Method for synthesis of dronedarone

A synthesis method and technology of dronedarone hydrochloride are applied in the field of synthetic process routes of the drug compound dronedarone, can solve the problems of trivial yield, low yield, low yield and the like, and achieve trivial operation and high yield. The effect of high rate and simple operation process

Active Publication Date: 2014-11-19
FUJIAN COSUNTER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Route (1) involves cumbersome operations in literature reports and the yield is very high, and the reproducibility of the reaction is poor; although the steps of route (2) are short, more expensive catalysts are used, and it is not easy to carry out large-scale production; The route (3) has a long step and a low yield; the route (4) has a long step and a large amount of mixed acid is used in the nitration process, which is not conducive to the treatment of the three wastes. In addition, the yield of the whole route is not high

Method used

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  • Method for synthesis of dronedarone
  • Method for synthesis of dronedarone

Examples

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Embodiment 1

[0044] 1, the preparation of 2-chloromethyl-4-nitrophenol

[0045] Add 60g of p-nitrophenol, 26.16g of paraformaldehyde, 432mL of concentrated hydrochloric acid and 5mL of concentrated HCl into a 1L three-neck flask 2 SO 4 , stirred, heated to 88 ~ 90 ° C, and reacted at this temperature for 4h. The reaction solution was cooled to room temperature, filtered, and the resulting solid was dried under reduced pressure to obtain 75.47 g of off-white to off-white solid, mp 121-125°C.

[0046] 2. Preparation of 2-hydroxy-5-nitrobenzyltriphenylphosphonium chloride

[0047] Add 50g of 2-chloromethyl-4-nitrophenol, 69.80g of triphenylphosphine and 1500mL of chloroform into a 3L three-necked flask, and heat to reflux for 1h. The reaction liquid was cooled to normal temperature, filtered, and dried to obtain 115.63 g of off-white to white solid, yield 96.4%, mp 262-265°C.

[0048] 3. Preparation of 2-n-butyl 5-nitrobenzofuran

[0049]Add 400mL of toluene, 45.4g of triethylamine, 60.1...

Embodiment 2

[0063] 1, the preparation of 2-chloromethyl-4-nitrophenol

[0064] Add 45g of p-nitrophenol, 19.6g of paraformaldehyde, 324mL of concentrated hydrochloric acid and 3mL of phosphoric acid into a 1L three-necked flask, stir, heat to 88-90°C, and react at this temperature for 4h. The reaction solution was cooled to room temperature, filtered, and the resulting solid was dried under reduced pressure to obtain 36.5 g of off-white to off-white solid, mp 124-127°C.

[0065] 2. Preparation of 2-hydroxy-5-nitrobenzyltriphenylphosphonium chloride

[0066] Add 50g of 2-chloromethyl-4-nitrophenol, 69.80g of triphenylphosphine and 1500mL of chloroform into a 3L three-necked flask, and heat to reflux for 1h. The reaction liquid was cooled to normal temperature, filtered, and dried to obtain 115.63 g of off-white to white solid, yield 96.4%, mp 262-265°C.

[0067] 3. Preparation of 2-n-butyl 5-nitrobenzofuran

[0068] Add 400mL of toluene, 45.4g of triethylamine, 60.11g of 2-hydroxy-5-nit...

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Abstract

The invention relates to a method for synthesis of dronedarone. The method comprises the following steps that 1), p-nitrophenol, paraformaldehyde and concentrated hydrochloric acid as raw materials undergo a condensation reaction in the presence of concentrated hydrochloric acid or phosphoric acid as a catalyst to produce 2-chloromethyl-4-nitrophenol; 2), 2-chloromethyl-4-nitrophenol and triphenylphosphine undergo a reflux reaction in the presence of chloroform to produce 2-hydroxy-5-nitrobenzyl-triphenyl-phosphonium chloride, and 3), 2-hydroxy-5-nitrobenzyl-triphenyl-phosphonium chloride and n-valeryl chloride undergo a condensation reaction in a toluene solution in the presence of triethylamine and n-pentanoic acid as catalysts to produce 2-(n-butyl)-5-nitrobenzofuran.

Description

technical field [0001] The present invention relates to a synthesis process route of the pharmaceutical compound dronedarone, in particular to the process conditions and methods for preparing corresponding intermediates in the process route. Background technique [0002] The chemical structure of dronedarone (common name: Dronedarone) is similar to the standard drug amiodarone for the treatment of atrial fibrillation, and the mechanism of action is the same, both of which are potassium ion channel blockers. European patent EP471609 reports that dronedarone has special significance as an antiarrhythmic drug, which can significantly reduce the morbidity and mortality of paroxysmal or persistent atrial fibrillation or atrial flutter; and can effectively prevent certain types of myocardial infarction Clinically, its hydrochloride, namely dronedarone hydrochloride, is usually used clinically. [0003] In the process of preparing dronedarone, 2-n-butyl 5-nitrobenzofuran is a key ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/80
Inventor 李国栋张明亮杨敏曾杰文陈仕魁杨喜鸿
Owner FUJIAN COSUNTER PHARMA CO LTD
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