Intermediate and method used for preparing dronedarone

A technology for dronedarone and intermediates, which is applied in the field of intermediates for the preparation of dronedarone, and can solve the problems of strict requirements on reaction conditions, increased costs, and unsuitability for industrial production.

Inactive Publication Date: 2012-07-04
TIANJIN KELIN CHEM
View PDF0 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation of this drug in the prior art is produced by 5-nitrobenzofuran derivatives, so that a hydrogenation catalytic reaction will be used in the later stage. This reaction uses platinum oxide as a catalyst, which greatly increases the cost, and the hydrogenation catalytic reaction itself has no effect on the reaction. The conditions are relatively strict and not suitable for industrial 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
  • Intermediate and method used for preparing dronedarone
  • Intermediate and method used for preparing dronedarone
  • Intermediate and method used for preparing dronedarone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Intermediates for the preparation of dronedarone and its synthesis process:

[0061]

[0062] Wherein R is acetyl or methanesulfonyl, R1 is H, methyl or ethyl.

[0063] The chemical names of the intermediates of dronedarone in this example are 2-n-butyl-3-(4-methoxy-benzoyl)-5-acetamidobenzofuran (compound 2), 2- n-Butyl-3-(4-methoxy-benzoyl)-5-methanesulfonylaminobenzofuran (compound 4), 2-n-butyl-3-(4-hydroxy-benzoyl)- 5-Acetamidobenzofuran (Compound 8) 9). The structural formula is as follows:

[0064]

[0065] A synthetic method for preparing an intermediate of dronedarone medicine, which comprises the following steps:

[0066] 1) Compound (1) reacts with p-methoxybenzoyl chloride under the catalysis of up to 5 equivalents of Lewis acid to obtain compound (2);

[0067] 2) compound (2) is obtained under the action of 10% to 36% concentrated hydrochloric acid to obtain compound (3);

[0068] 3) Compound (3) is obtained under the action of methanesulfonyl c...

Embodiment 2

[0092] Preparation of 2-n-butyl-3-(4-methoxy-benzoyl)-5-acetamidobenzofuran (Compound 2)

[0093]

[0094] Weigh 5g (21.6mmol) of 2-n-butyl-5-acetamidobenzofuran (compound 1) and 3.1g (23.8mmol) of p-methoxybenzoyl chloride into a 250ml three-necked flask, and use 40ml The dichloromethane was dissolved, cooled to 0-5 degrees with an ice-water bath, and 14.2g (54..7mmol) of tin tetrachloride was slowly added dropwise at this temperature. After the dropwise addition, stir at this temperature for 1 h and then at room temperature for 2 h. Then 100ml of water was added dropwise to the system, separated, the aqueous phase was extracted with 50ml of dichloromethane, the organic phase was combined, the organic phase was washed with saturated aqueous sodium carbonate (50ml*2), and dried over anhydrous sodium sulfate. Ethyl acetate: n-hexane 1:1 silica gel column separation to obtain 5.1 g of white solid compound (2) with a yield of 65%.

[0095] HNMR (CDCl 3 )δ: 0.85(t, 3H), 1.31...

Embodiment 3

[0097] Preparation of 2-n-butyl-3-(4-methoxy-benzoyl)-5-methanesulfonylaminobenzofuran (Compound 4)

[0098]

[0099] Weigh 5g (13..7mmol) 2-n-butyl-3-(4-methoxy-benzoyl)-5-acetamidobenzofuran (compound 2) into a 250ml flask, add 30ml of methanol Make it dissolve, then add 100ml of 15% hydrochloric acid, heat to reflux for 6h, cool, evaporate methanol under low pressure, cool in an ice-water bath, filter to obtain about 4.4g of white solid (compound 3), and then directly purify it without purification After drying, put it into a 100ml flask, add 40ml of toluene and 0.33g (3mmol) of tetramethylammonium chloride, heat to reflux, slowly add 2.8g (24.5mmol) of methanesulfonyl chloride dropwise under reflux, and continue to Reflux for 1h. Cool the reaction, add 40ml of ethyl acetate and 50ml of water solution, wash the organic phase with water (100ml*3), dry over anhydrous sodium sulfate, filter to remove the organic solvent, and obtain 4.4g of white solid (compound 4), two-ste...

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 an intermediate and method used for preparing dronedarone and belongs to the technical field of cardiovascular drugs. The method comprises the following steps of: using 2-n-butyl-5-acetamidobenzobfuran to react with p-anisoyl chloride under the catalysis of Lewis acid and obtain 2-n-butyl-3-(4-methoxy-benzoyl)-5-acetamidobenzobfuran; acidizing to obtain 2-n-butyl-3-(4-methoxy-benzoyl)-5-benzofuranamin hydrochloride, reacting with methylsulfonyl chloride to obtain 2-n-butyl-3-(4-methoxy-benzoyl)-5-methylsulfonylamidobenzobfuran; obtaining 2-n-butyl-3-(4-hydroxyl-benzoyl)-5-methylsulfonylamidobenzobfuran under the action of the Lewis acid; and reacting with 1,3-dibromopropane to obtain 2-n-butyl-3-[4-(gamma-bromopropyl)hydroxyl-benzoyl]-5-methylsulfonylamidobenzobfuran, and then reacting with di-n-butylamine to obtain dronedarone. The method avoids the catalytic hydrogenation reaction and has the advantages of available raw materials, simple operation process, high yield, easiness in industrialization and the like.

Description

technical field [0001] The invention belongs to the technical field of cardiac drugs, in particular to an intermediate for preparing dronedarone and a method thereof. Background technique [0002] Currently, Dronedarone is a new antiarrhythmic drug. The drug has similar electrophysiological effects to amiodarone and is an alternative to the latter because it does not contain iodine. Its chemical name is: N-[2-n-butyl-3-[4-[3-(dibutylamino)propoxy]phenylpropionyl]-5-benzofuryl]methanesulfonamide. The preparation of this drug in the prior art is produced by 5-nitrobenzofuran derivatives, so that a hydrogenation catalytic reaction will be used in the later stage. This reaction uses platinum oxide as a catalyst, which greatly increases the cost, and the hydrogenation catalytic reaction itself has no effect on the reaction. The condition requirements are relatively strict, and it is not suitable for industrialized production. Contents of the invention [0003] In order to so...

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): C07D307/80
CPCY02P20/55
Inventor 赵立新王水忠张腾张燕玲
Owner TIANJIN KELIN CHEM
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap