CN102174032A - New preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran - Google Patents
New preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran Download PDFInfo
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- CN102174032A CN102174032A CN2011100606516A CN201110060651A CN102174032A CN 102174032 A CN102174032 A CN 102174032A CN 2011100606516 A CN2011100606516 A CN 2011100606516A CN 201110060651 A CN201110060651 A CN 201110060651A CN 102174032 A CN102174032 A CN 102174032A
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- butyl
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Abstract
The invention belongs to the technical field of a chemical synthesis method, which mainly relates to a preparation method of a dronedarone intermediate 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. The preparation method of the 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran comprises the following step of: enabling the 2-n-butyl-5-nitrobenzofuran to be subjected to Friedel-Crafts acylation and 4-hydroxybenzoyl chloride reaction to obtain the 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (compound shown in the formula I). The method has the advantages of simple and convenient processes, low cost and easy acquisition of raw materials, high yield and high safety, and is suitable for industrial production.
Description
Technical field
The invention belongs to the technical field of Dronedarone intermediate preparation method; be specially the new preparation process of 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran, this compounds is a kind of important intermediate of synthetic antiarrhythmic Agents Dronedarone.
Background technology
Itself can be general in the preparation of various products for 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran as intermediate; intermediate in particular as last synthesizing amino alkoxy benzene formyl benzofuran derivative; especially at last the intermediate of acceptable salt is widely used on synthetic Dronedarone (chemistry 2-normal-butyl-3-[4-by name (the amino propoxy-of 3-di-n-butyl) benzoyl]-5-methylsulfonyl amido cumarone) and its pharmacology.
This aminoalkyl benzoyl benzofuran derivative and its pharmacy acceptable salt and treatment thereof are applied among the patent EP 0471609 and come forth.Shown this compound at cardiovascular field, particularly effective especially in the anti-arrhythmia field.
At present, people's rhythm of life is more and more faster, and the pressure from each side that bears is increasing, causes the quantity of China's cardiovascular patient also constantly to increase.Therefore developing Dronedarone will bring favorable economic benefit and social benefit, and its chemical structural formula is gone into shown in the following formula:
Dronedarone
2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran is the key intermediate of synthetic Dronedarone.Following information is disclosed among the patent US5223510:
Above-mentioned for preparing the method for 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran.Because aforesaid method relates to two-step reaction, complex manufacturing, cause the production cost height, and yield is on the low side.In disclosed report, there is not effective solution to the problems described above about the Dronedarone preparation method.
In view of the pharmacy value efficiently of Dronedarone and bright market outlook, seek a kind of can be simply, the effective ways of Synthetic 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran compound be imperative cheaply with good yield, technology.
Summary of the invention
The purpose of this invention is to provide that a kind of yield is good, technology is simple, the preparation method of lower-cost dronedarone key intermediate 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (formula I compound).
Ⅰ
The invention provides the method for a kind of 2-of preparation normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (formula I compound), may further comprise the steps:
Under an acidic catalyst existence condition; 2-normal-butyl-5-nitrobenzofuran is reacted through paying gram acylation reaction and 4-hydroxybenzoyl chloride; temperature of reaction is the reflux temperature of room temperature to solvent, makes 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (formula I compound).
Following is its reactions steps:
Described an acidic catalyst is an aluminum chloride, iron trichloride, and tin tetrachloride is preferably aluminum chloride.
The mol ratio of described reaction mass is: 2-normal-butyl-5-nitrobenzofuran: 4-hydroxybenzoyl chloride: aluminum chloride=1:(1.1-1.5): (1.5:3).
The temperature of described pair of gram acylation reaction is 30-60 ℃.
Described reaction solvent is a methylene dichloride, ethylene dichloride, trichloroethane, the mixture of one or several in the chloroform.
The invention has the beneficial effects as follows: the present invention is that raw material obtains 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran through single step reaction with 2-normal-butyl-5-nitrobenzofuran and 4-hydroxybenzoyl chloride; simplified technical process; the controllability of reaction is strong; safe; productive rate is higher, reaches 87%, and HPLC purity is 98.7%; raw material is cheap and easy to get, and cost is lower.Operational path novelty of the present invention, processing condition are reasonable, and reactions steps is short, and simple to operate, production cost is low, has bigger implementary value and economic results in society.
Product to the present invention obtains detects, and its data are as follows:
1H?NMR?(DMSO-d6)?δ:?0.92?(t,?3H,CH
3),?1.26?(m,?2H,C
H 2-CH
3),?1.68?(m,2H,C
H 2-CH
2-CH
3),?2.86?(m,2H,C
H 2-C＝),?6.32（d,
?J?=?9?Hz?1H，O
H）,?6.81?(d,
?J?=8.5Hz?2H,ArH),?7.74?(d,
?J?=?9?Hz?1H,ArH),?7.93?(d,
?J?=8.5Hz?2H,ArH),8.15?(dd,?
J?=?9?Hz,?
J?=?2.5?Hz?,1H,ArH),?8.49?(d,?
J?=?2.5?Hz,?1H,ArH)
Embodiment
Below by specific embodiment technical scheme of the present invention is described in detail, following embodiment is to describe in detail technical scheme of the present invention, and unrestricted the present invention.
Synthesizing of embodiment 1:2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran
Under the nitrogen protection condition, 2-normal-butyl-5-nitrobenzofuran 44.0 grams, 4-hydroxybenzoyl chloride 28.1 are restrained in 400 milliliters of ethylene dichloride and mix, add 40.1 gram aluminum chlorides, stirred 12 hours under the 30-40 ℃ of condition.Reaction solution is added in the entry, separate organic layer, steam ethylene dichloride, vacuum-drying obtains 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran, gets pale yellow solid 59.4 grams, yield 87.3%.HPLC purity is 98.4%.
Synthesizing of embodiment 2:2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran
Under the nitrogen protection condition, 2-normal-butyl-5-nitrobenzofuran 44.0 grams, 4-hydroxybenzoyl chloride 28.1 are restrained in 400 milliliters of trichloroethane and mix, add 78.0 gram tin tetrachloride room temperature conditions and stirred 12 hours down.Reaction solution is added in the entry, separate organic layer, steam trichloromethane, vacuum-drying obtains 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran, gets pale yellow solid 56.0 grams, yield 82.4%.HPLC purity is 97.5%.
Claims (6)
1. the new preparation process of a 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran may further comprise the steps:
Under an acidic catalyst existence condition; 2-normal-butyl-5-nitrobenzofuran is reacted through paying gram acylation reaction and 4-hydroxybenzoyl chloride; temperature of reaction is the reflux temperature of room temperature to solvent, makes 2-normal-butyl-3-(4-hydroxy benzoyl)-5-nitrobenzofuran (formula I compound).
2. preparation method according to claim 1 is characterized in that: described an acidic catalyst is an aluminum chloride, iron trichloride, and tin tetrachloride is preferably aluminum chloride.
3. preparation method according to claim 1 is characterized in that: acyl chlorides is the 4-hydroxybenzoyl chloride in the described pair of gram acylation reaction.
4. preparation method according to claim 1 is characterized in that: the temperature of described pair of gram acylation reaction is 30-60 ℃.
5. preparation method according to claim 1 is characterized in that: the mol ratio of material is 2-normal-butyl-5-nitrobenzofuran: 4-hydroxybenzoyl chloride: aluminum chloride=1:(1.1-1.5): (1.5:3).
6. preparation method according to claim 1 is characterized in that: the solvent of described reaction is a methylene dichloride, ethylene dichloride, trichloroethane, the mixture of one or several in the chloroform.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100606516A CN102174032A (en) | 2011-03-14 | 2011-03-14 | New preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran |
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| CN2011100606516A CN102174032A (en) | 2011-03-14 | 2011-03-14 | New preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran |
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| CN102174032A true CN102174032A (en) | 2011-09-07 |
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| CN2011100606516A Pending CN102174032A (en) | 2011-03-14 | 2011-03-14 | New preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440470A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2- butyl -3- (4- hydroxy benzoyls) benzofuran |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080154049A1 (en) * | 2004-11-02 | 2008-06-26 | Shasun Pharma Solutions Limited | Method for Acylation of an Aromatic Compound |
| CN101948455A (en) * | 2010-10-18 | 2011-01-19 | 山东邹平大展新材料有限公司 | Preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran |
-
2011
- 2011-03-14 CN CN2011100606516A patent/CN102174032A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080154049A1 (en) * | 2004-11-02 | 2008-06-26 | Shasun Pharma Solutions Limited | Method for Acylation of an Aromatic Compound |
| CN101948455A (en) * | 2010-10-18 | 2011-01-19 | 山东邹平大展新材料有限公司 | Preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran |
Non-Patent Citations (2)
| Title |
|---|
| 《石油化工高等学校学报》 20060930 胡应喜，刘霞，涂露寒 2,4,4'-三羟基二苯甲酮的合成 第45-47页 1-6 第19卷, 第3期 * |
| 胡应喜，刘霞，涂露寒: "2,4,4’-三羟基二苯甲酮的合成", 《石油化工高等学校学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440470A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2- butyl -3- (4- hydroxy benzoyls) benzofuran |
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Application publication date: 20110907 |