A continuous production method of isosorbide-5-mononitrate

Abstract

The present invention relates to a continuous production method of isosorbide-5-mononitrate, belonging to the technical field of medicine. Sorbitol is added to deionized water, and a solid acid catalyst is added. After vacuum distillation, ethyl acetate and methanol are added, the pH is adjusted, dried, filtered under pressure, rinsed with ethyl acetate, and the solvent is removed by distillation; after the system is heated up, it is added to a mixed solution of toluene, acetic acid and acetic anhydride. After cooling, fuming nitric acid is slowly added dropwise. After the reaction, it is poured into ice water, the pH is adjusted, separated, and the organic phase is washed with water; the aqueous phase is taken and extracted 3 times with 2-butanone. The extracted organic phases are combined, the solvent is removed by distillation, added to deionized water, sodium hydroxide solution is added dropwise, after the reaction, it is filtered, added to water to form a suspension, the pH is adjusted, extracted with 2-butanone, the solvent of the organic phase is removed by distillation, and then recrystallized with chloroform to obtain isosorbide-5-mononitrate; the isosorbide-5-mononitrate prepared by the present invention has a high purity and yield.

Description

Technical Field

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

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

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

[0004] The Chinese patent with the authorization announcement number of CN103641840B discloses a synthesis and purification method of isosorbide-5-mononitrate. A nitrating reagent is prepared by using concentrated nitric acid, acetic acid and acetic anhydride, and isosorbide is directly nitrated to obtain a mixture of isosorbide nitrates; then the reaction is quenched by adding water, and 2,5-dinitroisosorbide is precipitated and filtered off at 0°C to 5°C; then the filtrate reacts with sodium hydroxide to prepare the sodium salt hydrate of isosorbide-5-mononitrate to obtain a precipitate, and the sodium salt is hydrolyzed after filtration; finally, high-purity isosorbide-5-mononitrate is obtained through extraction, concentration and recrystallization.

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

[0006] The above patents and the 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 isosorbide-5-mononitrate, and its operation steps are as follows:

[0008] Preparation of isosorbide: Add 20 - 30 parts of sorbitol to 100 - 150 parts of deionized water. After stirring and dissolving, add 0.1 - 0.5 part of solid acid catalyst, and carry out vacuum distillation dehydration reaction. After the reaction ends, add 150 - 200 parts of ethyl acetate and 80 - 100 parts of methanol, adjust the pH to 6.5 - 7.0 with sodium hydroxide solution, dry with anhydrous magnesium sulfate, filter the reaction solution under pressure, wash with 1000 - 2000 parts of ethyl acetate, and after distilling off the solvent from the eluate, obtain colorless viscous liquid isosorbide;

[0009] S2 Nitration reaction: When the temperature of the system is raised to 50 - 60 °C, add isosorbide to a mixed solution of 5 - 10 parts of toluene, 40 - 50 parts of acetic acid, and 40 - 50 parts of acetic anhydride. Cool to 30 - 35 °C, stir and slowly dropwise add 1 - 5 parts of fuming nitric acid. After the reaction, pour the reaction solution into 400 - 500 parts of ice water, adjust the pH to 7.0 with sodium hydroxide solution, separate, and wash the organic phase with water;

[0010] S3 Salt formation reaction: Take the aqueous phase, extract it 3 times with 2 - butanone, combine the extracted organic phases, distill off the solvent, add it to 400 - 500 parts of deionized water, dropwise add 80 - 100 parts of sodium hydroxide solution, filter after the reaction, and obtain sodium 5 - mononitrate isosorbide hydrate;

[0011] S4 Neutralization reaction: Add sodium 5 - mononitrate isosorbide hydrate to water to form a suspension, adjust the pH to 6.0 with dilute hydrochloric acid to form an emulsion, extract with 2 - butanone, distill off the solvent from the organic phase, and then recrystallize with chloroform to obtain 5 - mononitrate isosorbide;

[0012] The solid acid catalyst is prepared by reacting sodium metal, ethanethiol, 6 - (ferrocenyl)hexanethiol, and pyridazine - 3 - thiol to obtain a mixed sodium thiolate solution, and then adding chloromethylstyrene - divinylbenzene - styrene copolymer resin, followed by filtration, separation, washing, and drying.

[0013] Furthermore, the reaction temperature of S1 is 120 - 130 °C, the reaction pressure is 0.1 MPa, and the time is 2 - 5 h.

[0014] Furthermore, the mass concentration of the sodium hydroxide solution is 20 - 30%.

[0015] Furthermore, the pressure filtration in S1 uses a mixed column filled with silica gel - activated carbon with a mass ratio of 1:(6 - 8).

[0016] Furthermore, the reaction temperature of S2 is 30 - 35 °C, and the time is 150 - 180 min.

[0017] Furthermore, the reaction temperature of S3 is 0 - 5°C and the time is 90 - 120 min.

[0018] Furthermore, the specific preparation method of the solid acid catalyst is as follows:

[0019] Preparation of mixed sodium mercaptide solution:

[0020] Under nitrogen protection, 3 - 6 parts of ethanethiol, 0.2 - 0.5 part of 6-(ferrocenyl)hexanethiol, and 0.02 - 0.05 part of pyridazine-3-thiol (CAS: 28544-77-6) are successively added to a reaction vessel, and then 1000 - 1200 parts of absolute ethanol are added to dissolve it; the system is cooled at low temperature, and 1 - 3 parts of metallic sodium are slowly added and stirred until completely dissolved to obtain a mixed sodium mercaptide solution;

[0021] Resin mercaptidation reaction:

[0022] 100 - 200 parts of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) are added to the above mixed sodium mercaptide solution, the temperature is controlled at 50 - 60°C, and the reaction is stirred for 9 - 12 hours to ensure a complete reaction;

[0023] Formation of solid acid catalyst:

[0024] After the mercaptidation reaction, 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 sulfuric acid with a mass percentage of 80 - 98%, and stirred and reacted at 80 - 90°C for 10 - 15 hours. After the reaction, it is filtered, washed with deionized water until neutral, and dried at 100 - 120°C to obtain the solid acid catalyst.

[0025] Reaction mechanism:

[0026] The preparation of this solid acid catalyst involves three key reaction stages, and the reaction mechanisms of each stage are as follows:

[0027] During the preparation of the mixed sodium mercaptide solution, metallic sodium reacts with ethanethiol, 6-(ferrocenyl)hexanethiol, and pyridazine-3-thiol. Metallic sodium loses electrons to form sodium ions, and the mercapto hydrogen in the mercaptan gains electrons to form hydrogen gas and escape, generating the corresponding sodium mercaptide; in the subsequent mercaptidation reaction, the mercaptide anion in the mixed sodium mercaptide acts as a nucleophile, attacks the chloromethyl group of the chloromethylstyrene-divinylbenzene-styrene copolymer resin, the chlorine atom leaves in the form of a chloride ion, and the mercaptide anion is connected to the benzene ring methylene group to achieve resin mercaptidation. In the stage of forming the solid acid catalyst, the hydrogen ions in sulfuric acid react with groups such as mercapto groups on the resin, and part of the mercapto groups are oxidized into acidic groups such as sulfonic acid groups, introducing acidic active sites on the resin surface and endowing it with solid acid catalytic performance.

[0028] A continuous production method of isosorbide-5-mononitrate according to the present invention has the following remarkable effects compared with the prior art:

[0029] 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 intramolecular dehydration reaction of sorbitol, 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%.

[0030] 2. Easy to separate and recycle: After the reaction, the solid acid catalyst can be separated from the reaction products by simple filtration operation, avoiding the problem of difficult separation of the traditional liquid acid catalyst, simplifying the post-treatment process and reducing the production cost.

[0031] 3. Reusable: After simple regeneration treatment such as washing and drying, the catalytic activity of the separated and recycled solid acid catalyst remains basically unchanged and can be reused multiple times; after 5 cycles of use, the activity of the catalyst can still maintain more than 80% of the initial activity.

[0032] 4. Environmentally friendly: Using a solid acid catalyst to replace a liquid acid catalyst avoids the generation of a large amount of acidic wastewater, reduces environmental pollution, and conforms to the development concept of green chemistry. Specific embodiments

[0033] To further elaborate on 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 examples and comparative examples:

[0034] Example 1: A continuous production method of isosorbide-5-mononitrate, and its operation steps are as follows:

[0035] S1 Preparation of isosorbide: Add 20 g of sorbitol to 100 g of deionized water, stir to dissolve, add 0.1 g of solid acid catalyst, and carry out vacuum distillation dehydration reaction; after the reaction, add 150 g of ethyl acetate and 80 g of methanol, adjust to pH 6.5 with sodium hydroxide solution, dry with anhydrous magnesium sulfate, filter the reaction solution under pressure, wash with 1000 g of ethyl acetate, and after distilling off the solvent from the eluate, obtain a colorless viscous liquid isosorbide;

[0036] S2 Nitration reaction: When the temperature of the system is raised to 50 °C, add isosorbide to a mixture of 5 g of toluene, 40 g of acetic acid, and 40 g of acetic anhydride, cool to 30 °C, slowly dropwise add 1 g of fuming nitric acid while stirring, pour the reaction solution into 400 g of ice water after the reaction, adjust to pH 7.0 with sodium hydroxide solution, separate, and take the organic phase to wash with water;

[0037] S3 Salt formation reaction: Take the aqueous phase, extract it three times with 2-butanone, combine the extracted organic phases, remove the solvent by distillation, add it to 400 g of deionized water, dropwise add 80 g of sodium hydroxide solution, filter after the reaction to obtain sodium 5-isosorbide mononitrate hydrate;

[0038] S4 Neutralization reaction: Add sodium 5-isosorbide mononitrate hydrate to water to form a suspension, adjust the pH to 6.0 with dilute hydrochloric acid to form an emulsion, extract with 2-butanone, remove the solvent from the organic phase by distillation, and then recrystallize with chloroform to obtain 5-isosorbide mononitrate.

[0039] The reaction temperature of S1 is 120 °C, the reaction pressure is 0.1 MPa, and the time is 2 h.

[0040] The mass concentration of the sodium hydroxide solution is 20%.

[0041] The pressure filtration in S1 uses a mixed column filled with silica gel and activated carbon, and the mass ratio is 1:6.

[0042] The reaction temperature of S2 is 30 °C, and the time is 150 min.

[0043] The reaction temperature of S3 is 0 °C, and the time is 90 min.

[0044] The preparation method of the solid acid catalyst is as follows:

[0045] A1 Preparation of mixed thiolate solution:

[0046] Under nitrogen protection, add 3 g of ethanethiol, 0.2 g of 6-(ferrocenyl)hexanethiol, and 0.02 g of pyridazine-3-thiol (CAS: 28544-77-6) to the reaction vessel in sequence, and then add 1000 g of absolute ethanol to dissolve it; cool the system at low temperature, slowly add 1 g of metallic sodium and stir until completely dissolved to prepare a mixed thiolate solution. Prevent oxidation with nitrogen and control the rate at low temperature during this process;

[0047] A2 Thiolation reaction of resin:

[0048] Add 100 g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the above mixed thiolate solution, control the temperature at 50 °C, stir and react for 9 hours to make the chloromethyl group undergo nucleophilic substitution with the mixed thiolate to achieve thiolation, and ensure sufficient reaction to improve the efficiency;

[0049] A3 Formation of solid acid catalyst:

[0050] After the thiolation reaction, the resin was filtered and separated, and dried in vacuo at 60 °C for 10 hours; the dried resin was added to 1000 g of sulfuric acid with a mass percentage of 80%, and stirred at 80 °C for 10 hours. After the reaction, it was filtered, washed with deionized water until neutral, and dried at 100 °C to obtain a solid acid catalyst.

[0051] Example 2: A continuous production method of isosorbide-5-mononitrate, and its operation steps are as follows:

[0052] S1 Preparation of isosorbide: 23 g of sorbitol was added to 110 g of deionized water, stirred and dissolved, then 0.2 g of solid acid catalyst was added, and vacuum distillation dehydration reaction was carried out; after the reaction, 160 g of ethyl acetate and 85 g of methanol were added, and the pH was adjusted to 6.5 with sodium hydroxide solution, dried over anhydrous magnesium sulfate, the reaction solution was filtered under pressure, rinsed with 1400 g of ethyl acetate, and after the solvent was removed by distillation of the eluate, a colorless viscous liquid isosorbide was obtained;

[0053] S2 Nitration reaction: When the system was heated to 55 °C, isosorbide was added to a mixed solution of 6 g of toluene, 43 g of acetic acid and 43 g of acetic anhydride, cooled to 30 °C, and 2 g of fuming nitric acid was slowly added dropwise with stirring. After the reaction, the reaction solution was poured into 440 g of ice water, and the pH was adjusted to 7.0 with sodium hydroxide solution, separated, and the organic phase was washed with water;

[0054] S3 Salt formation reaction: The aqueous phase was taken, extracted 3 times with 2-butanone, the extracted organic phases were combined, the solvent was removed by distillation, and then added to 440 g of deionized water, 85 g of sodium hydroxide solution was added dropwise, and after the reaction, it was filtered to obtain sodium isosorbide-5-mononitrate hydrate;

[0055] S4 Neutralization reaction: Sodium isosorbide-5-mononitrate hydrate was added to water to form a suspension, the pH was adjusted to 6.0 with dilute hydrochloric acid to form an emulsion, extracted with 2-butanone, the solvent of the organic phase was removed by distillation, and then recrystallized from chloroform to obtain isosorbide-5-mononitrate.

[0056] The reaction temperature of S1 is 125 °C, the reaction pressure is 0.1 MPa, and the time is 3 h.

[0057] The mass concentration of the sodium hydroxide solution is 25%.

[0058] The pressure filtration in S1 uses a silica gel-activated carbon mixed column, and the mass ratio is 1:7.

[0059] The reaction temperature of S2 is 30 °C, and the time is 160 min.

[0060] The reaction temperature of S3 is 0 °C, and the time is 100 min.

[0061] The preparation method of the solid acid catalyst is as follows:

[0062] Preparation of the A1 mixed sodium mercaptide solution:

[0063] 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) are successively added to a reaction vessel, and then 1050 g of absolute ethanol is added to dissolve them; the system is cooled at a low temperature, and 2 g of metallic sodium is slowly added and stirred until completely dissolved to obtain the mixed sodium mercaptide solution. During this process, nitrogen is used to prevent oxidation and the rate is controlled at a low temperature.

[0064] A2 resin mercaptidation reaction:

[0065] 140 g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) is added to the above-mentioned mixed sodium mercaptide solution, the temperature is controlled at 55 °C, and the reaction is stirred for 10 hours to carry out nucleophilic substitution between the chloromethyl group and the mixed sodium mercaptide to achieve mercaptidation, ensuring a sufficient reaction to improve the efficiency.

[0066] A3 formation of the solid acid catalyst:

[0067] After the mercaptidation reaction, the resin is filtered and separated, and dried in vacuo at 65 °C for 12 hours; the dried resin is added to 1050 g of sulfuric acid with a mass percentage of 85%, and the reaction is stirred at 85 °C for 12 hours. After the reaction, it is filtered, washed with deionized water until neutral, and dried at 105 °C to obtain the solid acid catalyst.

[0068] Example 3: A continuous production method of isosorbide-5-mononitrate, and its operation steps are as follows:

[0069] S1 Preparation of isosorbide: 28 g of sorbitol is added to 140 g of deionized water, stirred and dissolved, then 0.4 g of the solid acid catalyst is added, and a vacuum distillation dehydration reaction is carried out; after the reaction, 180 g of ethyl acetate and 95 g of methanol are added, the pH is adjusted to 7.0 with a sodium hydroxide solution, dried over anhydrous magnesium sulfate, the reaction solution is filtered under pressure, rinsed with 1800 g of ethyl acetate, and after the solvent is removed by distillation of the eluate, a colorless viscous liquid isosorbide is obtained.

[0070] S2 Nitration reaction: When the temperature of the system is raised to 55 °C, isosorbide is added to a mixed solution of 8 g of toluene, 48 g of acetic acid, and 48 g of acetic anhydride, cooled to 35 °C, and 4 g of fuming nitric acid is slowly added dropwise with stirring. After the reaction, the reaction solution is poured into 480 g of ice water, the pH is adjusted to 7.0 with a sodium hydroxide solution, separated, and the organic phase is washed with water.

[0071] S3 Salt formation reaction: Take the aqueous phase, extract it with 2-butanone three times, combine the extracted organic phases, distill off the solvent, add it to 480 g of deionized water, dropwise add 95 g of sodium hydroxide solution, filter after the reaction to obtain sodium 5-isosorbide mononitrate hydrate;

[0072] S4 Neutralization reaction: Add sodium 5-isosorbide mononitrate hydrate to water to form a suspension, adjust the pH to 6.0 with dilute hydrochloric acid to form an emulsion, extract it with 2-butanone, distill off the solvent from the organic phase, and then recrystallize it with chloroform to obtain 5-isosorbide mononitrate.

[0073] The reaction temperature of S1 is 125 °C, the reaction pressure is 0.1 MPa, and the time is 4 h.

[0074] The mass concentration of the sodium hydroxide solution is 25%.

[0075] The pressure filtration in S1 uses a mixed column filled with silica gel and activated carbon, and the mass ratio is 1:7.

[0076] The reaction temperature of S2 is 35 °C, and the time is 170 min.

[0077] The reaction temperature of S3 is 5 °C, and the time is 110 min.

[0078] The preparation method of the solid acid catalyst is as follows:

[0079] A1 Preparation of mixed thiolate solution:

[0080] Under nitrogen protection, add 5 g of ethanethiol, 0.4 g of 6-(ferrocenyl)hexanethiol, and 0.04 g of pyridazine-3-thiol (CAS: 28544-77-6) to the reaction vessel in sequence, and then add 1150 g of absolute ethanol to dissolve it; cool the system at low temperature, slowly add 2 g of metallic sodium and stir until completely dissolved to prepare a mixed thiolate solution. Nitrogen is used to prevent oxidation and the rate is controlled at low temperature during this process;

[0081] A2 Resin mercaptanization reaction:

[0082] Add 180 g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) to the above mixed thiolate solution, control the temperature at 55 °C, and stir and react for 11 hours to carry out nucleophilic substitution between chloromethyl and the mixed thiolate to achieve mercaptanization, ensuring sufficient reaction to improve efficiency;

[0083] A3 Formation of solid acid catalyst:

[0084] After the mercapto group reaction ended, the resin was filtered and separated, and vacuum dried at 75 °C for 16 hours; the dried resin was added to 1150 g of sulfuric acid with a mass percentage of 90%, and stirred at 85 °C for 14 hours. After the reaction ended, it was filtered, washed with deionized water until neutral, and dried at 115 °C to obtain a solid acid catalyst.

[0085] Example 4: A continuous production method of isosorbide-5-mononitrate, the operation steps are as follows:

[0086] S1 Preparation of isosorbide: Add 30 g of sorbitol to 150 g of deionized water, stir to dissolve, add 0.5 g of solid acid catalyst, and carry out a vacuum distillation dehydration reaction; after the reaction ends, add 200 g of ethyl acetate and 100 g of methanol, add sodium hydroxide solution to adjust to pH 7.0, dry over anhydrous magnesium sulfate, filter the reaction solution under pressure, wash with 2000 g of ethyl acetate, and after distilling off the solvent from the eluate, obtain a colorless viscous liquid isosorbide;

[0087] S2 Nitration reaction: When the system temperature is raised to 60 °C, add isosorbide to a mixed solution of 10 g of toluene, 50 g of acetic acid, and 50 g of acetic anhydride, cool to 35 °C, and slowly add 5 g of fuming nitric acid dropwise while stirring. After the reaction, pour the reaction solution into 500 g of ice water, add sodium hydroxide solution to adjust to pH 7.0, separate, and take the organic phase and wash it with water;

[0088] S3 Salt formation reaction: Take the aqueous phase, extract it 3 times with 2-butanone, combine the extracted organic phases, distill off the solvent, add it to 500 g of deionized water, dropwise add 100 g of sodium hydroxide solution, and filter after the reaction to obtain sodium isosorbide-5-mononitrate hydrate;

[0089] S4 Neutralization reaction: Add sodium isosorbide-5-mononitrate hydrate to water to form a suspension, adjust to pH 6.0 with dilute hydrochloric acid to form an emulsion, extract with 2-butanone, distill off the solvent from the organic phase, and then recrystallize with chloroform to obtain isosorbide-5-mononitrate.

[0090] The reaction temperature of S1 is 130 °C, the reaction pressure is 0.1 MPa, and the time is 5 h.

[0091] The mass concentration of the sodium hydroxide solution is 30%.

[0092] The pressure filtration in S1 uses a silica gel-activated carbon mixed column, and the mass ratio is 1:8.

[0093] The reaction temperature of S2 is 35 °C, and the time is 180 min.

[0094] The reaction temperature of S3 is 5 °C, and the time is 120 min.

[0095] The preparation method of the solid acid catalyst is as follows:

[0096] Preparation of mixed sodium mercaptide solution:

[0097] 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 successively added to the reaction vessel, and then 1200 g of absolute ethanol was added to dissolve it; the system was cooled at low temperature, and 3 g of metallic sodium was slowly added and stirred until completely dissolved to obtain a mixed sodium mercaptide solution. During this process, nitrogen was used to prevent oxidation and the rate was controlled at low temperature;

[0098] Thiolation reaction of resin:

[0099] 200 g of chloromethylstyrene-divinylbenzene-styrene copolymer resin (CAS: 55844-94-5) was added to the above mixed sodium mercaptide solution, the temperature was controlled at 60 °C, and the reaction was stirred for 12 hours to carry out nucleophilic substitution between chloromethyl and the mixed sodium mercaptide to achieve thiolation, ensuring sufficient reaction to improve efficiency;

[0100] Formation of solid acid catalyst:

[0101] After the thiolation reaction, the resin was filtered and separated, and dried in vacuum at 80 °C for 18 hours; the dried resin was added to 1200 g of sulfuric acid with a mass percentage of 98%, and the reaction was stirred at 90 °C for 15 hours. After the reaction, it was filtered, washed with deionized water until neutral, and dried at 120 °C to obtain the solid acid catalyst.

[0102] Comparative example 1: The solid acid catalyst was not added, and other conditions were the same as in Example 1.

[0103] Comparative example 2: Pyridazine-3-thiol was not added, and other conditions were the same as in Example 1.

[0104] Comparative example 3: 6-(Ferrocenyl)hexanethiol was not added, and other conditions were the same as in Example 1.

[0105] Purity test: High performance liquid chromatography was used.

[0106] The test results of the above examples and comparative examples are shown in Table 1 below.

[0107] Table 1: Test results of each example and comparative example

[0108]

[0109] Through the data analysis of the above examples and comparative examples, isosorbide-5-mononitrate prepared by the present invention has relatively high purity and yield.

[0110] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention has been disclosed above with the preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to equivalent embodiments by using the disclosed technical content within the scope of the technical solution of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention still fall 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 as follows: Preparation of isosorbide: Add 20 - 30 parts of sorbitol to 100 - 150 parts of deionized water. After stirring and dissolving, add 0.1 - 0.5 part of solid acid catalyst, and carry out vacuum distillation dehydration reaction; after the reaction ends, add 150 - 200 parts of ethyl acetate and 80 - 100 parts of methanol, adjust the pH to 6.5 - 7.0 with sodium hydroxide solution, dry with anhydrous magnesium sulfate, filter the reaction solution under pressure, wash with 1000 - 2000 parts of ethyl acetate, and after distilling off the solvent from the eluate, obtain colorless viscous liquid isosorbide; Nitration reaction: When the temperature of the system is raised to 50 - 60 °C, add isosorbide to a mixed solution 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 dropwise add 1 - 5 parts of fuming nitric acid while stirring, after the reaction, pour the reaction solution into 400 - 500 parts of ice water, adjust the pH to 7.0 with sodium hydroxide solution, separate, and wash the organic phase with water; Salt - formation reaction: Take the aqueous phase, extract it 3 times with 2 - butanone, combine the extracted organic phases, distill off the solvent, add it to 400 - 500 parts of deionized water, dropwise add 80 - 100 parts of sodium hydroxide solution, filter after the reaction, and obtain sodium 5 - mononitrate isosorbide hydrate; Neutralization reaction: Add sodium 5 - mononitrate isosorbide hydrate to water to form a suspension, adjust the pH to 6.0 with dilute hydrochloric acid to form an emulsion, extract with 2 - butanone, distill off the solvent from the organic phase, and then recrystallize with chloroform to obtain 5 - mononitrate isosorbide; The specific preparation method of the solid acid catalyst is as follows: Preparation of mixed sodium mercaptide solution: Under nitrogen protection, sequentially add 3 - 6 parts of ethanethiol, 0.2 - 0.5 part of 6 - (ferrocenyl) hexanethiol, and 0.02 - 0.05 part of pyridazine - 3 - thiol to the reaction vessel, and then add 1000 - 1200 parts of absolute ethanol to dissolve it; cool the system at low temperature, slowly add 1 - 3 parts of metallic sodium and stir until completely dissolved to prepare a mixed sodium mercaptide solution; Resin mercapto - group reaction: Add 100 - 200 parts of chloromethyl styrene - divinylbenzene - styrene copolymer resin to the above - mentioned mixed sodium mercaptide solution, control the temperature at 50 - 60 °C, and stir and react for 9 - 12 hours to ensure complete reaction; Formation of solid acid catalyst: After the mercapto - group reaction ends, filter and separate the resin, and dry it in vacuum at 60 - 80 °C for 10 - 18 hours; add the dried resin to 1000 - 1200 parts of sulfuric acid with a mass percentage of 80 - 98%, stir and react at 80 - 90 °C for 10 - 15 hours, after the reaction ends, filter, wash with deionized water until neutral, and dry at 100 - 120 °C to obtain the solid acid catalyst.

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

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 pressure filtration in S1 uses a mixed column filled with silica gel and activated carbon, and the mass ratio is 1:(6 - 8).

5. A continuous production method of isosorbide-5-mononitrate according to claim 1, characterized in that: The reaction time of S2 is 150 - 180 min.

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

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