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

Preparation method of nintedanib

A nintedanib and compound technology, applied in the field of drug synthesis, can solve the problems of long process route, unfavorable environment, complicated process operation, etc., and achieve the effect of simplifying the operation process, improving production efficiency and shortening the operation steps

Active Publication Date: 2016-04-06
HANGZHOU SINOPEP ALLSINO PHARMA TECH DEV CO LTD
View PDF3 Cites 21 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The literature report has the following disadvantages: the process route is relatively long, the operation of protecting and deprotecting groups is cumbersome, and the DMF solvent used is not environmentally friendly.
This route adopts a one-pot method, and the one-pot method is often difficult to control product quality in actual industrial production, and is not suitable for industrial scale-up, and DMF solvent is also used in the reaction process, which is not good for the environment
[0012] The present invention uses methyl 2-oxindole-6-carboxylate and benzaldehyde as starting raw materials, and prepares nintedanib by designing a new route and selecting safe and environment-friendly solvents and reagents, which solves the complicated and complicated operation of the existing process. Pollution of the environment, difficulty in realizing industrialization, etc.

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 nintedanib
  • Preparation method of nintedanib
  • Preparation method of nintedanib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of Compound IV

[0031]

[0032] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction flask, start stirring, then add 16.8ml (17.6g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 ℃, reacted for 2 hours, cooled naturally to 20℃-30℃, filtered the precipitate, washed the filter cake with absolute ethanol, and dried in vacuum at 50℃ for 5 hours to obtain 40.2g of yellow solid (IV), yield: 96.0%.

[0033] Preparation of Compound V

[0034]

[0035] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 9.6ml (29.9g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours. After the reaction was completed, the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and ...

Embodiment 2

[0042] Preparation of Compound IV

[0043] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction bottle, start stirring, then add 30.3ml (31.8g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 After reacting at ℃ for 2 hours, cool naturally to 20℃-30℃, filter the precipitate, wash the filter cake with absolute ethanol, and dry in vacuum at 50℃ for 5 hours to obtain 38.7g of yellow solid (IV), yield: 92.4%.

[0044] Preparation of Compound V

[0045] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 3.1ml (9.7g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours , the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and vacuum-dried at 60°C to obtain 36.1g of off-white solid ...

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 relates to a preparation method of nintedanib (I). The preparation method comprises the steps that 2-oxoindole-6-methyl formate (III) and benzaldehyde (II) are used as raw materials to generate a condensation reaction, so as to obtain a compound IV; then halogen or halogenating reagents are added to generate a substitution reaction, so as to obtain a compound V; the compound V and the compound IV are condensed under the action of alkali, so as to obtain the nintedanib (a compound I). The method has the advantages of short reaction time, low cost, high yield and environmental friendliness of used reagents and is suitable for industrial production. The structural formulas are shown in the description.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of nintedanib. Background technique [0002] Nintedanib ethanesulfonate is an oral triple tyrosine kinase inhibitor developed by Boehringer Ingelheim, Germany. It is currently mainly used in the treatment of tumors, such as colorectal cancer, ovarian cancer, and multiple myeloma. Research on respiratory diseases mainly revolves around the clinical treatment of advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). [0003] In June 2014, Boehringer Ingelheim announced that the marketing authorization application for nintedanib ethanesulfonate for the treatment of idiopathic pulmonary fibrosis (IPF) was confirmed by the European Medicines Agency (EMA) and included in the accelerated approval list by EMA . On October 15, 2014, the US Food and Drug Administration (FDA) approved nintedanib ethanesulfonate (trade name: Ofev), ...

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
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 李勇胡畏杜焕达王万青刘艳华
Owner HANGZHOU SINOPEP ALLSINO PHARMA TECH DEV CO LTD
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