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

Preparation method of alectinib intermediate

An intermediate and tinib technology, applied in the field of preparation of alectinib intermediates, can solve the problems of short technological process, difficult to obtain, use a large amount of solvents, etc., and achieve the effects of reasonable technical solution, simplified operation and less impurities

Active Publication Date: 2017-06-27
湖南润星制药有限公司
View PDF8 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The starting materials of the above two synthetic routes are relatively expensive and difficult to obtain, so they need to be synthesized and prepared; because the intermediate products and final products of the two synthetic routes contain many impurities and by-products, a large amount of solvents are required for purification, and the operation is cumbersome , the yield is low, which is not conducive to the promotion of industrial production. Therefore, it is necessary to explore the preparation method of Alectinib which is suitable for industrial production due to its short process flow, simple operation and low cost.

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 alectinib intermediate
  • Preparation method of alectinib intermediate
  • Preparation method of alectinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl triflate:

[0042] 2-(4-Ethyl-3-hydroxyphenyl)ethyl acetate (10.0g, 48.0mmol) was dissolved in triethylamine (9.7g, 95.9mmol), and trifluoromethanesulfonic anhydride (18.3g, 64.9mmol), stirred and reacted at 20°C for 2 hours, after post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained, light yellow solid (15.8g ), yield 97%.

[0043] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}acetate:

[0044] 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate (15.0g, 44.1mmol) was dissolved in N,N-dimethylformamide (250mL), and 4- (4-piperidinyl)morpholine (16.9g, 99.3mmol), sodium methoxide (6.0g, 111.1mmol), the reaction mixture was stirred and reacted at 100°C for 12 hours, the reaction solution was cooled to room temperature, added water (180mL), and cooled to Crystallized at 0°C for 3 hours, filtered to obtain e...

Embodiment 2

[0052] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl triflate:

[0053] 2-(4-Ethyl-3-hydroxyphenyl)ethyl acetate (12.0g, 57.6mmol) was dissolved in N,N-diisopropylethylamine (18.6g, 143.9mmol), slowly added trifluoroform Sulfonic acid anhydride (24.4g, 86.5mmol), stirred at 25°C for 1 hour, after post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained , light yellow solid (18.6g), yield 95%.

[0054] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}acetate:

[0055] 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate (18.0g, 52.9mmol) was dissolved in N,N-dimethylformamide (350mL), and 4- (4-piperidinyl)morpholine (24.3g, 142.7mmol), sodium ethoxide (10.8g, 158.7mmol), the reaction mixture was stirred at 110°C for 6 hours, the reaction solution was cooled to room temperature, added water (200mL), and cooled to Crystallized at 0°C for 3 hours and filtered to obta...

Embodiment 3

[0063] A) Preparation of 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl triflate:

[0064] 2-(4-Ethyl-3-hydroxyphenyl)ethyl acetate (2.0g, 9.6mmol) was dissolved in pyridine (1.2g, 15.2mmol), and trifluoromethanesulfonic anhydride (3.3g, 11.7mmol) was slowly added dropwise ), stirred and reacted at 0°C for 4 hours, after post-treatment and purification, 5-[(ethoxycarbonyl)methyl]-2-ethylphenyl trifluoromethanesulfonate was obtained as a light yellow solid (2.6g), Yield 80%.

[0065] B) Preparation of ethyl 2-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}acetate:

[0066] 5-[(Ethoxycarbonyl)methyl]-2-ethylphenyl triflate (2.5g, 7.3mmol) was dissolved in 1,4-dioxane (40mL), and 4-( 4-piperidinyl)morpholine (2.3g, 13.5mmol), sodium isopropoxide (1.2g, 14.6mmol), the reaction mixture was stirred at 90°C for 18 hours, the reaction solution was cooled to room temperature, water (30mL) was added, cooled Crystallize at 0°C for 3 hours, and filter to obtain ethyl 2-{4-ethyl-3-[4-(mo...

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 an alectinib intermediate, tert-butyl 4-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-4-methyl-3-oxovalerate. The preparation method comprises: subjecting ethyl 2-(4-ethyl-3-hydroxyphenyl)acetate and triflic anhydride to triflic acid esterification; subjecting the obtained 5-[(ethoxycarbonyl)methyl]-2-ethylphenyltriflate and 4-(4-piperidyl)morpholine to substitution reaction; subjecting the obtained ethyl 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}acetate and methyl iodide to bis-methylation reaction; hydrolyzing the obtained ethyl 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-2-methylpropanoate; subjecting the obtained 2-{4-ethyl-3-[4-(morpholine-4-yl)piperidine-1-yl]phenyl}-2-methylpropanoic acid and mono-tert-butyl malonate to condensation reaction to obtain the alectinib intermediate. The preparation method is simple to perform and low in cost, is a green technique and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of an alectinib intermediate. Background technique [0002] The chemical name of Alectinib, a novel anaplastic lymphoma kinase (ALK) inhibitor, is 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidine -1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, its chemical structure is: [0003] [0004] Alectinib is an innovative drug invented by Chugai Pharmaceutical, a subsidiary of Roche Pharmaceuticals. It has been approved as a breakthrough drug by the US FDA and has been approved for accelerated approval as a new oral anti-lung cancer drug for the treatment of advanced (metastatic) ALK gene mutations. Non-small cell lung cancer (NSCLC), or the treatment of patients resistant to crizotinib. [0005] Patents US20130143877 and WO2012023597A1 disclose a synthetic route for the preparation of Alectinib: starting...

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): C07D211/58
CPCC07D211/58
Inventor 陈健李涛钟云健
Owner 湖南润星制药有限公司
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