Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF6 Cites 4 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of cediranib
  • Preparation method of cediranib
  • Preparation method of cediranib

Examples

Experimental program
Comparison scheme
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%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com