A kind of preparation method of the intermediate of tyrosine kinase inhibitor

A tyrosine kinase and inhibitor technology, which is applied in the field of intermediate preparation, can solve the problems of many impurities, low purity, and difficulty in purification, and achieve simplified post-processing, improved purity and yield, and mild reaction conditions Effect

Active Publication Date: 2021-03-05
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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  • A kind of preparation method of the intermediate of tyrosine kinase inhibitor
  • A kind of preparation method of the intermediate of tyrosine kinase inhibitor
  • A kind of preparation method of the intermediate of tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 3.40 g (0.01510 mol) of compound II was placed in a 250 ml four-neck flask, and a mixed solution of ethyl acetate and water (34 ml / 20 ml) was added. At room temperature, 2.10 g (0.03925 mol, 2.6 eq) of ammonium chloride and 3.67 g (0.06553 mol, 4.34 eq) of reduced iron powder were successively added to the stirred reaction flask, and then the reaction system was heated to 40°C and stirred for 3 h . The progress of the reaction was checked by TLC. After the substrate is completely reacted, 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] 3.40 g of compound II was placed in a 250 ml four-neck flask, and a mixed solution of ethyl acetate and water (34 ml / 20 ml) was added. 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 h. The progress of the reaction was checked by TLC. After the substrate is completely reacted, 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] 3.40 g (0.01510 mol) of compound II was placed in a 250 ml four-neck flask, and a mixed solution of ethyl acetate and water (34 ml / 20 ml) was added. At room temperature, 1.61g (0.0302mol, 2.0eq) of ammonium chloride and 2.54g (0.0453mol, 3.0eq) of reduced iron powder were successively added to the stirred reaction flask, and then the reaction system was heated to 30°C and stirred for 3h . The progress of the reaction was checked by TLC. After the substrate is completely reacted, 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 of the present invention comprises the following steps: in ethyl acetate and water, under the action of ammonium chloride and iron powder, compound II is subjected to the following reaction to obtain compound I. The method has high product yield and purity, simple post-treatment, and is suitable for industrial production:

Description

technical field [0001] The invention relates to a preparation method of 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. of Japan, and its European and American markets are cooperated by AVEO Pharmaceuticals of the United States and Astellas Pharma of Japan develop. The vascular endothelial growth factor (VEGF) pathway plays an important role in angiogenesis, which is critical in cancer and is essential for angiogenesis, the formation of new blood vessels, for 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), and for optimal inhibition of the VEGF pathway, it is critical to effectively block all Three VEGF receptors, as they play an important role in cancer angioge...

Claims

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Application Information

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Patent Type & Authority Patents(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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