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

Method for preparing dovitinib intermediate with microchannel reaction device

A technology of microchannel reaction and dovitinib, applied in organic chemistry and other directions, can solve problems such as low product yield, and achieve the effect of reducing consumption and improving yield

Active Publication Date: 2018-10-02
NANJING UNIV OF TECH
View PDF5 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Purpose of the invention: in order to solve the above-mentioned problems existing in the prior art, the present invention provides a kind of method that adopts microchannel reaction device to prepare dovitinib intermediate, and this method can solve the dovitinib intermediate 4-(4- Methylpiperazin-1-yl)phenylenediamine has the problem of low product yield due to instability in the post-treatment process, which can improve reaction efficiency and is suitable for industrialized production

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
  • Method for preparing dovitinib intermediate with microchannel reaction device
  • Method for preparing dovitinib intermediate with microchannel reaction device
  • Method for preparing dovitinib intermediate with microchannel reaction device

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Synthesis of 5-(4-methylpiperazinyl-1-yl)-2-nitroaniline (compound b)

[0034]

[0035] a, adding ethanol to the reaction solution for reaction

[0036]Under nitrogen protection, add compound a (20g, 0.12mol) and N-methylpiperazine (50g, 0.50mol) into a 100mL three-necked flask, then add 75mL of ethanol, stir, heat the oil bath to reflux, and react for 24h , use thin layer chromatography to track whether a is completely reacted, if not, continue to react until a is completely reacted. Pour the reaction solution into a 1L beaker containing 400mL of water while it was hot. A yellow substance precipitated out. The suspension was mechanically stirred for half an hour, filtered with suction, and the filter cake was washed 2 to 3 times with ice-cold ethanol. The filtrate was discarded, and the obtained filter cake was dried in an oven at 60° C. to obtain the product compound b with a yield of 65%.

[0037] b. Do not add ethanol to the reaction solution

[0038] Unde...

Embodiment 2

[0049] The preparation method is the same as in Example 1, and step (1) adopts the b method of step (1) in Example (1), but the mol ratio of 5-chloro-2-nitroaniline to N-methylpiperazine is 1 : 2, the productive rate of 5-(4-methylpiperazinyl-1-yl)-2-nitroaniline is 79%;

[0050] Step (2) adopts the b method of step (2) in the embodiment (1), but 5-(4-methylpiperazinyl-1-yl)-2-nitroaniline and β-ethoxyl-β The molar ratio of ethyl iminopropionate hydrochloride is 1:1.2 to obtain ethyl-2-(6-(4-methylpiperazin-1-yl)benzimidazol-2-yl)ethyl acetate The yield was 82%;

[0051] Moles of ethyl-2-(6-(4-methylpiperazin-1-yl)benzimidazol-2-yl)ethyl acetate, 2-amino-6-fluorobenzonitrile, KHMDS in step (3) The ratio was 1:1.2:3, and the yield of dovitinib was 69%.

Embodiment 3

[0053] The preparation method is the same as in Example 1, and step (1) adopts the b method of step (1) in Example (1), but the mol ratio of 5-chloro-2-nitroaniline to N-methylpiperazine is 1 : 6, the productive rate of 5-(4-methylpiperazinyl-1-yl)-2-nitroaniline is 85%;

[0054] Step (2) adopts the b method of step (2) in the embodiment (1), but 5-(4-methylpiperazinyl-1-yl)-2-nitroaniline and β-ethoxyl-β The molar ratio of ethyl iminopropionate hydrochloride is 1:3 to obtain ethyl-2-(6-(4-methylpiperazin-1-yl)benzimidazol-2-yl)ethyl acetate The yield was 87%;

[0055] Moles of ethyl-2-(6-(4-methylpiperazin-1-yl)benzimidazol-2-yl)ethyl acetate, 2-amino-6-fluorobenzonitrile, KHMDS in step (3) The ratio was 1:1.5:4, and the yield of dovitinib was 73%.

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 method for preparing a dovitinib intermediate with a microchannel reaction device. The method comprises the following steps: (1) dissolving hydrochloric acid in ethanol to form a mixed solution, and enabling the mixed solution and an ethanol solution of 5-(4-methylpiperazin-1-yl)-2-nitroaniline to flow into a first microstructural reactor in the microchannel reaction device filled with zinc powder simultaneously and respectively for a reaction to obtain a reaction effluent; (2) enabling the reaction effluent in step (1) and an ethanol solution of ethyl-beta-imino-beta-ethoxypropionate to flow into a second microstructural reactor in the microchannel reaction device simultaneously and respectively for a reaction to obtain ethyl-2-(6-(4- methylpiperazin-1-yl) benzimidazol-2-yl) ethyl acetate, namely, the dovitinib intermediate. The method has the advantages that few side reactions are produced, yield is high, technological steps are simplified, production cost is low, and the industrial standard of profit maximization is met better.

Description

technical field [0001] The invention relates to a method for preparing dovitinib, in particular to an intermediate ethyl-2-(6-(4-methylpiperazin-1-yl)benzene prepared by using a microreactor in the synthesis process of dovitinib and imidazol-2-yl) ethyl acetate method. Background technique [0002] Dovitinib is an orally effective small molecule multi-target tyrosine kinase inhibitor, which has inhibitory effects on various growth factors, such as VEGFR1-3, FGFR1-3, PDGFR-β, c-KIT , Ret, TraA and csf-1. In clinical research, dovitinib is used to treat breast cancer, kidney cancer, multiple myeloma, acute leukemia, prostate cancer, etc. [0003] According to the reports on the synthetic route of dovitinib in domestic and foreign literature, the following reaction is generally carried out, under the protection of nitrogen, 5-chloro-2-nitroaniline and N-methylpiperazine are docked, and hydrogenated by Pd / C catalyst Reducing the nitro group, forming a ring with β-ethoxy-β-imi...

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): C07D235/16C07D401/04
CPCC07D235/16C07D401/04
Inventor 郭凯吴晓钰方正朱宁段金电欧阳平凯
Owner NANJING UNIV OF TECH
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