Preparation method of intermediate of tyrosine kinase inhibitor

The technology of tyrosine kinase and inhibitor is applied in the field of preparation of intermediates, which can solve the problems of many impurities, difficult purification and low purity of products, and achieve the effects of simplifying post-processing, improving purity and yield, and reducing costs.

Active Publication Date: 2018-11-02
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The problem to be solved by the present invention is to provide a preparation of intermediate I in order to overcome the defects of expensive catalysts, expensive pressure equipment, or products with many impurities, low purity, and difficult purification in the existing methods for preparing compound I. method

Method used

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  • Preparation method of intermediate of tyrosine kinase inhibitor
  • Preparation method of intermediate of tyrosine kinase inhibitor
  • Preparation method of intermediate of tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Put 3.40g (0.01510mol) of compound II in a 250ml four-necked flask, and add a mixed solution of ethyl acetate and water (34ml / 20ml). At room temperature, add 2.10g (0.03925mol, 2.6eq) of ammonium chloride and 3.67g (0.06553mol, 4.34eq) of reduced iron powder to the stirred reaction flask, then heat the reaction system to 40°C and stir for 3h . The progress of the reaction was checked by TLC. After the substrate is completely reacted, the excess iron powder is filtered out. The filter cake was rinsed three times with 15 ml of ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, and concentrated under reduced pressure to obtain 2.53 g of Compound I, yield: 86%, HPLC purity: 99.7%.

Embodiment 2

[0025] Put 3.40g of compound II in a 250ml four-necked flask, and add a mixed solution of ethyl acetate and water (34ml / 20ml). At room temperature, 3.55 g (0.06644 mol, 4.4 eq) of ammonium chloride and 5.92 g (0.1057 mol, 7 eq) of reduced iron powder were sequentially added to the stirred reaction flask, and then the reaction system was heated to 20° C. and stirred for 4 hours. The progress of the reaction was checked by TLC. After the substrate is completely reacted, the excess iron powder is filtered out. The filter cake was rinsed three times with 15 ml of ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, and concentrated under reduced pressure to obtain 2.79 g of compound I, yield: 94.7%, HPLC purity: 99.2%.

Embodiment 3

[0027] Put 3.40g (0.01510mol) of compound II in a 250ml four-necked flask, and add a mixed solution of ethyl acetate and water (34ml / 20ml). At room temperature, add 1.61g (0.0302mol, 2.0eq) of ammonium chloride and 2.54g (0.0453mol, 3.0eq) of reduced iron powder to the stirred reaction flask, then heat the reaction system to 30°C and stir for 3h . The progress of the reaction was checked by TLC. After the substrate is completely reacted, the excess iron powder is filtered out. The filter cake was rinsed three times with 15 ml of ethyl acetate. The organic layer was separated from the filtrate, washed with saturated brine, and concentrated under reduced pressure to obtain 2.65 g of Compound I, yield: 90%, HPLC purity: 99.0%.

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Abstract

The invention discloses a preparation method of an intermediate of a tyrosine kinase inhibitor. The preparation method of the intermediate of the tyrosine kinase inhibitor comprises the following steps of allowing a compound II and a compound I to give the following reaction as shown in the specification in ethyl acetate and water by the action of ammonium chloride and iron powder. A product of the method is high in productivity and purity, and the method is simple in post-treatment and suitable for industrial production.

Description

Technical field [0001] The invention relates to a method for preparing an intermediate of a tyrosine kinase inhibitor. Background technique [0002] Tivozanib hydrochloride monohydrate (AV-951) is an oral VEGF receptor tyrosine kinase inhibitor designed to treat Refractory Advanced RCC. It was discovered by Kirin Co., Ltd., and its European and American markets are co-operated by AVEO Pharmace-uticals in the United States and Astellas Pharma in Japan. Development. Vascular endothelial growth factor (VEGF) pathway plays an important role in angiogenesis, which is critical in cancer. It is necessary for angiogenesis, formation of new blood vessels, and endothelial cell proliferation, migration and survival. There are currently five known VEGF ligands (A, B, C, D, PLGF) and three VEGF receptors (1, 2 and 3). In order to optimally inhibit the VEGF pathway, the key is to effectively block all Three VEGF receptors, because they play an important role in cancer angiogenesis: 1) VEGF r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/22
CPCC07C221/00C07C225/22
Inventor 梁茜王哲烽益兵王圣利张红亮李昌盛
Owner SHANGHAI INST OF PHARMA IND CO LTD
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