WO2020006944A1

WO2020006944A1 - Method for synthesizing 5-isosorbide mononitrate by means of micro-channel reactor

Info

Publication number: WO2020006944A1
Application number: PCT/CN2018/112993
Authority: WO
Inventors: 张贵民; 陈成富; 朱健波
Original assignee: 山东新时代药业有限公司
Priority date: 2018-07-03
Filing date: 2018-10-31
Publication date: 2020-01-09
Also published as: CN108586477B; CN108586477A

Abstract

The present invention relates to the pharmaceutical synthesis field, and provides a method for synthesizing 5-isosorbide mononitrate by means of a micro-channel reactor. In the present invention, a nitrating reagent and isosorbide liquid are pumped into the micro-channel reactor respectively for mixing reaction; after the reaction is completed, a product flows out from an outlet of the micro-channel reactor, and is subjected to post-treatment, separation, and purification to obtain the target product 5-isosorbide mononitrate. According to the method provided in the present invention, reaction time is short, and compared with a conventional technology, the method is safe, and the yield of the 5-isosorbide mononitrate is greatly improved.

Description

Method for synthesizing 5 -isosorbide mononitrate by microchannel reactor Technical field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for synthesizing isosorbide 5 -mononitrate, in particular to a method for synthesizing isosorbide 5 -mononitrate in a microchannel reactor.

Background technique

[0002] 5-isosorbide mononitrate (1,4: 3, 6-dianhydro -D-sorbitol -5-nitrate, the structural formula is as the compound in formula I

1) is isosorbide nitrate (1,4: 3,6-dihydroanhydro-D-sorbitol-2,5 -dinitrate, the structural formula is as compound 2 in formula I

) The main metabolites in the body, compared with isosorbide nitrate and 2-isosorbide mononitrate (1,4: 3,6-dihydroanhydro-D-sorbitol-2 -nitrate, the structural formula is as shown in formula I Compound 3), which has the advantages of no liver first-pass effect after oral administration, high bioavailability, small side effects, and long duration of action. It was developed and marketed by the German Boe hringer Mannheim GmbH in 1981. It is widely used in clinical practice and has become the first-line medication for anti-angina pectoris.

[0003]

[0004] There are many reports on the synthesis route of isosorbide mononitrate, which are mainly divided into direct nitrification, selective reduction, and indirect nitrification. The mainstream industrialized production route still uses the direct nitrification method, which is mainly based on the advantages of short route, low cost, and simple operation of the direct nitrification method.

[0005] The specific route of the direct nitration method is as follows: Isosorbide (1,4: 3,6-dihydro-D-sorbitol, the structural formula is compound 4 in Formula I) is used as a starting material and a nitrating agent (such as nitric acid / Sulfuric acid, nitric acid / acetic anhydride, etc.) After the reaction, the target product can be obtained by separation and purification. Documents "Hayward, L. er d Can. J. Chem" 1967, 45, 2191-2194 ", patents US3886186, US4584391, JP5529996, CN103641840 etc. reported

l this method. The reaction route looks like this:

[0006]

[0007] However, there are also many problems with the direct nitrification method, which are mainly manifested in low yields. In fact, for mononitration of diols and polyols (such as 1,4-butanediol, glycerin, etc.), problems such as poor selectivity and excessive nitration are generally faced, and the yield is generally difficult to reach 50%. This is because the difference in the activity of the hydroxyl groups at each position is often small. Compared to the mononitration of symmetric diols (such as 1,4-butanediol, mononitration at the 1-position and mononitration at the 4-position to the same compound), the two hydroxyl groups of isosorbide It is asymmetric, and it is the target product when the 5-hydroxy hydroxynitrate is esterified, while the 2-nitro hydroxynitrate is isosorbide 2-mononitrate. Therefore, it is more difficult to synthesize 5 -isosorbide mononitrate by direct nitration, and the yield is lower. At present, the yield of isosorbide 5 -mononitrate by direct nitration method has not exceeded 40%.

[0008] Another major problem with the synthesis of 5-sorbate isosorbide by the direct nitration method is the high process safety risk. Because the nitrating agent and the nitrate product are explosive, especially isosorbide nitrate containing two nitrate groups Esters are produced in large quantities during the synthesis process, and the reaction conditions (temperature, pressure) need to be strictly controlled. Generally, low-temperature, automatic reaction chain protection devices are required, but this cannot effectively reduce potential safety hazards, especially when the batch size is increased. It increases exponentially, which limits the expansion of production capacity to a certain extent.

[0009] In recent years, due to its size effect, the microchannel reactor can make the reactants mix more fully, control the temperature accurately, reduce side reactions and hidden safety hazards caused by mass and poor heat transfer, and the reaction liquid is continuously Forward flow, which reduces the occurrence of overreaction due to "backmixing". In addition, the microchannel system is much smaller than the kettle reaction, which greatly reduces the potential risks of the process. Since an uninterrupted flux reaction can be achieved, the annual flux can reach the scale of thousands of tons. These advantages make microchannel reactors get great attention and use in the field of medicine and chemical industry, especially in dangerous processes such as nitrification, hydrogenation, and diazotization.

Summary of invention

technical problem [0010] Aiming at the defects of low yield, poor reaction selectivity, and potential safety hazards existing in the direct nitrification method in the prior art, the inventor has provided a safe and efficient microchannel reactor through a large number of experiments Method for synthesizing 5 -isosorbide mononitrate.

Problem solution

Technical solutions

[0011] Using a direct nitration method in a microchannel reactor to safely and efficiently nitrate isosorbide with a more difficult asymmetric diol structure, and then synthesize 5 -isosorbide mononitrate is our research direction. . The reason for the low yield of the direct nitration method is mainly due to the fact that the 2-hydroxy and 5-hydroxy isosorbide activities are not much different, and both hydroxyl groups may be nitrated. In order to obtain higher yields, isosorbide needs to be improved. The activity of the hydroxyl group at the 5-position of the alcohol, the inventors found through further experimental research that lowering the reaction temperature is beneficial to increase the activity of the isosorbide at the 5-position, and further increase the yield of the target product, 5-isosorbide mononitrate.

[0012] The inventors also found that the addition of isosorbide nitrate by-product to the reaction system can effectively reduce the occurrence of isosorbide nitrate side reactions; the nitration of isosorbide to isosorbide mononitrate improves the raw material isosorbide Utilization.

[0013] In the present invention, the prepared nitrating reagent and isosorbide solution are separately pumped into a microchannel reactor for mixed reaction, the molar ratio of isosorbide and the nitrating reagent is controlled by the liquid flow rate, and the temperature is controlled by integration in the microchannel reactor The medium controls the reaction temperature; the reaction residence time of the reaction solution in the microchannel reactor is controlled by the number of reaction plates in series. The reaction solution flowing from the outlet of the microchannel reactor was post-processed and separated and purified to obtain isosorbide 5-mononitrate.

[0014] The nitrating agent of the present invention is fuming nitric acid and acetic anhydride. Isosorbide is a solution that dissolves isosorbide in acetic acid. However, the melting point of acetic acid is 16.6 ° C. At lower temperatures, the solution system will solidify and block the microchannels. Therefore, an auxiliary solvent needs to be added to dilute the isosorbide solution to lower the freezing point of the solution system. After a lot of experiments, the inventors unexpectedly found that the addition of a solvent containing a furan ring can not only dilute the isosorbide solution, but also greatly increase the activity of the 5-position hydroxyl group, thereby further improving the yield of the target product 5-isosorbide mononitrate and reducing Formation of by-product 2-isosorbide mononitrate.

[0015] The object of the invention is achieved as follows:

[0016] A method for synthesizing isosorbide 5-mononitrate in a microchannel reactor, comprising the steps of pumping a nitrating agent and an isosorbide solution into a microchannel reactor to perform a mixing reaction, and after the reaction is completed, The outlet of the channel reactor flows out, and is processed and separated and purified to obtain the target product 5-isosorbide mononitrate.

[0017] Specifically, a method for synthesizing 5 -isosorbide mononitrate in a microchannel reactor includes the following steps:

[0018] (1) Preparation of nitrating reagent: At 0 ~ 10 ° C, fuming nitric acid is slowly added dropwise to acetic anhydride, and it is kept warm for future use.

[0019] (2) Preparation of isosorbide solution: Dissolve isosorbide and isosorbide nitrate in acetic acid and auxiliary solvents, stir until the dissolution is complete, and set aside.

[0020] (3) The reaction temperature is set, and the above-mentioned nitrating reagent and isosorbide solution are pumped into a microchannel reactor to perform a mixed reaction. After the reaction is completed, the product flows out of the reactor outlet to obtain an effluent.

[0021] (4) The effluent obtained in step (3) is subjected to post-treatment, separation and purification to obtain the target product 5-isosorbide mononitrate.

[0022] In one embodiment, the molar ratio of step (1) fuming nitric acid to acetic anhydride is

In another preferred embodiment, the molar ratio of fuming nitric acid to acetic anhydride in step (1) is 1: 1 to 1.5.

[0023] In step (2), the mass ratio of isosorbide to isosorbide nitrate is 1: 0.05 to 0.3.

[0024] Step (2) The selection principle of the auxiliary solvent is not to participate in the reaction and to lower the freezing point of the reaction solution; the auxiliary solvent is selected from one of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran. Or several. In one embodiment, the auxiliary solvent in step (2) is a mixed solution of tetrahydrofuran and acetone, ethyl acetate or dichloromethane; in another embodiment, the auxiliary solvent in step (2) is 2- A mixed solution of methyltetrahydrofuran and acetone, ethyl acetate or dichloromethane; in a preferred embodiment, the auxiliary solvent in step (2) is tetrahydrofuran or 2-methyltetrahydrofuran; in a preferred embodiment In the step (2), the auxiliary solvent is 2-methyltetrahydrofuran. When the auxiliary solvent contains tetrahydrofuran or 2-methyltetrahydrofuran, the activity of the isosorbide at the 5-position hydroxyl group is significantly higher than that of the auxiliary solvent without the furan ring. The solvent is active at the 5-hydroxy group of isosorbide.

[0025] In one embodiment, in step (2), the volume ratio of acetic acid to the auxiliary solvent is 1: 0.5 ~ 2, and the mass-volume ratio of isosorbide to acetic acid is

Wherein the mass is in g and the volume is in mL.

[0026] In one embodiment, the molar ratio of isosorbide to fuming nitric acid is

In another preferred embodiment, the molar ratio of isosorbide to fuming nitric acid is 1: 1.2 to 1.5.

[0027] In one embodiment, the reaction residence time of step (3) of the microchannel reactor is 15 to 300 s, and the reaction temperature is -15 to 20 ° C; In a preferred embodiment, step (3) micro Reaction time of the channel reactor The time is 15 ~ 60 s, and the reaction temperature is -15 ~ 0 ° C.

[0028] The molar ratio of fuming nitric acid to isosorbide of the present invention can be controlled by the liquid flow rate of the nitrating reagent and isosorbide liquid pumped into the microchannel reactor;

Preferably

5.

[0029] The reaction temperature of the microchannel reactor of the present invention is controlled by a temperature control medium coupled to the microchannel reactor, and the cooling medium is circulated through the interlayer of the microchannel reactor. The reaction temperature is -15 ~ 20 ° C, preferably -15 ~ 0 ° C. When the reaction temperature is -15 ~ 0 ° C, the activity of the 5-position hydroxyl group of isosorbide is higher than the reaction temperature of 0 ~ 20 ° C. Isosorb 5-hydroxy position activity.

[0030] The residence time of the reaction liquid in the microchannel of the present invention is controlled by the amount of feed liquid and the content of the microchannel reactor (the liquid holding capacity of each microchannel plate multiplied by the number of connected plates). The feed of material liquid is controlled by independent metering pump, and the flow range can be adjusted from 1 to 100 mL / min. The microchannel plates are connected in series and can be increased or decreased according to the experiment. The nitration reaction solution is controlled to stay in the microchannel reactor for 15 to 300 s, preferably 15 to 60 s.

[0031] In step (4), the post-processing method is to concentrate the effluent obtained in step (3) under reduced pressure, add purified water to the concentrated solution, stir and crystallize, and then remove isosorbide nitrate by filtration. GC detection of the filtrate. The filtrate was reacted with sodium hydroxide solution to form a salt to obtain crude 5-isosorbide monosodium mononitrate. The crude 5-isoisosorbate sodium mononitrate was acidified and purified to obtain the target product 5-isosorbide mononitrate. ester.

[0032] The invention does not limit the type, material, etc. of the microchannel reactor. Any microchannel reactor that can be used to implement the technical solution of the present invention can be used.

The beneficial effects of the invention

Beneficial effect

[0033] The reaction is performed in a continuous flow method in a microchannel reactor. For chemical reactions with a fast reaction speed, the reaction time in the microchannel reactor can be precisely controlled by adjusting the flow rate of the reactants and the length of the microchannel. .

[0034] The present invention uses a microchannel reactor to obtain 5-isoisosorbate mononitrate through a direct nitration method, which has the following advantages:

[0035] 1. In the reaction system, by-product isosorbide nitrate is added without adding a large amount of nitrating reagent, so that isosorbide mononitrates, and the progress of the side reaction to isosorbide nitrate can be reduced, so that isosorbide can be made. To The reaction of isosorbide mononitrate improves the utilization of isosorbide. In addition, the reaction material liquid continues to flow forward, and the liquid holding capacity is greatly reduced compared to the kettle reaction, which greatly reduces the potential safety hazards caused by the intense heat generation of nitrification and the material itself.

[0036] 2. In the micro-channel reactor, the reaction material and liquid are mixed efficiently and rapidly, and the reaction temperature is accurately controlled.

The selectivity of the 5- and 2-positions of isosorbide can be increased from 3: 1 to 5.2: 1 in the kettle type; more importantly, the addition of a furan ring-containing solvent to dilute the isosorbide solution can also greatly improve its The activity of the 5-position hydroxyl group can further increase the yield of the target product 5-isosorbide mononitrate and reduce the formation of the byproduct 2-isosorbide mononitrate. The furan ring solvent can make the 5 -position of isosorbide / 2- Bit selectivity increased from 5.2: 1 to above 8.0: 1. According to the present invention, the yield of 5-isosorbide mononitrate can be increased from 44.5% to 68.6% or more, and the total yield can be increased from 34.8% to 56.2% or more.

[0037] 3. The reaction time is shortened from several hours in a kettle to less than ten seconds to several minutes, which greatly shortens the process time, and can realize the safe expansion of production capacity through continuous and equipment scale.

Invention Examples

Embodiments of the invention

[0038] The present invention is further described below with reference to specific embodiments, but the following embodiments are used for illustrative purposes only and are not intended to limit the protection scope of the present invention.

[0039] The microchannel reactor used in the following examples is a Hastelloy microchannel reactor. The present invention is not limited to a microchannel reactor, and any microchannel reactor that can be used to implement the technical solution of the present invention can be used. Unless otherwise specified, the solvents used in the following examples are all commercially available.

Example 1

[0041] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g 2.5 mol), control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

[2] Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol) and isosorbide nitrate (12.5 g, 0.053 mol), and add 750

mL of acetic acid / ethyl acetate (v / v = 2: l) mixed solvent, stir to dissolve and set aside.

(3) The nitrating reagent and the isosorbide solution are fed into a microchannel reactor through a respective metering pump to perform a mixing reaction, and the flow rate of the nitrating reagent is set to 15 mL / min, and the flow rate of the isosorbide solution is 45 mL / min, control The reaction temperature was 0 ° C. Five templates were connected in series with a holding capacity of 50 mL. The reaction time of the reaction solution in the microchannel reactor was 50 s.

(4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC and calculated. The remaining amount of isosorbide and the Yield. The specific results are shown in Table 1.

Table 1

[0046] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-sodium isonitrate monosodium wet product. The target product was obtained by acidification and purification. The total yield was 59.4%, and the detection purity was 99.10%.

Example 2

[0048] (1) Preparation of nitrating reagent: In a 1 L dry three-neck flask, add acetic anhydride (347.0 g, 3.4 mol

), Control the temperature of 0 ~ 10 ° C, slowly add fuming nitric acid (108.0 g, 1.7 mol), after the dropwise addition, keep it warm for future use.

[0049] (2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol) and isosorbide nitrate (37.5 g, 0.159 mol), and add 750

mL of a mixed solvent of acetic acid / dichloromethane (v / v = 1: 2), stir to dissolve and set aside.

[0050] (3) The nitrating reagent and the isosorbide solution are fed into a microchannel reactor through a respective metering pump to perform a mixed reaction, and the flow rate of the nitrating reagent is set to 5 mL / min, and the flow rate of the isosorbide solution is 15 mL / min, control the reaction temperature to 20 ° C, connect 10 templates in series with a holding capacity of 100 mL, and the reaction time of the reaction solution in the microchannel reactor is 300 s.

[0051] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled for GC detection, and the remaining isosorbide and each product were calculated. Yield. The specific results are shown in Table 2.

Table 2

[0053] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-isoisosorbate monosodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 56.2%. The purity by HPLC was 99.08%.

Example 3

[0055] (1) Preparation of nitrating reagent: In a 1 L dry three-neck flask, add acetic anhydride (347.0 g, 3.4 mol).

[0056] (2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), isosorbide nitrate (75.0 g, 0.318 mol), and add 950 mL of acetic acid. / Dichloroformamidine / tetrahydrofuran ( _v / _v / _v = 3 _: 1: l) mixed solvent, stir to dissolve and set aside.

[0057] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through a respective metering pump to perform a mixed reaction, and the flow rate of the nitrating reagent is set to 20 mL / min, and the flow rate of the isosorbide solution is 50 mL / min, control the reaction temperature to 10 ° C, connect 5 templates in series, hold 50 mL of liquid, and the reaction time of the reaction solution in the microchannel reactor is 43 s.

[0058] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC and calculated. The remaining amount of isosorbide and the amount of each product were calculated. Yield. The specific results are shown in Table 3.

Table 3

[0060] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-sodium mononitrate isosorbide sodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 62.8%, and the detection purity was 99.14%. Example 4

[0062] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (208.0 g 2.0 mol), control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), isosorbide nitrate (50.0 g, 0.212 mol), and add 800 mL of acetic acid. / Ethyl acetate / 2-methyltetrahydrofuran (v / v / v = 2: 1: l) mixed solvent, stir to dissolve and set aside.

[0064] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through the respective metering pumps to perform a mixing reaction. The flow rate of the nitrating reagent is set to 40 mL / min, and the flow rate of the isosorbide solution is 80 mL. / min, control the reaction temperature to 0 ° C, connect 3 templates in series, hold 30 mL of liquid, and the reaction time of the reaction solution in the microchannel reactor is 15 s.

[0065] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC to calculate the remaining amount of isosorbide and the yield of each product. Yield. The specific results are shown in Table 4.

Table 4

[0067] The above filtrate was reacted with a 30% sodium hydroxide solution to obtain 5-isoisosorbate sodium mononitrate as a wet product. The target product was obtained by acidification and purification. The total yield was 65.5%. The purity by HPLC was 99.08%.

Example 5

[0069] (1) Preparation of nitrating reagent: In a 1 L dry three-neck flask, add acetic anhydride (208.0 g, 2.0 mol

[0070] (2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), isosorbide nitrate (50.0 g, 0.212 mol), and add 800

mL of a mixed solvent of acetic acid / acetone / tetrahydrofuran (v / v / v = 2: l: l), stir and dissolve it for later use. [0071] (3) The nitrating reagent and the isosorbide solution are fed into a microchannel reactor through a respective metering pump to perform a mixed reaction, and the flow rate of the nitrating reagent is set to 30 mL / min, and the flow rate of the isosorbide solution is 30 mL / min, controlling the reaction temperature to -15 ° C, connecting 5 templates in series, holding a volume of 50 mL, and the reaction time of the reaction solution in the microchannel reactor was 60 s.

[0072] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC to determine the remaining amount of isosorbide and the yield of each product. Yield. The specific results are shown in Table 5.

Table 5

[0074] The above filtrate was reacted with a 30% sodium hydroxide solution to obtain 5-isoisosorbate sodium salt as a wet product. The target product was obtained by acidification and purification, with a total yield of 68.8%, 1 ^ 1 ^: the detection purity was 99.18%.

Example 6

[0076] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g 2.5 mol), control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), isosorbide nitrate (50.0 g, 0.212 mol), and add 750

mL of acetic acid / 2-methyltetrahydrofuran (v / v = 2: l) mixed solvent, stir to dissolve and set aside.

[0078] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through respective metering pumps to perform a mixed reaction. The flow rate of the nitrating reagent is set to 20 mL / min, and the flow rate of the isosorbide solution is 60 mL. / min, the control reaction temperature was -10 ° C, 5 templates were connected in series, the holding capacity was 50 mL, and the reaction time of the reaction solution in the microchannel reactor was 38 s.

[0079] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled for GC detection, and the remaining isosorbide and Yield. Concrete knot The results are shown in Table 6.

Table 6

[0081] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare a 5-sodium isonitrate monosodium salt wet product. After acidification and purification, the target product was obtained. The total yield was 69.2%, and the detection purity was 99.16%.

Example 7

[0083] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g 2.5 mol), control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol) and isosorbide nitrate (25.0 g, 0.106 mol), and add 750

mL of acetone / tetrahydrofuran (v / v = 2: l) mixed solvent. Stir and dissolve before use.

[0085] (3) The nitrating reagent and the isosorbide solution are fed into a microchannel reactor through a respective metering pump to perform a mixing reaction. The flow rate of the nitrating reagent is set to 20 mL / min, and the flow rate of the isosorbide solution is 60 mL. / min, the control reaction temperature was -10 ° C, 5 templates were connected in series, the holding capacity was 50 mL, and the reaction time of the reaction solution in the microchannel reactor was 38 s.

(4) The reaction effluent was concentrated under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC and calculated. The remaining amount of isosorbide and the yield of each product were calculated. rate. The specific results are shown in Table 7.

Table 7

[0088] The above filtrate was reacted with a 30% sodium hydroxide solution to obtain 5-isoisosorbate monosodium salt as a wet product. The target product was obtained by acidification and purification, with a total yield of 66.5% and a detection purity of 99.13%.

Comparative Example 1

[0090] In a 100 mL dry three-necked flask, add acetic anhydride (23.0 g, 0.22 mol), control the system temperature not higher than 10 ° C, and slowly add fuming nitric acid (10.8 g, 0.17 mol) to prepare a nitrating agent, Keep it warm.

[0091] In a 500 mL dry three-necked flask, add isosorbide (25.0 g, 0.17 mol), acetic acid (50 mL)

After stirring and dissolving, control the temperature not higher than 10 ° C, slowly add the above-mentioned nitrating reagent to the reaction. After the reaction is complete, the reaction effluent is concentrated under reduced pressure, and 2 L of purified water is added. After stirring and crystallization, suction filtration is used to remove nitric acid. Sorbate and filtrate were sampled and tested by GC to calculate the remaining amount of isosorbide and the yield of each product. The specific results are shown in Table 8.

Table 8

[0093] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare a 5-sodium isonitrate monosodium wet product. The target product was obtained by acidification and purification. The total yield was 34.8%, and the purity was 98.82% by HPLC.

Comparative Example 2

[0095] In a 100 mL dry three-necked flask, add acetic anhydride (23.0 g, 0.22 mol), control the temperature of the system to not higher than 10 ° C, and slowly add fuming nitric acid (10.8 g, 0.17 mol) to prepare a nitrating agent, Keep it warm.

[0096] In a 500 mL dry three-neck flask, add isosorbide (25.0 g, 0.17 mol), isosorbide nitrate (5.0 g, 0.021 mol), and acetic acid (50 mL). After stirring and dissolving, the temperature control is not high. At 10 ° C, slowly add the above-mentioned nitrating reagent to the reaction. After the reaction is completed, the reaction effluent is concentrated under reduced pressure, and 2 L of purified water is added. After stirring for crystallization, the isosorbide nitrate is removed by suction filtration. The filtrate is sampled by GC and calculated. The remaining amount of isosorbide and the yield of each product were obtained. The specific results are shown in Table 9.

Table 9

[]

[0098] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-isoisosorbate sodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 36.1%. The purity by HPLC was 98.91%.

Comparative Example 3

[0100] In a 100 mL dry three-necked flask, add acetic anhydride (23.0 g, 0.22 mol), control the system temperature to not higher than 10 ° C, and slowly add fuming nitric acid (10.8 g, 0.17 mol) to prepare a nitrating agent, Keep it warm.

[0101] In a 500 mL dry three-necked flask, add isosorbide (25.0 g, 0.17 mol), acetic acid (50 mL)

, 2-Methyltetrahydrofuran (25 mL), after stirring and dissolving, control the temperature not higher than 0 ° C, slowly add the above-mentioned nitrating reagent to the reaction. After the reaction is complete, concentrate the reaction effluent under reduced pressure, and add 2 L of purified water. After crystallization with stirring, isosorbide nitrate was removed by suction filtration, and the filtrate was sampled by GC to determine the remaining amount of isosorbide and the yield of each product. The specific results are shown in Table 10.

Table 10

[0103] The above-mentioned filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-sodium mononitrate isosorbide sodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 39.8%. The purity by HPLC was 98.97%.

Comparative Example 4

[0105] In a 100 mL dry three-necked flask, add acetic anhydride (23.0 g, 0.22 mol), control the system temperature to not higher than 10 ° C, and slowly add fuming nitric acid (10.8 g, 0.17 mol) to prepare a nitrating agent, Keep it warm.

[0106] In a 500 mL dry three-necked flask, add isosorbide (25.0 g, 0.17 mol), isosorbide nitrate (5.0 g, 0.21 mol), acetic acid (50 mL), 2-methyltetrahydrofuran (25 mL) ) After stirring and dissolving Control the temperature not higher than o ° C, slowly add the above-mentioned nitrating agent to the reaction. After the reaction is completed, the reaction effluent is concentrated under reduced pressure, and 2 L of purified water is added. After stirring for crystallization, the isosorbide nitrate is removed by filtration. Sampling GC detection, the remaining amount of isosorbide and the yield of each product were calculated. The specific results are shown in Table 11.

Table 11

[0108] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-sodium mononitrate isosorbide sodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 42.6%. The purity by HPLC was 99.00%.

Comparative Example 5

[0110] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g 2.5 mol), and control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol) and isosorbide nitrate (50.0 g, 0.212 mol), and add 750

[0112] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through the respective metering pumps to perform a mixing reaction. The flow rate of the nitrating reagent is set to 40 mL / min, and the flow rate of the isosorbide solution is 20 mL. / min, the control reaction temperature was -10 ° C, 5 templates were connected in series, the holding capacity was 50 mL, and the reaction time of the reaction solution in the microchannel reactor was 38 s.

(4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC and calculated. The remaining isosorbide and each product were calculated. Yield. The specific results are shown in Table 12.

Table 12

[]

[0115] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare 5-sodium mononitrate isosorbide sodium salt as a wet product. The target product was obtained by acidification and purification. The total yield was 49.4%. The purity by HPLC was 99.03%.

Comparative Example 6

[0117] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g, 2.5 mol), and control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), isosorbide nitrate (50.0 g, 0.212 mol), and add 750 mL of acetic acid. / Methanol (v / v = 2: l) mixed solvent, stir to dissolve and set aside.

[0119] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through the respective metering pumps to perform a mixed reaction. The flow rate of the nitrating reagent is set to 20 mL / min, and the flow rate of the isosorbide solution is 60 mL. / min, control the reaction temperature to -10 ° C, connect 5 templates in series, hold 50 mL of liquid, and the reaction time of the reaction solution in the microchannel reactor is 38s.

[0120] (4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled for GC detection, and the remaining amount of isosorbide and the Yield. The specific results are shown in Table 13.

Table 13

[0122] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare a 5-isoisosorbate sodium salt wet product. The target product was obtained by acidification and purification. The total yield was 35.4%. The purity by HPLC was 99.02%. Comparative Example 7

[0124] (1) Preparation of nitrating reagent: In a 500 mL dry three-necked flask, add acetic anhydride (260.0 g 2.5 mol), and control the temperature at 0-10 ° C, and slowly add fuming nitric acid (108.0 g, 1.7 mol). ), After the addition is complete, keep warm for future use.

(2) Preparation of isosorbide solution: In a 2 L dry three-neck flask, add isosorbide (250.0 g, 1.7 mol), and add 750 mL of acetic acid / 2-methyltetrahydrofuran (v / v = 2 : l) mixed solvent

[0126] (3) The nitrating reagent and the isosorbide solution are fed into the microchannel reactor through the respective metering pumps to perform a mixed reaction. The flow rate of the nitrating reagent is set to 20 mL / min, and the flow rate of the isosorbide solution is 60 mL. / min, the control reaction temperature was -10 ° C, 5 templates were connected in series, the holding capacity was 50 mL, and the reaction time of the reaction solution in the microchannel reactor was 38 s.

(4) After concentrating the reaction effluent under reduced pressure, 2 L of purified water was added, and after stirring for crystallization, the isosorbide nitrate was removed by suction filtration. The filtrate was sampled by GC and calculated. The remaining amount of isosorbide and the Yield. The specific results are shown in Table 14.

Table 14

[0129] The above filtrate was reacted with a 30% sodium hydroxide solution to prepare a 5-sodium isonitrate monosodium wet product. The target product was obtained by acidification and purification. The total yield was 64.8%. The purity by HPLC was 99.06%.

Claims

Claim

[Claim 1] A method for synthesizing 5 -isosorbide mononitrate in a microchannel reactor, characterized in that the specific steps are:

Preparation of nitrating reagents: Slowly add fuming nitric acid to acetic anhydride at 0 ~ 10 ° C, keep it warm until use;

Preparation of isosorbide solution: Dissolve isosorbide and isosorbide nitrate in acetic acid and auxiliary solvent, stir until the dissolution is complete, set aside;

Set the reaction temperature, pump the above-mentioned nitrating reagent and isosorbide solution into the microchannel reactor respectively for mixing reaction. After the reaction is completed, the product flows out from the reactor outlet to obtain the effluent; the effluent obtained in step (3) is post-processed. 2. Isolate and purify the target product 5-isosorbide mononitrate.

[Claim 2] The method according to claim 1, wherein in step (1), the molar ratio of fuming nitric acid and acetic anhydride is

It is preferably 1: 1 to 1.5.

[Claim 3] The method according to claim 1, wherein in step (2), the mass ratio of isosorbide to isosorbide nitrate is 1: 0.05 to 0.3.

[Claim 4] The method according to claim 1, wherein in step (2), the auxiliary solvent is selected from the group consisting of acetone, ethyl acetate, methylene chloride, tetrahydrofuran, and 2-methyltetrahydrofuran. One or more.

[Claim 5] The method according to claim 1, wherein in the step (2), the auxiliary solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[Claim 6] The method according to claim 1, characterized in that, in step (2), the volume ratio of acetic acid to the auxiliary solvent is 1: 0.5 to 2.

[Claim 7] The method according to claim 1, wherein the mass-to-volume ratio of isosorbide to acetic acid is 1: 1 to 2, wherein the mass is in g and the volume is in mL.

[Claim 8] The method according to claim 1, wherein in step (3), the nitrating reagent and the isosorbide solution are separately pumped into a microchannel reactor, and the molar ratio of isosorbide to fuming nitric acid is 1: 1 ~ 3, preferably 1: 1.2 ~ 1.5.

[Claim 9] The method according to claim 1, wherein the reaction temperature in step (3) is -1 5 ~ 20 ° C, preferably -15 ~ 0 ° C.

[Claim 10] The method according to claim 1, characterized in that, in step (3), the residence time of the nitrating agent and the isosorbide solution in the microchannel reactor is 15 to 300 s, preferably 15 to 60 s.