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Palbociclib and preparation method of intermediate of palbociclib

A compound and equivalent technology, applied in the preparation of tert-butyl 4-{6-[amino]-3-pyridyl}-1-piperazinecarboxylate, palbociclib and its new key intermediates, The field of preparation of the drug palbociclib and its intermediates can solve the problems of difficult removal of impurities, low product purity, and difficult purification, and achieve the effects of simple operation, control of impurity content, and easy availability of raw materials

Inactive Publication Date: 2017-06-13
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, in the preparation method of palbociclib reported in the above literature, it is easy to introduce impurity A and impurity B (structure as follows) in the finished product, thereby causing low product purity, and these impurities are difficult to remove from the finished product, making purification difficult

Method used

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  • Palbociclib and preparation method of intermediate of palbociclib
  • Palbociclib and preparation method of intermediate of palbociclib
  • Palbociclib and preparation method of intermediate of palbociclib

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Example 1: 4-{6-[(6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2 ,3-D]pyrimidin-2-yl)amino]-3-pyridyl}-1-piperazinecarboxylate tert-butyl ester (synthesis of compound 2) was prepared by referring to the method in patent WO2005 / 005426

[0038] Under nitrogen atmosphere, mix 4.7L n-butanol, 768gXT46-A, 275mL DIPEA and 395g vinyl butyl ether, stir nitrogen replacement 3 times, add 22g catalyst Pd(dppf)2Cl2, and nitrogen replacement 3 times again, then It was heated to 95° C. under the protection of nitrogen, and the stirring reaction was continued at this temperature for 20 hours. The resulting light red slurry was diluted with 4 L of octane, cooled to 5°C, added with 1 L of saturated potassium carbonate aqueous solution, filtered and washed with 500 mL of octane. After hours at 45°C, 664 g of off-white solid (compound 2) were obtained, yield: 83%.

[0039] It was confirmed to be compound 2 by detection.

Embodiment 2

[0040] Example 2: Intermediate 4-{6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-D]pyrimidine -2-yl)amino]-3-pyridyl}-1-piperazinecarboxylic acid tert-butyl ester (preparation of compound 1)

[0041] Add 50.00 mL of methanol and 3.32 g of compound 2 into a 100 mL three-necked flask, cool down to 0-10° C. in an ice-water bath, and add 20 mL of 1N phosphoric acid dropwise. After the addition was completed, the temperature was controlled at 25°C and the reaction was stirred for 16 hours. The reaction solution was filtered and rinsed with methanol. Dissolve the solid in 50 mL of methanol and heat to reflux until the solid dissolves. After stirring for another 0.5 hour, cool to room temperature, filter, and rinse with methanol. The solid was dried in a vacuum oven at 40° C. for 12 hours to obtain 2.41 g of a yellow solid (compound 1), yield: 80%.

[0042] It was confirmed to be compound 1 by detection.

[0043] 1 H-NMR (CD 3 Cl):1.49(9H,s);1.69(2H,m);1.90(2H,...

Embodiment 3

[0048] Add 50.00 mL of methanol and 3.32 g of compound 2 into a 100 mL three-necked flask, cool down to 0-10° C. in an ice-water bath, and add 35 mL of 0.5 N sulfuric acid dropwise. After the addition, the temperature was controlled to 25°C and the reaction was stirred for 16 hours. The reaction solution was filtered and rinsed with methanol. Dry in a vacuum oven at 40° C. for 12 hours to obtain 2.63 g of a yellow solid (compound 1), yield: 87%.

[0049] It was confirmed to be compound 1 by detection.

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Abstract

The invention provides palbociclib and a preparation method of an intermediate of palbociclib. The preparation method comprises the following steps: converting a vinyl ether group into a carbonyl by a 4-{6-[(6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydroppyridino-[2, 3-D] pyrimidine-2-yl) amino]-3-pyridyl}-1-piperazine carboxylic acid tert-butyl ester compound 2 under an acidic condition, so as to obtain a key intermediate compound 1; further recrystallizing the compound 1, so as to obtain a purified product; removing t-butyloxycarboryl (Boc) in the compound 1 under an acidic condition, so as to obtain palbociclib. According to the method provided by the invention, impurities can be effectively removed, the content of the impurities is controlled, and the purity of an impurity A and the purity of an impurity B in a finished product are both less than 0.1%, so that the purity of the product is high. The preparation method has the advantages that the steps are less, raw materials are easily obtained, and the operation is simple and convenient, therefore, the preparation method is suitable for industrial product and has comparatively great application value.

Description

technical field [0001] The present invention relates to the preparation of medicines, in particular to the preparation method of palbociclib and its intermediates, especially to palbociclib and its new key intermediate 4-{6-[(6-acetyl-8- Cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-D]pyrimidin-2-yl)amino]-3-pyridyl}-1-piperazinecarboxylic acid Preparation of tert-butyl esters. Background technique [0002] Palbociclib (Palbociclib) is a selective inhibitor of protein kinases CDK4 and CDK6 developed by Pfizer, and is a small molecule inhibitor that can regulate cell cycle regulation. Approved by the FDA on February 3, 2015 for the treatment of advanced / metastatic breast cancer in postmenopausal women. Its chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-8H-pyrido[2, 3-D] pyrimidin-7-one. The structure is shown in the following formula compound 3: [0003] [0004] US Patent No. 6,936,612 discloses the structure of palbocic...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘学军许振民陈春根陈晓冬
Owner SHANGHAI SUNTECH PHARMA
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