 4; performing substitution reaction on a raw material 5-bromo-2-nitropyridine and a raw material tert-butyl 1-piperazinecarboxylate to obtain an intermediate 5, and reducing the intermediate 5 to obtain an intermediate 6; performing substitution reaction on the intermediate 4 and the intermediate 6, and performing deprotection to obtain the target product 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one with the yield of 45% or more. A brand-new route is employed, the reaction raw materials are cheap and easy to obtain, reaction conditions are mild, noble metal catalysts are avoided, and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of a compound Palbociclib which selectively inhibits cyclin-dependent kinases CDK4 and CDK6. technical background [0002] Palbociclib (officially known as PD-0332991) was the result of a project initiated by researchers at Parke-Davis, which was acquired by Pfizer. It first entered people's field of vision at the 2012 San Antonio Breast Cancer Conference (SABCS), and once released, it attracted widespread attention from the industry. Palbociclib is an oral inhibitor of cyclin-dependent kinases CDK4 and CDK6, which mainly regulates the cell cycle and inhibits the activity of CDK4 / 6 to prevent cells from G1 phase to S phase and inhibit DNA synthesis. The results of the study showed that Palbociclib combined with letrozole can increase the median disease-free survival (PFS) of breast cancer patients to 26.1 months, while the PFS of let...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 韩小军黄双钱刚刘力萍绳则翠
Owner JIANGSU ZHONGBANG PHARMA
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