阅读说明：本技术 由山梨醇制2-乙酸-5-硝酸异山梨醇酯的方法 (Method for preparing 2-acetic acid-5-nitric acid isosorbide ester from sorbitol ) 是由 车鹏华 徐杰 高进 马红 黄义争 苗虹 于维强 于 2019-11-01 设计创作，主要内容包括：本发明公开了一种由山梨醇制备2-乙酸-5-硝酸异山梨醇酯的方法,其中,使含有山梨醇、乙酰化剂和硝化剂的物料,与固体酸催化剂接触,发生酰化反应和硝化反应,得到2-乙酸-5-硝酸异山梨醇酯。本发明将山梨醇经一锅转化制备2-乙酸-5-硝酸异山梨醇酯,大大简化操作流程,提高合成效率；所用固体酸催化剂对设备腐蚀性小,易与产物分离；且反应条件温和,避免了高真空、高温等高能耗运作。(The invention discloses a method for preparing 2-acetic acid-5-nitric acid isosorbide ester from sorbitol, wherein a material containing sorbitol, an acetylating agent and a nitrating agent is contacted with a solid acid catalyst to carry out acylation reaction and nitration reaction to obtain the 2-acetic acid-5-nitric acid isosorbide ester. According to the invention, sorbitol is converted into 2-acetic acid-5-isosorbide dinitrate in one pot, so that the operation process is greatly simplified, and the synthesis efficiency is improved; the solid acid catalyst has small corrosion to equipment and is easy to separate from the product; and the reaction condition is mild, and the operation with high energy consumption such as high vacuum, high temperature and the like is avoided.)

1. A method for preparing isosorbide 2-acetate-5-nitrate from sorbitol, which comprises contacting a material containing sorbitol, an acetylating agent and a nitrating agent with a solid acid catalyst to perform acylation and nitration reactions to obtain isosorbide 2-acetate-5-nitrate.

2. The process of claim 1, wherein the solid acid catalyst has both dehydration activity and esterification activity.

3. The method of claim 1, wherein the solid acid catalyst comprises at least one of a sulfonic resin, a Keggin-type heteropoly acid, and an imidazolesulfonate heteropoly acid salt.

4. The method of claim 3,

the sulfonic acid type resin comprises at least one of Amberlyst-15, Amberlyst-70 and Nafion 50;

the Keggin type heteropoly acid comprises phosphotungstic heteropoly acid or silicotungstic heteropoly acid;

the imidazole sulfonic heteropoly acid salt comprises at least one of 1-propanesulfonic acid group-3-methylimidazole phosphotungstate, 1-butanesulfonic acid group-3-methylimidazole phosphotungstate, 1-propanesulfonic acid group-3-methylimidazole silicotungstate and 1-butanesulfonic acid group-3-methylimidazole silicotungstate;

preferably, the mass ratio of the solid acid catalyst to the sorbitol is 0.01: 1-1: 1, preferably 0.05: 1-1: 1.

5. The method of claim 1, wherein the acetylating agent comprises at least one of glacial acetic acid, acetic anhydride,

preferably, the molar ratio of the acetylating agent to sorbitol is 0.5:1 to 3:1, preferably 0.6:1 to 3: 1.

6. The method of claim 1, wherein the nitrating agent comprises nitric acid and acetic anhydride;

the nitric acid is selected from fuming nitric acid or concentrated nitric acid;

preferably, the molar ratio of the nitrating agent to the sorbitol is 0.5: 1-2: 1 based on the amount of nitric acid.

7. The method of claim 6, wherein the nitrating agent comprises a mixture of nitric acid and acetic anhydride;

preferably, in the mixture, the mixing molar ratio of the nitric acid to the acetic anhydride is 1: 0.5-1: 4, preferably 1: 1-1: 1.5.

8. Method according to claim 1, characterized in that it comprises at least the following steps:

1) contacting a material containing sorbitol and an acetylating agent with a solid acid catalyst to perform acylation reaction to prepare 2-isosorbide acetate;

2) adding a material containing a nitrating agent into the 2-isosorbide acetate obtained in the step 1), and carrying out nitration reaction under the catalysis of solid acid to generate the 2-isosorbide acetate-5-nitrate.

9. The method according to claim 1, wherein the acylation reaction temperature is 100 to 180 ℃ and the reaction time is 1 to 24 hours.

10. The method according to claim 1, wherein the temperature of the nitration reaction is 0 to 20 ℃ and the time of the nitration reaction is 1 to 5 hours.

Technical Field

The invention relates to the field of preparation of 2-acetic acid-5-isosorbide dinitrate, in particular to a method for preparing 2-acetic acid-5-isosorbide dinitrate from sorbitol, and particularly relates to a method for preparing 2-acetic acid-5-isosorbide dinitrate by catalyzing sorbitol through a one-pot method.

Background

Isosorbide 5-mononitrate (5-ISMN) is a very important nitrate medicine for preventing and treating angina pectoris in the field of medicine, and the synthesis of the medicine needs to be carried out by using an important intermediate of isosorbide 2-acetate-5-nitrate (2, 5-ISAN). Currently, sorbitol is generally used as a raw material for preparing 2-acetic acid-5-nitric acid isosorbide, and complicated acid catalysis dehydration, acetylation and nitric acid esterification steps are required. Moreover, the sorbitol dehydration reaction needs a maintenance system with high vacuum degree, and after the reaction is finished, high-purity isosorbide can be obtained by adopting high-energy-consumption purification such as high-vacuum high-temperature distillation and the like, so that the method can be used for subsequent reaction. In addition, liquid acids such as concentrated sulfuric acid, p-toluenesulfonic acid and the like are commonly used as acid catalysts in sorbitol dehydration, isosorbide acetylation and subsequent nitric acid esterification reactions, so that the problems of equipment corrosion, complex three-waste treatment process and the like exist.

Disclosure of Invention

The invention aims to provide a method for preparing 2-acetic acid-5-isosorbide dinitrate, which is simple to operate, mild, safe and low in energy consumption, in particular to a method for preparing the 2-acetic acid-5-isosorbide dinitrate by catalyzing sorbitol by a one-pot method, so as to overcome the defects of complicated operation steps, high energy consumption, high corrosion resistance, high equipment requirement and the like in the prior art.

To this end, the present invention provides a method for preparing isosorbide 2-acetate-5-nitrate from sorbitol, characterized in that the method comprises bringing a material containing sorbitol, an acetylating agent and a nitrating agent into contact with a solid acid catalyst to cause acylation and nitration, thereby obtaining isosorbide 2-acetate-5-nitrate.

In a preferred embodiment of the process of the present invention, the solid acid catalyst has both dehydrating activity and esterification activity.

In a more preferred embodiment of the process of the present invention, the solid acid catalyst comprises at least one of a sulfonic acid type resin, a Keggin type heteropolyacid, an imidazolesulfonic acid heteropolyacid salt.

Preferably, the sulfonic resin is a sulfonic cation exchange resin, preferably comprising at least one of Amberlyst-15, Amberlyst-70, Nafion 50;

the Keggin type heteropoly acid comprises phosphotungstic heteropoly acid or silicotungstic heteropoly acid;

the imidazole sulfonic acid heteropoly acid salt comprises 1-propanesulfonic acid group-3-methylimidazole phosphotungstate [ MIMPS ]]₃PW₁₂1-butanesulfonic acid group-3-methylimidazol phosphotungstate [ MIMBS ]]₃PW₁₂1-Propenesulfonic acid-3-methylimidazol silicotungstate [ MIMPS]₄SiW₁₂1-butanesulfonic acid group-3-methylimidazol silicotungstate [ MIMBS ]]₄SiW₁₂At least one of (1).

In a preferred embodiment of the method of the present invention, the mass ratio of the solid acid catalyst to sorbitol is 0.01:1 to 1:1, preferably 0.05:1 to 1:1.

Specifically, the upper limit of the mass ratio of the solid catalyst to sorbitol is independently selected from 0.05:1, 0.2:1, 0.3:1, 0.4:1, 0.7:1, 1: 1; the lower limit of the mass ratio of the solid catalyst to sorbitol is independently selected from 0.01:1, 0.05:1, 0.2:1, 0.3:1, 0.4:1, 0.7: 1.

For example, the mass ratio of solid catalyst to sorbitol can be 0.05:1, 0.2:1, 0.3:1, 0.4:1, 0.7:1, or 1:1.

The concentration of the acid active center is reduced due to the excessively low dosage of the catalyst, so that effective contact between substrate molecules and an acid site of the catalyst is not facilitated, and the substrate conversion rate is reduced; the catalyst dosage is too high, side reactions such as polymerization and the like are easily aggravated, and the selectivity of key intermediate products and target products is reduced.

In a preferred embodiment of the process of the present invention, the acetylating agent comprises at least one of glacial acetic acid, acetic anhydride.

Preferably, the molar ratio of the acetylating agent to sorbitol is 0.5:1 to 3:1, preferably 0.6:1 to 3: 1.

Specifically, the molar ratio of acetylating agent to sorbitol may be 0.5:1, 0.68:1, 0.85:1, 0.9:1, 1:1, 1.1:1 or 3: 1.

When the molar ratio of the acetylating agent to the sorbitol is less than 0.5:1, the utilization rate of sorbitol atoms is not high, and the economic benefit is low; when the molar ratio of the acetylation reagent to sorbitol is greater than 3:1, deep esterification is likely to occur, and isosorbide diacetate is produced.

In a preferred embodiment of the process of the present invention, the nitrating agent comprises nitric acid and acetic anhydride.

Preferably, the molar ratio of the nitrating agent to the sorbitol is 0.5: 1-2: 1 based on the amount of nitric acid.

Specifically, the molar ratio of nitrating agent to sorbitol may be 0.5:1, 0.6:1, 0.7:1, 0.8:1, or 1:1.

When the molar ratio of the nitrating agent to the sorbitol is less than 0.5:1, the nitration efficiency is not high; when the molar ratio of the nitrating agent to the sorbitol is more than 2:1, the excessive use of nitric acid increases the difficulty of treatment after reaction.

In a more preferred embodiment of the process of the present invention, the nitrating agent is a mixture of nitric acid and acetic anhydride.

Preferably, the mixing molar ratio of the nitric acid to the acetic anhydride is 1: 0.5-1: 4, preferably 1: 1-1: 1.5.

Specifically, the mixing molar ratio of nitric acid to acetic anhydride may be 1:0.5, 1:1, 1: 1.5.

In the present invention, the nitric acid may be selected from fuming nitric acid or concentrated nitric acid.

In the context of the present invention, concentrated nitric acid is commercially available nitric acid with a mass fraction of 68%, and fuming nitric acid is commercially available nitric acid with a mass fraction of 86-97.5%.

In a preferred embodiment of the process of the invention, the process comprises at least the following steps:

1) contacting a material containing sorbitol and an acetylating agent with a solid acid catalyst to perform acylation reaction to prepare 2-isosorbide acetate;

2) adding a material containing a nitrating agent into the 2-isosorbide acetate obtained in the step 1), and carrying out nitration reaction under the catalysis of solid acid to generate the 2-isosorbide acetate-5-nitrate.

Specifically, the method for preparing the 2-acetic acid-5-nitric acid isosorbide ester from the sorbitol is a one-pot method, and the 2-acetic acid-5-nitric acid isosorbide ester is prepared by catalyzing the sorbitol through the one-pot method. More specifically, sorbitol is used as a raw material, solid acid with dehydration and esterification activity is used as a catalyst, glacial acetic acid or acetic anhydride is used as an acetylating agent, and 2-acetic acid isosorbide is generated through one-step dehydration acetylation; then directly adding a nitrating agent, and catalyzing and nitrifying by solid acid to generate the 2-acetic acid-5-nitric acid isosorbide ester (the reaction process is shown in the following formula). The method avoids the separation and purification of intermediate products and greatly simplifies the operation flow.

In a preferred embodiment of the method of the present invention, the acylation reaction temperature is 100 to 180 ℃ and the reaction time is 1 to 24 hours.

The acylation reaction temperature is too low to reach the activation energy of sorbitol dehydration, the catalyst efficiency is reduced, and sorbitol dehydration and cyclization are difficult to perform; when the reaction temperature is too high, the reaction is too violent, so that excessive reaction is easily caused, and the yield of the target product, namely the 2-isosorbide acetate, is reduced. The acylation reaction time is 1-24 hours. The one-step catalytic preparation of 2-isosorbide acetate from sorbitol is a series of reactions, in which sorbitol is dehydrated to generate an isosorbide intermediate product, and then mono-esterification reaction is carried out to selectively generate the 2-isosorbide acetate. Thus, the reaction time is a key factor affecting the distribution of the esterification products. The reaction time is too short, sorbitol dehydration is used as a main reaction, and the accumulation of an isosorbide intermediate is formed; with the prolonging of the reaction time, the isosorbide intermediate is further subjected to esterification reaction with an acetylating agent to prepare a target product, namely 2-isosorbide acetate; the reaction time is continuously prolonged, side reactions such as excessive esterification and polymerization are easily caused, and the yield of the 2-isosorbide acetate is reduced.

In a preferred embodiment of the method, the nitration reaction temperature is 0-20 ℃, and the nitration reaction time is 1-5 hours.

Compared with the prior art, the invention has the following advantages:

1) the invention directly takes sorbitol as raw material to prepare the 2-acetic acid-5-nitric acid isosorbide ester.

2) The solid acid catalyst with both dehydration activity and esterification activity is used for replacing strong corrosive liquid acid catalysts such as sulfuric acid and the like, and the method has the advantages of easiness in separation, recyclability, no corrosion to equipment and the like, the reaction process has no requirement on vacuum degree, and simultaneously, an intermediate product does not need to be separated, so that the key drug precursor 2-acetic acid-5-nitric acid isosorbide can be synthesized by one-pot conversion of sorbitol with low energy consumption.

Detailed Description

The present invention is further described with reference to specific examples, but the scope of the present invention is not limited to the examples.

The raw materials, instruments and the like used in the present invention are known in the art and are commercially available.

In the examples of the present invention, unless otherwise specified, concentrated nitric acid refers to a commercially available nitric acid with a mass fraction of 68%, and fuming nitric acid refers to a commercially available nitric acid with a mass fraction of 86 to 97.5%.

In the present invention, the yield of the product, for example, isosorbide 2-acetate-5-nitrate, is the yield in sorbitol by gas chromatography, and is calculated by the following formula:

example 1

1.82g (10mmol) of sorbitol, 0.41g (6.8mmol) of glacial acetic acid and 0.364g of the solid acid catalyst phosphotungstic heteropoly acid (H)₃PW₁₂O₄₀) Putting into a reaction kettle, replacing with nitrogen, sealing the reactor, and magnetically stirring at 150 ℃ for reaction for 12 hours; the temperature of the ice-water bath was adjusted to 20 ℃ and mixed acid prepared from 0.441g (7mmol) of fuming nitric acid and 0.714g (7mmol) of acetic anhydride was added directly and reacted for 2 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 28 mol% (based on sorbitol).

Example 2

1.82g (10mmol) of sorbitol, 0.60g (10mmol) of glacial acetic acid and 0.364g of the solid acid catalyst silicotungstic heteropoly acid (H)₄SiW₁₂O₄₀) Putting into a reaction kettle, and adding nitrogenGas replacement, sealing the reactor, and magnetically stirring at 140 ℃ for reaction for 18 hours; the temperature of the ice-water bath was adjusted to 15 ℃ and mixed acid prepared from 0.504g (8mmol) of concentrated nitric acid and 1.224g (12mmol) of acetic anhydride was added directly and reacted for 3 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 29 mol% (based on sorbitol).

Example 3

Putting 1.82g (10mmol) of sorbitol, 1.80g (30mmol) of glacial acetic acid and 0.728g of solid acid catalyst Amberlyst-15 into a reaction kettle, replacing the mixture with nitrogen, sealing the reactor, and magnetically stirring the mixture at 140 ℃ for reaction for 12 hours; the temperature of the ice-water bath was adjusted to 20 ℃, mixed acid prepared from 0.63g (10mmol) of concentrated nitric acid and 1.02g (10mmol) of acetic anhydride was directly added, and the reaction was carried out for 3 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 22 mol% (based on sorbitol).

Example 4

Putting 1.82g (10mmol) of sorbitol, 0.30g (5mmol) of glacial acetic acid and 0.546g of solid acid catalyst Amberlyst-70 into a reaction kettle, replacing the mixture with nitrogen, sealing the reactor, and magnetically stirring the mixture at 180 ℃ for reaction for 2 hours; the temperature of the ice-water bath was adjusted to 10 ℃, mixed acid prepared from 0.378g (6mmol) of fuming nitric acid and 0.612g (6mmol) of acetic anhydride was directly added, and the reaction was carried out for 3 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 25 mol% (based on sorbitol).

Example 5

Putting 1.82g (10mmol) of sorbitol, 0.87g (8.5mmol) of acetic anhydride and 0.100g of solid acid catalyst Nafion 50 into a reaction kettle, replacing with nitrogen, sealing the reactor, and magnetically stirring at 110 ℃ for reacting for 8 hours; the temperature of the ice-water bath was adjusted to 5 ℃ and mixed acid prepared from 0.63g (10mmol) of concentrated nitric acid and 0.51g (5mmol) of acetic anhydride was added directly and reacted for 4 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 23 mol% (based on sorbitol).

Example 6

1.82g (10mmol) sorbitol, 1.12g (11mmol) acetic acid and 1.27g solid acid catalyst 1-propanesulfonic acid-3-methylimidazol phosphotungstate [ MIMPS [ ]]₃PW₁₂Putting into a reaction kettle, replacing with nitrogen, sealing the reactor, and magnetically stirring at 120 ℃ for reaction for 5 hours; the temperature of the ice-water bath was adjusted to 10 ℃, and mixed acid prepared from 0.504g (8mmol) of concentrated nitric acid and 0.816g (8mmol) of acetic anhydride was directly added, and the reaction was magnetically stirred for 1.5 hours. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 30 mol% (based on sorbitol).

Example 7

1.82g (10mmol) sorbitol, 0.918g (9mmol) acetic acid and 1.82g solid acid catalyst 1-butanesulfonic acid-3-methylimidazol silicotungstate [ MIMBS ]]₄SiW₁₂Putting into a reaction kettle, replacing with nitrogen, sealing the reactor, and magnetically stirring at 130 ℃ for reaction for 1 hour; the temperature of the ice-water bath was adjusted to 5 ℃, mixed acid prepared from 0.63g (10mmol) of concentrated nitric acid and 1.02g (10mmol) of acetic anhydride was directly added, and the reaction was carried out for 2 hours with magnetic stirring. At the end of the reaction, the product was quantitatively analyzed by gas chromatography, expressed as mole percent (mol%). The gas chromatography yield of isosorbide 2-acetate-5-nitrate was 31 mol% (based on sorbitol).

Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.