TW202017898A - Method for preparing nitrate ester - Google Patents

Abstract

A method for preparing a nitrate ester is provided. The method includes providing a first solution consisting of a compound (which has at least one hydroxyl group) and a carboxylic acid having 2-5 carbon atoms; providing a second solution consisting of nitric acid, acetic anhydride and acetic acid; transferring the first solution and the second solution to a microreactor, obtaining a nitrate ester after a residence time. In particular, the ratio of the weight of nitric acid to the total volume of the acetic anhydride and acetic acid is 1:1 to 1:3.5. The ratio of the molar amount of nitric acid to the equivalent amount of the acetic anhydride and acetic acid is 1:1 to 15:1.

Description

Preparation method of nitrate compound

The present disclosure relates to a method for preparing a nitrate compound.

Nitrate is an important class of organic compounds, which has a very wide range of uses in the field of modern science. In the field of military industry, polyol nitrate is an important component of explosives and rocket propellants; in the field of medicine, nitrate can be used as a cardiotonic agent and vasodilator; and, in the field of petroleum processing, alkyl nitrate can be used as a diesel alkyl Value accelerator.

Unfortunately, the preparation of organic nitrates (especially nitrates with more than one nitryloxy group, such as glyceryl trinitrate) poses a safety problem because organic nitrates are explosive and difficult to use even in dilute solutions deal with. In addition to the use of highly corrosive acids, the need to process large amounts of aqueous nitrate waste also increases the difficulty of industrial production of organic nitrates. In addition, even if a batch reactor is used for the preparation of organic nitrate esters, it may cause danger due to local overheating due to uneven distribution of the reactants.

Continuous improvement and control of chemical reactions (eg, improved safety, increased reaction yield, and increased purity) are the goals of continuous efforts in the chemical industry. Based on the above, the industry needs a novel organic nitrate preparation method to solve the problems encountered by the conventional technology.

According to an embodiment of the present disclosure, the present disclosure provides a method for preparing a nitrate compound, which includes providing a first solution, wherein the first solution is composed of a compound and a C _2-5 carboxylic acid, wherein the compound has at least one hydroxyl group; Providing a second solution, wherein the second solution is composed of nitric acid, acetic anhydride, and acetic acid; and, the first solution and the second solution are transferred to a microreactor to form a mixture, and after a residence time To obtain a mononitrate compound. Among them, the ratio of the weight of nitric acid to the volume of acetic anhydride and acetic acid is 1:1 to 1:3.5. In addition, before the residence time, the ratio of the molar number of nitric acid in the mixture (that is, when the first solution has not yet reacted with the second solution) to the equivalent number of hydroxyl groups of the compound is 1:1 to 15:1.

The present disclosure provides a method for preparing a nitrate compound. The preparation method of the nitrate ester compound in the present disclosure is a continuous process, for example, the preparation method of the continuous nitrate compound using a micro-channel/micro-reactor system.

Due to the preparation method of the nitrate ester compound disclosed in the present disclosure, the use of a micro-reactor with micro-channels, only by adding micro-channels in the micro-reactor can lightly increase the scale of the reaction without safety concerns, compared with the traditional Batch reactor, when the nitration reaction is amplified, the safety and process stability are increased, and the reaction time can be greatly shortened. In addition, the method for preparing the nitrate ester compound of the present disclosure, in addition to using a micro-reactor with a micro flow channel to improve the safety of nitrate ester compound preparation, also uses a specific nitrating agent (with a specific composition and ratio) Use and specific ratio of nitrating agent and alcohol compound to achieve the purpose of increasing the yield and purity of nitrate compound.

According to an embodiment of the present disclosure, the method for preparing the nitrate compound in the present disclosure includes transferring a solution containing an alcohol compound (such as isosorbide) and a solution containing a nitrating agent to a microreactor for synthesizing a nitrate compound (such as It is used to treat 療cardiac dinitrate 異 mountain nitrate ester (isosorbide dinitrate).

In addition, the preparation method of the nitrate ester compound of the present disclosure can also be widely applied to other alcohol compounds (such as glycerin, pentaerythritol nitrate, mannitol, trimethylolpropane, Or 3-chloro-1,2-propanediol (3-monochloro-1,2-propanodiol) nitration reaction for the preparation of nitrate compounds (such as glyceryl trinitrate (glyceryl trinitrate), pentaerythritol tetranitrate (pentaerythritol tetranitrate ), mannitol hexanitrate, propatyl trinitrate, or clonitrate).

FIG. 1 is a flowchart of steps of the method for preparing a nitrate compound according to the disclosed embodiment. In the present disclosure, the method for preparing a nitrate ester compound provides a first solution (step 11), wherein the first solution is composed of a compound and a C _2-5 carboxylic acid, wherein the compound has at least one hydroxyl group; Two solutions (step 13), wherein the second solution is composed of nitric acid, acetic anhydride, and acetic acid; and, the first solution and the second solution are separately sent to a microreactor to react to form a mononitrate compound (step 15).

According to an embodiment of the present disclosure, the compound described in the first solution is a compound having at least one hydroxyl group, that is, the compound is an alcohol compound. According to an embodiment of the present disclosure, the compound in the first solution has no other functional groups that can undergo the nitration reaction except the hydroxyl group. According to an embodiment of the present disclosure, the compound and C _2-5 carboxylic acid may be a carboxylic acid having two carbon atoms, a carboxylic acid having three carbon atoms, a carboxylic acid having four carbon atoms, or a carboxylic acid having five carbon atoms carboxylic acid. For example, the C _2-5 carboxylic acid may be acetic acid, propionic acid, butyric acid, or valeric acid.

According to an embodiment of the present disclosure, the ratio of the volume of C _2-5 carboxylic acid in the first solution to the weight of the compound may be 1 mL/g to 10 mL/g, such as 2 mL/g, 3 mL/g, 4 mL/g, 5 mL/ g, 6mL/g, 7mL/g, 8mL/g, or 9mL/g.

According to an embodiment of the present disclosure, the nitric acid in the second solution has a concentration of not less than 98%, for example, a concentration of 98% to 100%. In other words, the purer the nitric acid used in the present disclosure, the better, but since nitric acid will inevitably adsorb moisture in actual use, the second solution of the present disclosure can use nitric acid with a concentration of not less than 98% as much as possible. Since the second solution of the present disclosure is composed of nitric acid, acetic anhydride, and acetic acid, the second solution does not substantially include water (that is, water is not intentionally added to the second solution). According to the embodiments of the present disclosure, if the concentration of nitric acid used in the second solution is less than 98% or the second solution substantially contains water (that is, deliberately added water), the yield and purity of the resulting nitrate compound are likely to decrease.

According to an embodiment of the present disclosure, the volume ratio of acetic anhydride and acetic acid is 3:1 to 1:3, such as 2:1, 1:1, or 1:2. According to an embodiment of the present disclosure, the ratio of the weight of nitric acid to the total volume of acetic anhydride and acetic acid is 1:1 to 1:3.5, such as 1:1.5, 1:2, 1:2.5, or 1:3. If the ratio of the weight of nitric acid to the total volume of acetic anhydride and acetic acid is too low or too high, the yield and purity of the resulting nitrate compound are likely to decrease.

According to an embodiment of the present disclosure, the second solution of the present disclosure is used as a nitrating agent for performing a nitration reaction on a hydroxyl-containing compound to obtain a nitrate compound. According to an embodiment of the present disclosure, the second solution of the present disclosure does not contain sulfuric acid, so as to avoid a decrease in the purity of the resulting nitrate compound. In addition, according to an embodiment of the present disclosure, the second solution of the present disclosure does not include a chlorine-containing compound (such as dichloromethane). If the second solution contains dichloromethane, when the first solution reacts with the second solution in the microchannel of the microreactor, the dichloromethane has a lower boiling point and the reaction is exothermic, which may easily cause dichloromethane gasification . According to the embodiments of the present disclosure, since the nitrating reagent used in the method for preparing the nitrate ester compound of the present disclosure is composed of only nitric acid, acetic anhydride and acetic acid, the nitric acid after the reaction can be reused after a simple treatment.

According to an embodiment of the present disclosure, the mixture of the first solution and the second solution initially mixed in the microreactor has a ratio of the molar number of nitric acid to the equivalent number of hydroxyl groups of the compound of 1:1 to 15:1. In other words, when the first solution has not reacted with the second solution, the ratio of the molar number of nitric acid of the mixture in the microreactor to the equivalent number of hydroxyl groups of the compound is 1:1 to 15:1. According to an embodiment of the present disclosure, the ratio of the molar number of nitric acid to the equivalent number of hydroxyl groups of the compound may be, for example, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 , 10:1, 11:1, 12:1, 13:1, or 14:1. If the molar ratio of nitric acid to the equivalent number of hydroxyl groups of the compound is too low, it is easy to cause incomplete nitration reaction, resulting in a decrease in the yield of nitrate compounds. If the molar ratio of nitric acid to the equivalent number of hydroxyl groups of the compound is too high, it is easy to cause waste of raw materials, increase costs, and require more alkaline aqueous solution for neutralization.

Please refer to FIG. 2, which is a micro-reactor system 100 used in the method for preparing a nitrate ester compound according to an embodiment of the present disclosure. In this embodiment, the first solution is placed in a first tank 10 of the microreactor system 100, and the second solution is placed in a second tank 20 of the microreactor system 100. . The first tank 10 and the second tank 20 can each have a control unit to transfer the first solution from the first tank 10 to the microreactor 30 through a first channel 12 at a first flow rate , And the second solution is transferred from the second tank 20 to the microreactor 30 through a second channel 12 at a second flow rate.

After the first solution and the second solution are transferred to the microreactor 30 to form a mixture and undergo a residence time (for example, 30 seconds to 200 seconds), a mononitrate compound can be obtained in a collection tank 40. According to an embodiment of the present disclosure, the microreactor 30 has at least one set of microchannels, wherein the inner diameter of the microchannels is 0.05 mm to 2 mm, such as 0.1 mm, 0.5 mm, 0.8 mm, 1 mm, or 1.5 mm. According to an embodiment of the present disclosure, the first flow rate of the first solution in the first channel 12 is 0.05 mL/min to 1.5 mL/min, and the second flow rate of the second solution in the second channel 22 is 0.05 mL/min min to 1.5 mL/min. According to the embodiment of the present disclosure, the temperature of the microreactor can be controlled at 0°C-30°C.

According to the embodiment of the present disclosure, by adjusting the first flow rate and the second flow rate, the purpose of controlling the ratio of the molar number of nitric acid in the microreactor 30 to the equivalent number of hydroxyl groups of the compound can be achieved. According to the embodiments of the present disclosure, the method for preparing the nitrate ester compound of the present disclosure utilizes the excellent heat transfer capability of the micro-channels in the micro-reactor to solve the problem of local reaction overheating and make the process safer and more stable. In addition, in the microreactor, the reaction is carried out in a continuous flow mode. By adjusting the flow rate of the reactants and the length of the microchannel in the microreactor, their residence time (reaction time) in the microreactor can be precisely controlled.

In order to make the above-mentioned and other purposes, features, and advantages of this disclosure more obvious and understandable, the following specific examples are given as follows:

)與乙酸(acetic acid、20mL)混合得到一第一溶液(乙酸的體積與異山梨酯的重量比為5.46:1)，並將第一溶液放置於一第一槽體內。接著，將硝酸(濃度為98%、10mL)(硝酸莫耳數為234.85mmol)、乙酸酐(acetic anhydride、25ml)、及乙酸(acetic acid、15ml) 混合得到一第二溶液(硝酸的重量與乙酸酐和乙酸體積總合的比為1:2.7、且乙酸酐和乙酸的體積比為5:3)，並將第二溶液放置於一第二槽體內。接著，以0.2 mL/min的流速將第一溶液由第一槽體經由一通道輸送至微反應器、並以0.5 mL/min的流速將第二溶液由第二槽體經由一通道輸送至微反應器。其中，當第一溶液與第二溶液在微反應器中初始混合時，硝酸的莫耳數與異山梨酯之羥基的當量數比約為5:1。第一溶液及第二溶液在微反應器的微流道內反應(微反應器溫度控制約在20℃)，其中微反應器內的微流道長度約為105cm，且微反應器內的微流道材質為聚四氟乙烯(PTFE、內徑為1mm)。第一溶液及第二溶液在微反應器之微流道內的滯留時間(反應時間)約為70秒，且微反應器之微流道終端係設置一收集槽，且收集槽內加入水。反應後所得溶液直接由微流道導入收集槽(溫度設置為0℃)中，可觀察到白色固體直接在冰水中析出，過濾烘乾後可得硝酸異山梨酯(isosorbide dinitrate)。表1顯示所得硝酸異山梨酯(isosorbide dinitrate)(結構為

)的產率及純度(以純氣相層析法(gas chromatography)決定)。利用核磁共振光譜分析硝酸異山梨酯，所得光譜資訊如下：¹ H NMR (CDCl₃ , 400 MHz) spectrum data : δ5.42-5.39(m, 2H), 5.05-5.01(m,1H), 4.62-4.59(m,1H), 4.20-4.10(m,3H), 3.99-3.94(m,1H)。Example 1 Isosorbide (isosorbide, 25.04 mmol) (structure is

) Is mixed with acetic acid (20 mL) to obtain a first solution (the volume ratio of acetic acid to isosorbide is 5.46:1), and the first solution is placed in a first tank. Next, nitric acid (concentration: 98%, 10 mL) (molar number of nitrate is 234.85 mmol), acetic anhydride (acetic anhydride, 25 ml), and acetic acid (acetic acid, 15 ml) are mixed to obtain a second solution (the weight of nitric acid and The total volume ratio of acetic anhydride and acetic acid is 1:2.7, and the volume ratio of acetic anhydride and acetic acid is 5:3), and the second solution is placed in a second tank. Next, the first solution is transferred from the first tank to the microreactor at a flow rate of 0.2 mL/min, and the second solution is transferred from the second tank to the microreactor at a flow rate of 0.5 mL/min. reactor. When the first solution and the second solution are initially mixed in the microreactor, the equivalent number ratio of the molar number of nitric acid to the hydroxyl group of isosorbide is about 5:1. The first solution and the second solution react in the micro-channel of the micro-reactor (the temperature of the micro-reactor is controlled at about 20°C), wherein the length of the micro-channel in the micro-reactor is about 105 cm, and the micro The material of the flow channel is polytetrafluoroethylene (PTFE, inner diameter is 1mm). The residence time (reaction time) of the first solution and the second solution in the microchannel of the microreactor is about 70 seconds, and a collection tank is provided at the end of the microchannel of the microreactor, and water is added to the collection tank. After the reaction, the resulting solution was directly introduced into the collection tank (temperature set to 0°C) from the micro-channel, and it was observed that white solid precipitated directly in ice water. After filtration and drying, isosorbide dinitrate was obtained. Table 1 shows the resulting isosorbide dinitrate (structure is

) Yield and purity (determined by pure gas chromatography). Using nuclear magnetic resonance spectroscopy to analyze isosorbide nitrate, the obtained spectral information is as follows: ¹ H NMR (CDCl ₃ , 400 MHz) spectrum data: δ5.42-5.39(m, 2H), 5.05-5.01(m,1H), 4.62- 4.59(m,1H), 4.20-4.10(m,3H), 3.99-3.94(m,1H).

Comparative Example 1 was carried out in the same manner as Example 1, except that the flow rate of the second solution described in Example 1 was reduced from 0.5 mL/min to 0.06 mL/min, so that when the first solution and the second solution were in the microreactor During initial mixing, the equivalent number ratio of the molar number of nitric acid to the hydroxyl group of isosorbide is about 0.6:1. Table 1 shows the yield and purity of isosorbide dinitrate obtained in Comparative Example 1.

Comparative Example 2 was carried out in the same manner as in Example 1, except that the nitric acid with a concentration of 98% described in Example 1 was replaced with nitric acid with a concentration of 65%. Table 1 shows the yield and purity of isosorbide dinitrate obtained in Comparative Example 2.

Comparative Example 3 It was carried out in the same manner as in Example 1, except that the nitric acid with a concentration of 98% described in Example 1 was replaced with nitric acid with a concentration of 80%. Table 1 shows the yield and purity of isosorbide dinitrate obtained in Comparative Example 3.

Example 2 Performed in the same manner as Example 1, except that the flow rate of the second solution described in Example 1 was reduced from 0.5 mL/min to 0.25 mL/min, so that when the first solution and the second solution were in the microreactor During initial mixing, the equivalent number ratio of the molar number of nitric acid to the hydroxyl group of isosorbide is about 2.5:1. Table 1 shows the yield and purity of isosorbide dinitrate obtained in Example 2.

Table 1

It can be seen from Table 1 that when the molar ratio of nitric acid to the equivalent number of hydroxyl groups of isosorbide is too low, or the concentration of nitric acid used is less than 98%, the yield or purity of isosorbide obtained is Significantly decreased (as in Comparative Examples 1-3). On the contrary, when the concentration of nitric acid used is not less than 98%, and the equivalent number ratio of the molar number of nitric acid to the hydroxyl group of isosorbide is between 2:1 and 15:1, Examples 1 and 2 The yield of the obtained isosorbide dinitrate may be greater than or equal to 80%, and the purity may be greater than or equal to 88%.

Although this disclosure has been disclosed above in several embodiments, it is not intended to limit this disclosure. Anyone who has ordinary knowledge in this technical field can make any changes and modifications without departing from the spirit and scope of this disclosure. Therefore, the scope of protection disclosed in this disclosure shall be deemed as defined by the scope of the attached patent application.

10: First tank 11, 13, 15: Step 12: First channel 20: Second tank 22: Second channel 30: Microreactor 40: Collection tank; and 100: Microreactor system

FIG. 1 is a flow chart showing the steps of the method for preparing a nitrate ester compound disclosed in an embodiment; and FIG. 2 is a schematic diagram of a microreactor system used in the method for preparing a nitrate ester compound disclosed in an embodiment.

11, 13, 15: Steps

Claims (11)

A method for preparing a nitrate compound, comprising: providing a first solution, wherein the first solution is composed of a compound and a C _2-5 carboxylic acid, wherein the compound has at least one hydroxyl group; providing a second solution, wherein the The second solution is composed of nitric acid, acetic anhydride and acetic acid, wherein the ratio of the weight of nitric acid to the total volume of acetic anhydride and acetic acid is 1:1 to 1:3.5; and the first solution and the second solution are transported to A mixture is formed in a microreactor, and after a residence time, a mononitrate compound is obtained, wherein the ratio of the molar number of nitric acid in the mixture to the equivalent number of hydroxyl groups of the compound is 1:1 to 15:1. The method for preparing a nitrate ester compound as described in item 1 of the patent application scope, wherein nitric acid has a concentration of not less than 98%. The method for preparing a nitrate ester compound as described in item 1 of the patent application scope, wherein the C _2-5 carboxylic acid is acetic acid, propionic acid, butyric acid, or valeric acid. The method for preparing a nitrate ester compound as described in item 1 of the patent application, wherein the residence time is 30 seconds to 200 seconds. The method for preparing a nitrate ester compound as described in item 1 of the patent application range, wherein the flow rate of the first solution to the microreactor is 0.05 mL/min to 1.5 mL/min. The method for preparing a nitrate ester compound as described in item 1 of the patent application scope, wherein the flow rate of the second solution to the microreactor is 0.05 mL/min to 1.5 mL/min. The method for preparing a nitrate ester compound as described in item 1 of the patent application scope, wherein the volume ratio of the acetic anhydride and acetic acid is 3:1 to 1:3. The method for preparing a nitrate ester compound as described in item 1 of the patent application range, wherein the inner diameter of the micro-channel in the micro-reactor is 0.05 mm to 2 mm. The method for preparing a nitrate ester compound as described in item 1 of the patent application scope, wherein the ratio of the volume of the C _2-5 carboxylic acid to the weight of the compound is 1 mL/g to 10 mL/g. The preparation method of the nitrate ester compound as described in item 1 of the patent application scope, wherein the compound is isosorbide, glycerin, pentaerythritol nitrate, mannitol, trimethylolpropane (trimethylolpropane), or 3-chloro-1,2-propanediol (3-monochloro-1,2-propanodiol). The preparation method of the nitrate compound as described in item 1 of the patent application scope, wherein the nitrate compound is isosorbide dinitrate, glyceryl trinitrate, pentaerythritol tetranitrate, Mannitol hexanitrate, propatyl trinitrate, or clonitrate.

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