Continuous production method of 5-isosorbide mononitrate

Abstract

The invention relates to a continuous production method of 5-isosorbide mononitrate, and belongs to the technical field of medicines. The preparation method comprises the following steps: adding sorbitol into deionized water, adding a solid acid catalyst, carrying out reduced pressure distillation, adding ethyl acetate and methanol, adjusting the pH value, drying, carrying out pressure filtration, washing with ethyl acetate, and distilling to remove a solvent; heating the system, adding the system into a mixed solution of toluene, acetic acid and acetic anhydride, cooling, slowly dropwise adding fuming nitric acid, reacting, pouring into ice water, adjusting the pH, separating, taking an organic phase, and washing with water; taking a water phase, extracting with 2-butanone for three times, combining extracted organic phases, distilling to remove a solvent, adding into deionized water, dropwise adding a sodium hydroxide solution, filtering after reaction, adding into water to form turbid liquid, adjusting pH, extracting with 2-butanone, distilling the organic phases to remove the solvent, and recrystallizing with chloroform to obtain 5-isosorbide mononitrate; the 5-isosorbide mononitrate prepared by the method disclosed by the invention has relatively high purity and yield.

Description

Technical Field

[0001] The invention relates to the field of medical technology, in particular to a continuous production method of 5-isosorbide mononitrate. Background Art

[0002] Isosorbide 5-mononitrate (5ISMN) is a new generation of nitrate antianginal drugs, with the chemical name of 1,4,3,6-dianhydro D-sorbitol 5-mononitrate. Compared with isosorbide dinitrate (also known as isosorbide dinitrate), this product has fast absorption and distribution, no first-pass effect in the liver, and a bioavailability of up to 100%.

[0003] The Chinese patent with the authorization announcement number CN110407846B discloses a method for preparing 5-isosorbide mononitrate, which uses isosorbide as a raw material, TMSCl and nitrate as nitrating agents, and selectively nitrates the 5-hydroxyl group of dehydrated sorbitol under the action of aluminum chloride. After the reaction is completed, the reaction solution is poured into ice water, the pH value is adjusted to neutral, the precipitate is filtered out, the phases are separated, the aqueous phase is extracted with an organic solvent, the organic phase is dried by adding a desiccant, decolorized with activated carbon, and concentrated to dryness under reduced pressure to obtain high-purity 5-isosorbide mononitrate.

[0004] The Chinese patent with authorization announcement number CN103641840B discloses a method for synthesizing and purifying 5-isosorbide mononitrate, wherein concentrated nitric acid, acetic acid and acetic anhydride are used to prepare a nitrating agent, and isosorbide is directly nitrated to obtain an isosorbide nitrate mixture; water is then added to quench the reaction, and 2,5-isosorbide dinitrate is precipitated at 0°C to 5°C and filtered out; the filtrate is then reacted with sodium hydroxide to prepare isosorbide mononitrate sodium salt hydrate to obtain a precipitate, which is then filtered and hydrolyzed into sodium salt; finally, high-purity 5-isosorbide mononitrate is obtained through extraction, concentration and recrystallization.

[0005] The Chinese patent with the authorization announcement number CN108658998B discloses an isosorbide lipid plasticizer and its preparation method and application, wherein the isosorbide synthesis part adopts a vacuum controlled reaction in a molten state, and the obtained isosorbide reaction liquid is directly esterified to prepare the plasticizer.

[0006] The above patents and prior art have complex processes, cumbersome operations, difficult separation of impurities, and low product purity and yield. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a continuous production method of 5-isosorbide mononitrate, and the operating steps are as follows: S1 Preparation of isosorbide: 20-30 parts of sorbitol are added to 100-150 parts of deionized water, stirred and dissolved, and then 0.1-0.5 parts of a solid acid catalyst are added to perform a dehydration reaction by vacuum distillation; after the reaction is completed, 150-200 parts of ethyl acetate and 80-100 parts of methanol are added, and a sodium hydroxide solution is added to adjust the pH to 6.5-7.0, and the reaction solution is dried over anhydrous magnesium sulfate, and the reaction solution is filtered under pressure, and washed with 1000-2000 parts of ethyl acetate. After the eluent is distilled to remove the solvent, a colorless viscous liquid isosorbide is obtained; S2 nitration reaction: when the system is heated to 50-60°C, add isosorbide to a mixture of 5-10 parts of toluene, 40-50 parts of acetic acid and 40-50 parts of acetic anhydride, cool to 30-35°C, slowly add 1-5 parts of fuming nitric acid dropwise with stirring, after the reaction, pour the reaction solution into 400-500 parts of ice water, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 400-500 parts of deionized water, add 80-100 parts of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize with chloroform to obtain 5-isosorbide mononitrate; The solid acid catalyst is prepared by reacting metallic sodium, ethanethiol, 6-(ferrocenyl)hexanethiol and pyridazine-3-thiol to obtain a mixed sodium thiolate solution, and then adding chloromethylstyrene-divinylbenzene-styrene copolymer resin, filtering, separating, washing and drying.

[0008] Furthermore, the reaction temperature of S1 is 120-130° C., the reaction pressure is 0.1 MPa, and the reaction time is 2-5 h.

[0009] Furthermore, the mass concentration of the sodium hydroxide solution is 20-30%.

[0010] Furthermore, the S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1: (6-8).

[0011] Furthermore, the reaction temperature of S2 is 30-35°C and the reaction time is 150-180min.

[0012] Furthermore, the reaction temperature of S3 is 0-5°C and the reaction time is 90-120min.

[0013] Furthermore, the specific preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 3-6 parts of ethanethiol, 0.2-0.5 parts of 6-(ferrocenyl)hexanethiol, and 0.02-0.05 parts of pyridazine-3-thiol (CAS: 28544-77-6) are sequentially added to a reaction container, and then 1000-1200 parts of anhydrous ethanol are added to dissolve them; the system is cooled at low temperature, and 1-3 parts of metallic sodium are slowly added and stirred until completely dissolved to prepare a mixed sodium thiolate solution; A2 resin thiolation reaction: Add 100-200 parts of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the above mixed sodium thiolate solution, control the temperature at 50-60°C, and stir the reaction for 9-12 hours to ensure sufficient reaction; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 60-80° C. for 10-18 hours; the dried resin is added to 1000-1200 parts of 80-98% sulfuric acid by mass, stirred and reacted at 80-90° C. for 10-15 hours, filtered after the reaction is completed, washed with deionized water until neutral, and dried at 100-120° C. to obtain a solid acid catalyst.

[0014] Reaction mechanism: The preparation of the solid acid catalyst involves three key reaction stages, and the reaction mechanisms of each stage are as follows: When preparing the mixed sodium thiolate solution, metallic sodium reacts with ethanethiol, 6-(ferrocenyl)hexanethiol, and pyridazine-3-thiol. The metallic sodium loses electrons to form sodium ions, and the thiol hydrogen in the thiol gains electrons to form hydrogen gas to escape, generating the corresponding sodium thiolate; in the subsequent thiolation reaction, the thiol anion in the mixed sodium thiolate acts as a nucleophilic reagent to attack the chloromethyl group of the chloromethylstyrene-divinylbenzene-styrene copolymer resin, and the chlorine atom leaves in the form of chloride ions, and the thiol anion is connected to the benzene ring methylene to achieve the thiolation of the resin. In the solid acid catalyst formation stage, the hydrogen ions in the sulfuric acid react with the thiol and other groups on the resin, and some thiol groups are oxidized to acidic groups such as sulfonic acid groups, introducing acidic active sites on the resin surface to give it solid acid catalytic properties.

[0015] The continuous production method of 5-isosorbide mononitrate of the present invention has the following remarkable effects compared with the prior art: 1. High catalytic activity: The solid acid catalyst prepared by the present invention has abundant acidic active sites, which can effectively reduce the activation energy of the dehydration reaction within the sorbitol molecule, and significantly improve the reaction rate and the yield of isosorbide; under the same reaction conditions, compared with the traditional liquid acid catalyst, the yield of isosorbide can be increased by 10-15%.

[0016] 2. Easy to separate and recycle: After the reaction is completed, the solid acid catalyst can be separated from the reaction product by simple filtration operation, avoiding the problem of difficult separation of traditional liquid acid catalysts, simplifying the post-processing process and reducing production costs.

[0017] 3. Reusable: After separation and recovery, the solid acid catalyst undergoes simple regeneration treatment, such as washing and drying, and its catalytic activity remains basically unchanged, and it can be reused many times; after 5 cycles of use, the activity of the catalyst can still maintain more than 80% of the initial activity.

[0018] 4. Environmentally friendly: Using solid acid catalysts instead of liquid acid catalysts avoids the generation of a large amount of acidic wastewater, reduces environmental pollution, and is in line with the development concept of green chemistry. DETAILED DESCRIPTION

[0019] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the following is a detailed description in combination with embodiments and comparative examples: Embodiment 1: A method for the continuous production of 5-isosorbide mononitrate, the operating steps of which are: S1 Preparation of isosorbide: 20 g of sorbitol was added to 100 g of deionized water, stirred and dissolved, and then 0.1 g of a solid acid catalyst was added to perform a dehydration reaction by vacuum distillation; after the reaction was completed, 150 g of ethyl acetate and 80 g of methanol were added, and sodium hydroxide solution was added to adjust the pH to 6.5, and dried over anhydrous magnesium sulfate. The reaction solution was filtered under pressure, rinsed with 1000 g of ethyl acetate, and the eluent was distilled to remove the solvent to obtain colorless viscous liquid isosorbide; S2 Nitration reaction: When the system is heated to 50°C, add isosorbide to a mixture of 5g toluene, 40g acetic acid and 40g acetic anhydride, cool to 30°C, slowly add 1g fuming nitric acid dropwise with stirring, pour the reaction solution into 400g ice water after the reaction, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 400g of deionized water, add 80g of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize from chloroform to obtain 5-isosorbide mononitrate.

[0020] The reaction temperature of S1 is 120°C, the reaction pressure is 0.1MPa, and the reaction time is 2h.

[0021] The mass concentration of the sodium hydroxide solution is 20%.

[0022] The S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1:6.

[0023] The reaction temperature of S2 is 30°C and the reaction time is 150 minutes.

[0024] The reaction temperature of S3 is 0°C and the reaction time is 90 minutes.

[0025] The preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 3 g of ethanethiol, 0.2 g of 6-(ferrocenyl)hexanethiol, and 0.02 g of pyridazine-3-thiol (CAS: 28544-77-6) were added to the reaction container in sequence, and then 1000 g of anhydrous ethanol was added to dissolve them; the system was cooled at low temperature, 1 g of metallic sodium was slowly added and stirred until it was completely dissolved to obtain a mixed sodium thiolate solution. In this process, nitrogen was used to prevent oxidation and the rate was controlled at low temperature; A2 resin thiolation reaction: Add 100g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the mixed sodium thiolate solution, control the temperature at 50°C, and stir for 9 hours to allow the chloromethyl group to undergo nucleophilic substitution with the mixed sodium thiolate to achieve thiolization, ensuring sufficient reaction to improve efficiency; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 60° C. for 10 hours; the dried resin is added to 1000 g of 80% sulfuric acid by mass, stirred and reacted at 80° C. for 10 hours, filtered after the reaction is completed, washed with deionized water until neutral, and dried at 100° C. to obtain a solid acid catalyst.

[0026] Embodiment 2: A method for the continuous production of 5-isosorbide mononitrate, the operating steps of which are: S1 Preparation of isosorbide: 23 g of sorbitol was added to 110 g of deionized water, stirred and dissolved, and then 0.2 g of a solid acid catalyst was added to perform a dehydration reaction by vacuum distillation; after the reaction was completed, 160 g of ethyl acetate and 85 g of methanol were added, and sodium hydroxide solution was added to adjust the pH to 6.5, and dried over anhydrous magnesium sulfate. The reaction solution was filtered under pressure, rinsed with 1400 g of ethyl acetate, and the eluent was distilled to remove the solvent to obtain colorless viscous liquid isosorbide; S2 Nitration reaction: When the system is heated to 55°C, add isosorbide to a mixture of 6g toluene, 43g acetic acid and 43g acetic anhydride, cool to 30°C, slowly add 2g fuming nitric acid dropwise with stirring, pour the reaction solution into 440g ice water after the reaction, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 440g of deionized water, add 85g of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize from chloroform to obtain 5-isosorbide mononitrate.

[0027] The reaction temperature of S1 is 125°C, the reaction pressure is 0.1MPa, and the reaction time is 3h.

[0028] The mass concentration of the sodium hydroxide solution is 25%.

[0029] The S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1:7.

[0030] The reaction temperature of S2 is 30°C and the reaction time is 160 min.

[0031] The reaction temperature of S3 is 0°C and the reaction time is 100 min.

[0032] The preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 4 g of ethanethiol, 0.3 g of 6-(ferrocenyl)hexanethiol, and 0.03 g of pyridazine-3-thiol (CAS: 28544-77-6) were added to the reaction container in sequence, and then 1050 g of anhydrous ethanol was added to dissolve them; the system was cooled at low temperature, and 2 g of metallic sodium was slowly added and stirred until it was completely dissolved to obtain a mixed sodium thiolate solution. In this process, nitrogen was used to prevent oxidation and the rate was controlled at low temperature; A2 resin thiolation reaction: Add 140g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the mixed sodium thiolate solution, control the temperature at 55°C, and stir for 10 hours to allow the chloromethyl group to undergo nucleophilic substitution with the mixed sodium thiolate to achieve thiolization, ensuring sufficient reaction to improve efficiency; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 65° C. for 12 hours; the dried resin is added to 1050 g of 85% sulfuric acid by mass, stirred and reacted at 85° C. for 12 hours. After the reaction is completed, it is filtered, washed with deionized water until neutral, and dried at 105° C. to obtain a solid acid catalyst.

[0033] Embodiment 3: A method for the continuous production of 5-isosorbide mononitrate, the operating steps of which are: S1 Preparation of isosorbide: 28g of sorbitol was added to 140g of deionized water, stirred and dissolved, and then 0.4g of a solid acid catalyst was added to perform a dehydration reaction by vacuum distillation; after the reaction was completed, 180g of ethyl acetate and 95g of methanol were added, and sodium hydroxide solution was added to adjust the pH to 7.0, and the reaction solution was dried over anhydrous magnesium sulfate, and the reaction solution was filtered under pressure, rinsed with 1800g of ethyl acetate, and the eluent was distilled to remove the solvent to obtain colorless viscous liquid isosorbide; S2 Nitration reaction: When the system is heated to 55°C, add isosorbide to a mixture of 8g toluene, 48g acetic acid and 48g acetic anhydride, cool to 35°C, slowly add 4g fuming nitric acid dropwise with stirring, pour the reaction solution into 480g ice water after the reaction, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 480g of deionized water, add 95g of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize from chloroform to obtain 5-isosorbide mononitrate.

[0034] The reaction temperature of S1 is 125°C, the reaction pressure is 0.1MPa, and the reaction time is 4h.

[0035] The mass concentration of the sodium hydroxide solution is 25%.

[0036] The S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1:7.

[0037] The reaction temperature of S2 is 35°C and the reaction time is 170 minutes.

[0038] The reaction temperature of S3 is 5°C and the reaction time is 110 min.

[0039] The preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 5 g of ethanethiol, 0.4 g of 6-(ferrocenyl)hexanethiol, and 0.04 g of pyridazine-3-thiol (CAS: 28544-77-6) were added to the reaction container in sequence, and then 1150 g of anhydrous ethanol was added to dissolve them; the system was cooled at low temperature, and 2 g of metallic sodium was slowly added and stirred until it was completely dissolved to obtain a mixed sodium thiolate solution. In this process, nitrogen was used to prevent oxidation and the rate was controlled at low temperature; A2 resin thiolation reaction: Add 180g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the mixed sodium thiolate solution, control the temperature at 55°C, and stir for 11 hours to allow the chloromethyl group to undergo nucleophilic substitution with the mixed sodium thiolate to achieve thiolization, ensuring sufficient reaction to improve efficiency; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 75°C for 16 hours; the dried resin is added to 1150g of 90% sulfuric acid by mass, stirred and reacted at 85°C for 14 hours, filtered after the reaction is completed, washed with deionized water until neutral, and dried at 115°C to obtain a solid acid catalyst.

[0040] Embodiment 4: A method for the continuous production of 5-isosorbide mononitrate, the operating steps of which are: S1 Preparation of isosorbide: 30 g of sorbitol was added to 150 g of deionized water, stirred and dissolved, and then 0.5 g of a solid acid catalyst was added to perform a dehydration reaction by vacuum distillation; after the reaction was completed, 200 g of ethyl acetate and 100 g of methanol were added, and a sodium hydroxide solution was added to adjust the pH to 7.0, and the reaction solution was dried over anhydrous magnesium sulfate, and the reaction solution was filtered under pressure, rinsed with 2000 g of ethyl acetate, and the eluent was distilled to remove the solvent to obtain a colorless viscous liquid isosorbide; S2 Nitration reaction: When the system is heated to 60°C, add isosorbide to a mixture of 10g toluene, 50g acetic acid and 50g acetic anhydride, cool to 35°C, slowly add 5g fuming nitric acid dropwise with stirring, pour the reaction solution into 500g ice water after the reaction, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 500g of deionized water, add 100g of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize from chloroform to obtain 5-isosorbide mononitrate.

[0041] The reaction temperature of S1 is 130°C, the reaction pressure is 0.1MPa, and the reaction time is 5h.

[0042] The mass concentration of the sodium hydroxide solution is 30%.

[0043] The S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1:8.

[0044] The reaction temperature of S2 is 35°C and the reaction time is 180 min.

[0045] The reaction temperature of S3 is 5°C and the reaction time is 120 min.

[0046] The preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 6 g of ethanethiol, 0.5 g of 6-(ferrocenyl)hexanethiol, and 0.05 g of pyridazine-3-thiol (CAS: 28544-77-6) were added to the reaction container in sequence, and then 1200 g of anhydrous ethanol was added to dissolve them; the system was cooled at low temperature, and 3 g of metallic sodium was slowly added and stirred until it was completely dissolved to obtain a mixed sodium thiolate solution. In this process, nitrogen was used to prevent oxidation and the rate was controlled at low temperature; A2 resin thiolation reaction: Add 200g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the mixed sodium thiolate solution, control the temperature at 60°C, and stir for 12 hours to allow the chloromethyl group to undergo nucleophilic substitution with the mixed sodium thiolate to achieve thiolization, ensuring sufficient reaction to improve efficiency; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 80° C. for 18 hours; the dried resin is added to 1200 g of 98% sulfuric acid by mass, stirred and reacted at 90° C. for 15 hours. After the reaction is completed, it is filtered, washed with deionized water until neutral, and dried at 120° C. to obtain a solid acid catalyst.

[0047] Comparative Example 1: No solid acid catalyst was added, and the rest was the same as in Example 1.

[0048] Comparative Example 2: Pyridazine-3-thiol was not added, and the other steps were the same as those in Example 1.

[0049] Comparative Example 3: No 6-(ferrocenyl)hexanethiol was added, and the rest was the same as in Example 1.

[0050] Purity test: using high performance liquid chromatography.

[0051] The test results of the above embodiments and comparative examples are shown in Table 1 below.

[0052] Table 1: Test results of various embodiments and comparative examples

[0053] Through the data analysis of the above examples and comparative examples, the 5-isosorbide mononitrate prepared by the present invention has higher purity and yield.

[0054] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A continuous production method of isosorbide-5-mononitrate, characterized in that: The operation steps are: S1 Preparation of isosorbide: 20-30 parts of sorbitol are added to 100-150 parts of deionized water, stirred and dissolved, and then 0.1-0.5 parts of a solid acid catalyst are added to perform a dehydration reaction by vacuum distillation; after the reaction is completed, 150-200 parts of ethyl acetate and 80-100 parts of methanol are added, and a sodium hydroxide solution is added to adjust the pH to 6.5-7.0, and the reaction solution is dried over anhydrous magnesium sulfate, and the reaction solution is filtered under pressure, and washed with 1000-2000 parts of ethyl acetate. After the eluent is distilled to remove the solvent, a colorless viscous liquid isosorbide is obtained; S2 nitration reaction: when the system is heated to 50-60°C, add isosorbide to a mixture of 5-10 parts of toluene, 40-50 parts of acetic acid and 40-50 parts of acetic anhydride, cool to 30-35°C, slowly add 1-5 parts of fuming nitric acid dropwise with stirring, after the reaction, pour the reaction solution into 400-500 parts of ice water, add sodium hydroxide solution to adjust the pH to 7.0, separate, and wash the organic phase with water; S3 salt-forming reaction: take the aqueous phase, extract it with 2-butanone for 3 times, combine the extracted organic phases, distill to remove the solvent, add it to 400-500 parts of deionized water, add 80-100 parts of sodium hydroxide solution dropwise, filter after reaction, and obtain 5-isosorbide mononitrate sodium salt hydrate; S4 Neutralization reaction: add 5-isosorbide mononitrate sodium salt hydrate to water to form a suspension, add dilute hydrochloric acid to adjust the pH to 6.0 to form an emulsion, extract with 2-butanone, distill the organic phase to remove the solvent, and then recrystallize with chloroform to obtain 5-isosorbide mononitrate; The solid acid catalyst is prepared by reacting metallic sodium, ethanethiol, 6-(ferrocenyl)hexanethiol and pyridazine-3-thiol to obtain a mixed sodium thiolate solution, and then adding chloromethylstyrene-divinylbenzene-styrene copolymer resin, filtering, separating, washing and drying.

2. A method for continuously producing isosorbide-5-mononitrate according to claim 1, characterized in that: The reaction temperature of S1 is 120-130°C, the reaction pressure is 0.1MPa, and the reaction time is 2-5h.

3. A continuous production method of isosorbide-5-mononitrate according to claim 1, characterized in that: The mass concentration of the sodium hydroxide solution is 20-30%.

4. A continuous production method of isosorbide-5-mononitrate according to claim 1, characterized in that: The S1 pressure filtration adopts a silica gel-activated carbon mixed column with a mass ratio of 1: (6-8).

5. A method for continuously producing isosorbide-5-mononitrate according to claim 1, characterized in that: The reaction temperature of S2 is 30-35°C and the reaction time is 150-180 minutes.

6. A method for continuously producing isosorbide-5-mononitrate according to claim 1, characterized in that: The reaction temperature of S3 is 0-5°C and the reaction time is 90-120min.

7. A method for continuously producing isosorbide-5-mononitrate according to claim 1, characterized in that: The specific preparation method of the solid acid catalyst is: A1 Preparation of mixed sodium thiolate solution: Under nitrogen protection, 3-6 parts of ethanethiol, 0.2-0.5 parts of 6-(ferrocenyl)hexanethiol, and 0.02-0.05 parts of pyridazine-3-thiol are sequentially added to a reaction container, and then 1000-1200 parts of anhydrous ethanol are added to dissolve them; the system is cooled to low temperature, and 1-3 parts of metallic sodium are slowly added and stirred until completely dissolved to prepare a mixed sodium thiolate solution; A2 resin thiolation reaction: Add 100-200 parts of chloromethylstyrene-divinylbenzene-styrene copolymer resin to the mixed sodium thiolate solution, control the temperature at 50-60°C, and stir the reaction for 9-12 hours to ensure sufficient reaction; A3 solid acid catalyst formation: After the thiolation reaction is completed, the resin is filtered and separated, and vacuum dried at 60-80° C. for 10-18 hours; the dried resin is added to 1000-1200 parts of 80-98% sulfuric acid by mass, stirred and reacted at 80-90° C. for 10-15 hours, filtered after the reaction is completed, washed with deionized water until neutral, and dried at 100-120° C. to obtain a solid acid catalyst.

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