Preparation method of cediranib

A technology of cediranib and condensation reaction, which is applied in the design of organic synthesis routes and the preparation of raw materials and intermediates, to achieve the effects of improving product quality, promoting development, and improving atom economy

Active Publication Date: 2013-09-04
迁安华韵知识产权服务中心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In March 2010, AstraZeneca announced that the direct comparison clinical study of cediranib with bevacizumab separately and combined with chemotherapy for metastatic colorectal cancer failed to meet the primary endpoint
[0009] Investigate the preparation method of cediranib at present, although the second method saves the step of hydroxyl protection and deprotection, the quinazoline core and side chain 4-fluoro-5-hydroxyl-2-methylindole ( The condensation of III) needs to be realized by chlorination

Method used

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  • Preparation method of cediranib
  • Preparation method of cediranib
  • Preparation method of cediranib

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Under nitrogen protection, 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-3,4-dihydroquinazolin-4-one (II) (3.03g , 10 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, 4-fluoro-5-hydroxy-2-methylindole (III) (2.48 g, 15 mmol) and sodium hydride (0.37 g, 15 mmol) were added, the temperature was raised to 80°C, and the reaction was stirred for 5 hours , TLC monitored the end of the reaction....

Embodiment 2

[0026] Under nitrogen protection, 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-3,4-dihydroquinazolin-4-one (II) (3.03g , 10 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) (1.86 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, 4-fluoro-5-hydroxy-2-methylindole (III) (2.48 g, 15 mmol) and sodium hydride (0.37 g, 15 mmol) were added, the temperature was raised to 80°C, and the reaction was stirred for 5 hours , TLC monitored the end of the reaction. ...

Embodiment 3

[0028] Under nitrogen protection, 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-3,4-dihydroquinazolin-4-one (II) (3.03g , 10mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.63g, 15mmol), 4-fluoro-5-hydroxyl-2-methyl Indole (III) (2.48 g, 15 mmol) and N, N-dimethylformamide 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 90° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 2.80 g of off-white solid cediranib (I), with a yield of 62.2%.

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Abstract

The invention discloses a preparation method of cediranib. The preparation method comprises the step that 6-methoxy-7-(3-pyrrolidine-1-yl-propoxy)-3,4-dihydroquinazoline-4-ketone (II) and 4-fluro-5-hydroxy-2-methylindole (III) carry out one-step condensation reaction under the actions of an organic alkali and a condensing agent to prepare cediranib (I). Compared with the prior art, the preparation method is easy in obtainment of raw materials, concise in process and mild in conditions, has the effects on optimizing the environment and improving the quality, is suitable for industrial production, and promotes development of the economic technology of active pharmaceutical ingredients.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of cediranib. Background technique [0002] Cediranib (Cediranib) is an oral small molecule multi-target receptor tyrosine kinase inhibitor being developed by AstraZeneca that may be used in the treatment of cancer. In March 2010, AstraZeneca announced that cediranib failed to meet the primary endpoint in the direct comparison clinical study of cediranib with bevacizumab separately and combined with chemotherapy for metastatic colorectal cancer. At present, multiple clinical studies of cediranib on other solid tumors such as glioma, lung cancer, breast cancer and prostate cancer are still in progress. [0003] The chemical name of cediranib is: 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-[3-(pyrrolidin-1- base) propoxy] quinazoline. [0004] [0005] Patent No. WO20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12
Inventor 许学农
Owner 迁安华韵知识产权服务中心
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