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Preparation method and application of benzofuran derivate

A reaction and compound technology, applied in the field of preparation of benzofuran derivatives, can solve problems such as poor solubility and impact on yield

Inactive Publication Date: 2012-09-05
ZHEJIANG ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] This method is relatively reasonable, but it also has certain defects, because the 3-(dibutylamino)propoxy]benzoyl chloride hydrochloride used in the final stage has poor solubility when the Friedel-Crafts reaction occurs , thus affecting yield (this step reaction yield is only 65.9%)

Method used

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  • Preparation method and application of benzofuran derivate
  • Preparation method and application of benzofuran derivate
  • Preparation method and application of benzofuran derivate

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preparation example Construction

[0047] The compound represented by formula I obtained by the preparation method of the present invention can be used to prepare dronedarone and pharmaceutically acceptable salts thereof. Therefore, the present invention also relates to the compound represented by formula I as an intermediate, which is subjected to N-alkylation reaction with dibutylamine for the final synthesis of dronedarone and its pharmaceutically acceptable salt.

[0048] The N-alkylation reaction can be carried out in polar organic solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, ethanol, isopropanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate ester, butyl acetate, ether, or tetrahydrofuran, or non-polar organic solvents such as substituted benzene, n-hexane, cyclohexane, or petroleum ether, or water, or a mixture of the above solvents, or in the presence of no solvent. Among them, dimethylformamide and acetonitrile are preferable.

[0049] The N-alkylation reac...

Embodiment 1

[0068] Step a) the preparation of 4-(3-chloropropoxy) methyl benzoate

[0069] 17.2 g of bromochloropropane, 15.2 g of methyl p-hydroxybenzoate, 15.8 g of anhydrous potassium carbonate and 100 ml of toluene were added to a 250 ml reaction flask, and the mixture was stirred and refluxed for 6 hours. After cooling to room temperature, it was filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain an off-white solid, which was directly used in the next reaction.

[0070] Step b) Preparation of 4-(3-chloropropoxy)benzoic acid

[0071] The above obtained methyl 4-(3-chloropropoxy)benzoate was added to 50 ml of methanol, heated and dissolved, then 20 ml of 6M sodium hydroxide solution was added, and the mixture was refluxed for 1 hour.

[0072] The reaction solution was acidified to pH=2 with dilute hydrochloric acid. Filter, wash, and dry to obtain 20 g of white solid powder, the total yield of the two steps is 93%. 1 H-NMR (CDCl 3 )...

Embodiment 2

[0082] Preparation of N-[2-butyl-3-[4-[3-chloropropoxy]phenyl]-5-benzofuryl]-methanesulfonamide

[0083] 3 g of N-(2-butyl-5-benzofuryl)methanesulfonamide was dissolved in 15 ml of dichloromethane, and 3 g of aluminum trichloride was added in batches. At room temperature, 2.33 g of 4-(3-chloropropoxy)benzoyl chloride prepared as described in Example 1 was added, and the reaction was stirred for 1 hour. After the reaction is complete, pour it into 150ml of ice water, stir, separate the liquids, and after drying, concentrate to dryness under reduced pressure to obtain N-[2-butyl-3-[4-[3-chloropropoxy]phenyl]- 4.1 g of 5-benzofuryl]-methanesulfonamide, the yield was 88.3%. The NMR was consistent with Example 1.

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Abstract

The invention discloses a preparation method and application of a benzofuran derivate. The preparation method of the benzofuran derivate comprises the following steps: (a) carrying out an organic reaction on a compound shown in formula II with a compound shown in formula III to obtain a compound shown as formula I, wherein X represents chlorine, bromine, iodine, amino, substituted amino, hydroxyl or substituted hydroxyl; the substituted amino is -NR1R2, the substituted hydroxyl is -O-SO2R3, wherein R1 and R2 respectively represent hydrogen, tert-butoxycarbonyl, carboxybenzyl, toluenesulfonyl, trifluoroacetyl, formoxyl and triphenylmethyl; R3 represents methyl, ethyl, propyl, phenyl and p-methylphenyl; and Y represents fluorine, chlorine or bromine. The invention also discloses the application of the prepared benzofuran derivate as an intermediate in preparing Dronedarone.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method and application of benzofuran derivatives. Background technique [0002] 2-Butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-methanesulfonylaminobenzofuran (commonly known as Dronedarone, is A new antiarrhythmic drug, researched and developed by Sanofi-Aventis, approved for marketing in the United States on July 1, 2009 (the first approval in the world), for acute atrial fibrillation (AF) and atrial flutter AFL was approved by EU EMEA on December 16, 2009. It was approved for clinical use in my country in July 2006. [0003] Clinical research results show that dronedarone has certain effects of class I, class II, and class IV antiarrhythmic drugs, can inhibit sodium, potassium, and calcium influx, and can also antagonize α and β adrenergic receptors. Different from amiodarone, dronedarone seldom affects thyroid receptors. It has good curative effect in treating...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/80
Inventor 杨叶伟王尊元马臻沈正荣李忠吴波峰
Owner ZHEJIANG ACAD OF MEDICAL SCI
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