阅读说明：本技术 一种决奈达隆中间体杂质及其制备方法 (Dronedarone intermediate impurity and preparation method thereof ) 是由 周步高 魏洋飞 郭强 于 2020-12-17 设计创作，主要内容包括：本发明提供了一种决奈达隆中间体杂质及其制备方法,该杂质结构如式I。该杂质的制备方法包括：第一步将氯化锌、乙酸和溶剂先加入反应釜中,控制釜内温度,再加入化合物II和化合物III,保温反应至终点,得到化合物IV；第二步,将化合物IV、氢卤酸水溶液、季铵盐加入反应釜中,升温至回流,反应至终点,得到化合物I。本发明提供的式I化合物可以作为决奈达隆中间体有关物质检测用的对照品,用于决奈达隆中间体以及决奈达隆原料药的纯度控制。(The invention provides a dronedarone intermediate impurity and a preparation method thereof, wherein the impurity has a structure shown in a formula I. The preparation method of the impurity comprises the following steps: firstly, adding zinc chloride, acetic acid and a solvent into a reaction kettle, controlling the temperature in the kettle, adding a compound II and a compound III, and carrying out heat preservation reaction to the end point to obtain a compound IV; and secondly, adding the compound IV, a halogen acid aqueous solution and quaternary ammonium salt into a reaction kettle, heating to reflux, and reacting to the end point to obtain a compound I. The compound of the formula I provided by the invention can be used as a reference substance for detecting related substances of a dronedarone intermediate, and is used for controlling the purity of the dronedarone intermediate and a dronedarone raw material drug.)

1. A compound having the structure shown in formula I:

。

2. a process for the preparation of compound I according to claim 1, comprising the steps of:

firstly, adding zinc chloride, acetic acid and a solvent into a reaction kettle, controlling the temperature in the kettle, adding a compound II and a compound III, and carrying out heat preservation reaction to the end point to obtain a compound IV;

secondly, adding the compound IV, a halogen acid aqueous solution and quaternary ammonium salt into a reaction kettle, heating to reflux, and reacting to the end point to obtain a compound I; expressed by the reaction formula:

。

3. the method of claim 2, wherein the solvent in the first step is dichloromethane, 1, 2-dichloroethane, 1, 2-dichloropropane, 1, 3-dichloropropane, or chloroform.

4. The method according to claim 2, wherein the temperature in the first step is 10 to 20 ℃.

5. The method according to claim 2, wherein the feeding molar ratio of the compound II to the compound III is 1: 1-1.2, the feeding molar ratio of the zinc chloride to the compound II is 0.3-0.6: 1, and the feeding molar ratio of the acetic acid to the compound II is 1.8-2: 1.

6. The method according to claim 2, wherein the hydrohalic acid in the second step is hydrobromic acid or hydrochloric acid, and the feeding molar ratio of the hydrohalic acid to the compound IV is 8-15: 1.

7. The method according to claim 2 or 6, wherein the concentration of the aqueous solution of the halogen acid in the second step is 30 to 50%.

8. The method according to claim 2, wherein the quaternary ammonium salt in the second step is tetrabutylammonium bromide, tetrabutylammonium chloride or benzyltriethylammonium chloride, and the mass ratio of the quaternary ammonium salt to the compound IV is 0.02-0.05: 1.

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a dronedarone intermediate impurity and a preparation method thereof.

Background

Dronedarone is a new medicine developed by Senofu Anthrate company of Sunnofu, France, the structure and characteristics of the medicine are similar to cardiovascular medicine amiodarone, and the medicine is a potassium channel retarder, but the medicine does not contain iodine and has low lipophilicity, so the medicine does not cause adverse reaction related to iodine.

Dronedarone is an antiarrhythmic drug which is proved by clinical tests to be capable of remarkably reducing morbidity and mortality of patients suffering from atrial fibrillation/atrial flutter, is an American FDA priority evaluation variety, is approved by the FDA to be on the market in 7 months in 2009, and is approved by the European Union in 12 months in 2009. Therefore, the development of dronedarone can bring better economic benefit and social benefit.

2-n-butyl-3- (4-hydroxybenzoyl) -5-nitrobenzofuran is one of key intermediates for preparing dronedarone bulk drugs, and a plurality of unknown process impurities generated by a preparation process often exist in the intermediates (reference documents US4766223A, US4001426A, CN102382087A and US 3975537A) obtained by a conventional preparation method, so that the difficulty in controlling the quality of dronedarone intermediates and raw material drugs is improved.

Disclosure of Invention

The purpose of the invention is as follows: the invention provides a dronedarone intermediate impurity, and provides a preparation method of the impurity compound.

The technical scheme is as follows: the dronedarone intermediate impurity disclosed by the invention has the following structure as shown in the formula I:

。

the preparation method of the compound I is as follows:

。

the specific process comprises the following steps: firstly, adding zinc chloride, acetic acid and a solvent into a reaction kettle, controlling the temperature in the kettle, adding a compound II and a compound III, and carrying out heat preservation reaction to the end point to obtain a compound IV; and secondly, adding the compound IV, a halogen acid aqueous solution and quaternary ammonium salt into a reaction kettle, heating to reflux, and reacting to the end point to obtain a compound I.

Wherein, the solvent in the first step is an inert solvent, and can be dichloromethane, 1, 2-dichloroethane, 1, 2-dichloropropane, 1, 3-dichloropropane, chloroform and the like; the temperature in the first step is 0-30 ℃, preferably 10-20 ℃. The feeding molar ratio of the compound II to the compound III is 1: 1-1.2, the feeding molar ratio of the zinc chloride to the compound II is 0.3-0.6: 1, and the feeding molar ratio of the acetic acid to the compound II is 1.8-2: 1.

Wherein, the hydrohalic acid in the second step comprises hydrofluoric acid, hydrobromoic acid or hydrochloric acid, preferably the hydrobromoic acid or hydrochloric acid, the concentration of the hydrohalic acid aqueous solution is 30-50%, and the feeding molar ratio of the hydrohalic acid to the compound IV is 8-15: 1. The quaternary ammonium salt plays a role of a catalyst in the reaction, and is preferably tetrabutylammonium bromide, tetrabutylammonium chloride or benzyltriethylammonium chloride, and the addition amount of the quaternary ammonium salt is 2-5% of the mass of the compound IV.

Has the advantages that: 1. the compound of formula I provided by the invention can be used as an impurity reference substance to control the purity of the dronedarone intermediate. 2. The preparation method of the compound of the formula I provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, high conversion rate and yield of the obtained target product, and can achieve the purity of more than 99% without adopting column chromatography purification.

Detailed Description

The present invention is further illustrated by the following examples, but the invention is not limited to the scope of the claims.

Example 1

(1) Process for the preparation of compound IV

100g of 1, 2-dichloroethane, 3.9g of zinc chloride and 11.1g of acetic acid are put into a 500mL reaction bottle, the temperature is controlled to be about 10 ℃, 20.00g of the compound II is added, 16.06g of 1, 2-dichloroethane solution (20 mL) of the compound III is added dropwise, and after the dropwise addition is finished, the temperature is kept between 10 ℃ and 20 ℃ for reaction for 5 hours. 60g of water is added dropwise to quench the reaction, the mixture is kept stand for liquid separation, an organic phase is concentrated to be dry and then is recrystallized by isopropanol, and 30g of white solid is obtained, and the HPLC purity is 99.2%.¹HNMR（CDCl₃，400MHz）:δppm8.37(s,1H)，8.25~8.22（m,3H），7.72~7.69(m,2H)，7.59~7.57(m, 2H)，6.91~6.89（m,1H），3.95（s,3H），2.95~2.91（m,2H），2.28（s,3H），1.82~1.75（m,2H），1.40~1.35（m,2H），0.93~0.91（m,3H）。m/z[M+H]⁺：368.09。

(2) Process for the preparation of compounds I

88.00g of 50% hydrobromic acid, 25.00g of compound IV and 1.25g of tetrabutylammonium chloride are put into a 500mL reaction bottle, fully stirred, heated to reflux and reacted for 4 hours. Cooling to room temperature, dripping 5% sodium bicarbonate water solution to quench reaction, extracting the reaction solution with dichloromethane, separating liquid,the organic phase was concentrated to no distillate and evaporated, and the crude product was recrystallized from chlorobenzene to yield 21.8g of a white-like refined product with a purity of 99.6%.¹HNMR（CDCl₃，400MHz）:δppm8.37(s，1H)，8.25~8.23（m，1H），7.73(s，1H)，7.62~7.57(m，2H)，6.88~6.86（m，1H），5.58（s，1H），2.95~2.91（m，2H），2.33（s，3H），1.82~1.75（m，2H），1.42~1.27（m，2H），0.93~0.91（m，3H）。m/z[M+H]+：354.17。

Example 2

(1) Process for the preparation of compound IV

100g of chloroform, 7.91g of zinc chloride and 10.0g of acetic acid are put into a 500mL reaction bottle, the temperature is controlled to be about 20 ℃, 20.00g of the compound II is added, 19.63g of the compound III in 1, 2-dichloroethane solution is added dropwise, and after the dropwise addition, the temperature is kept between 10 and 20 ℃ for reaction for 3 hours. 58.78g of water was added dropwise to quench the reaction, the mixture was left to stand for liquid separation, and the organic phase was concentrated to dryness and then recrystallized from isopropanol to obtain 31g of a white solid, which was compound IV with an HPLC purity of 99%.

(2) Process for the preparation of compounds I

150.00g of 40% hydrobromic acid, 25.00g of compound IV and 0.5g of tetrabutylammonium bromide are put into a 500mL reaction bottle, fully stirred, heated to reflux and reacted for 3 h. Cooling to room temperature, dropwise adding 5% sodium bicarbonate water solution to quench reaction, extracting the reaction liquid with dichloromethane, separating liquid, concentrating an organic phase until no fraction is evaporated, and recrystallizing the crude product in chlorobenzene to obtain 22g of off-white refined product with the purity of 99%.

Example 3

(1) Process for the preparation of compound IV

98g of 1, 3-dichloropropane, 7g (0.058 mol) of zinc chloride and 11g of acetic acid are put into a 500mL reaction bottle, the temperature is controlled to be about 15 ℃, 20.00g (0.09 mol) of a compound II is added, 18g of a 1, 3-dichloropropane solution (20 mL) of a compound III is added dropwise, and after the dropwise addition is finished, the temperature is kept between 10 and 20 ℃ for reaction for 3 hours. 58g of water is added dropwise to quench the reaction, the mixture is kept stand for liquid separation, and the organic phase is concentrated to be dry and then recrystallized by isopropanol to obtain 30.5g of white solid with the HPLC purity of 99.3 percent.

(2) Process for the preparation of compounds I

275.00g of 30% hydrobromic acid, 25.00g of compound IV and 1g of benzyltriethylammonium chloride are put into a 500mL reaction bottle, fully stirred, heated to reflux and reacted for 2 h. Cooling to room temperature, dropwise adding 5% sodium bicarbonate water solution to quench reaction, extracting the reaction liquid with dichloromethane, separating liquid, concentrating an organic phase until no fraction is evaporated, and recrystallizing the crude product in chlorobenzene to obtain 22.5g of off-white refined product with the purity of 99.7%.

Example 4

(1) Process for the preparation of compound IV

100g of dichloromethane, 5.7g of zinc chloride and 10.5g of acetic acid are put into a 500mL reaction bottle, 20.00g (0.09 mol) of the compound II is added into the reaction bottle while controlling the temperature to be 10-15 ℃, 17.8g of dichloromethane solution (20 mL) of the compound III is added dropwise, and after the dropwise addition is finished, the reaction is carried out for 3 hours at the temperature of 10-20 ℃. 56g of water is added dropwise to quench the reaction, the mixture is kept stand for liquid separation, and the organic phase is concentrated to be dry and then recrystallized by isopropanol to obtain 30.8g of white solid with the HPLC purity of 99.2%.

(2) Process for the preparation of compounds I

85.00g of 35% hydrochloric acid, 25.00g of compound IV and 0.8g of tetrabutylammonium bromide are put into a 500mL reaction bottle, fully stirred, heated to reflux and reacted for 3 hours. Cooling to room temperature, dropwise adding 5% sodium bicarbonate water solution to quench reaction, extracting the reaction liquid with dichloromethane, separating liquid, concentrating an organic phase until no fraction is evaporated, and recrystallizing the crude product in chlorobenzene to obtain 22.3g of off-white refined product with the purity of 99.4%.