CN110407846B - Preparation method of 5-isosorbide mononitrate - Google Patents
Preparation method of 5-isosorbide mononitrate Download PDFInfo
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Abstract
The invention provides a method for synthesizing 5-isosorbide mononitrate. The method comprises the following steps: using isosorbide as a raw material, using TMSCl and nitrate as nitrating agents to selectively nitrify 5-hydroxyl on sorbitan under the action of aluminum trichloride, pouring reaction liquid into ice water after the reaction is finished, adjusting the pH value to be neutral, filtering out precipitates, carrying out phase separation, extracting and separating liquid by using an organic solvent in a water phase, adding an organic phase into a drying agent for drying, decoloring by using activated carbon, and carrying out reduced pressure concentration to be dry to obtain the high-purity 5-isosorbide mononitrate. The method has the advantages of mild reaction conditions, high nitration selectivity, simple post-treatment, high product yield and purity, and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of isosorbide mononitrate.
Background
Isosorbide 5-mononitrate (5-ISMN), a nitrate-based anti-anginal drug developed in 1981 by bochriger Cnbh, germany. 5-ISMN is an in vivo metabolite of isosorbide dinitrate, has no liver first-pass effect after being taken, has high bioavailability, and has the advantages of quick response, small side effect, high drug effect, long action duration and the like. The 5-isosorbide mononitrate is suitable for long-term treatment of coronary heart disease, prevention of angina pectoris and treatment of continuous angina after myocardial infarction, is widely applied to clinic since the eighties, and is generally popular with patients. 5-ISMN has the chemical name of 1, 4; 3, 6-dianhydro-D-sorbitol-5-mononitro ester, English name 1, 4; 3, 6-Dianlydo-D-Glueitol-5-Mononitate. Molecular weight is 191, molecular formula is C6H9NO6，CAS：16051-77-7。
There are many reports on the synthesis method of 5-isosorbide mononitrate, and the summary can be roughly divided into three methods: direct nitration processes, selective reduction processes, and esterification nitration processes.
Wherein the direct nitration process:
isosorbide 5-mononitrate, which was first synthesized by Hayward L D in 1965, has a chemical reaction equation as shown in 1, and further, among them, patents US3886186, JP5529996, German Pat. No. 2221080; such methods are reported in earlier documents, i.e., G.Czizmodia, L.D.Hayward "Photochem.Photobiol.4657 (1965)", L.D.Hayward "Synthesis of isospecific-5-mono nitrate (Can.J.chem, 1967, (45): 2191), Lucchi O.De." Chemoselective reduction of isospecific-2, 5-dintrate (GazzettaChimica Italiana, 1897, (17): 173) ". In the method, isosorbide is used as a raw material and fuming nitric acid is used for direct nitration. Isosorbide is directly nitrified by nitric acid, and generated substances comprise 2-isosorbide mononitrate, isosorbide dinitrate, 5-isosorbide mononitrate and unreacted isosorbide. And separating the reaction mixture by a column chromatography method to obtain pure isosorbide 5-mononitrate. However, the yield of 5-isosorbide mononitrate produced by the method is low, and the by-product 2, 5-isosorbide mononitrate has the risk of explosion under the process conditions of heating or pressurization, so that the method is not suitable for industrial production.
Synthetic route of 1.5-isosorbide mononitrate
US45843922 and Baozhiwu et al have improved the process for synthesizing isosorbide mononitrate ([ J ] (J.) (J. China journal of modern pharmaceutical applications, 1998, vol. 15, 5, p. 30) in the text of solvent, etc. it discloses that adding fuming nitric acid dropwise under a mixed solvent of benzene, acetic acid and acetic anhydride to control the nitration temperature to obtain isosorbide mononitrate sodium salt hydrates with yields of 35.8% and 38%, respectively, and adjusting the pH value to 7 with an acid to obtain isosorbide mononitrate yields of 73.5% and 83%, respectively.
In 5-Synthesis of isosorbide mononitrate (J, J. Med. am. J. 2011 42 (7): 489) sorbitol is dehydrated, purified by high-temperature high-vacuum distillation, filtered by silica gel-activated carbon, evaporated to remove solvent from filtrate, directly nitrated by fuming nitric acid with toluene-acetic acid-acetic anhydride mixed solution as solvent, treated by sodium hydroxide solution, and adjusted to pH 6.0 by hydrochloric acid to obtain the product with a total yield of 18.3% (calculated on sorbitol).
Esterification nitration process
The literature uses sorbitol as a starting material, sulfuric acid as a catalyst, and xylene as a reaction solvent. The authors use xylene as solvent, mainly because xylene and water constitute a binary azeotropic system, by which the water produced can be removed from time to time, thus facilitating the dehydration reaction. Pure isosorbide (62%) was obtained by high temperature high vacuum distillation. Then, dichloromethane is used as solvent, pyridine is used as catalyst, acetic anhydride is used as acylation reagent to carry out acylation reaction, and the obtained reaction substrate is not required to be separated and is directly subjected to nitration reaction. The authors used fuming nitric acid/acetic anhydride as the nitrating solvent. And finally, hydrolyzing potassium hydroxide/ethanol to obtain 5-isosorbide mononitrate. The reaction equation is shown in fig. 2:
synthetic route of 2, 5-isosorbide mononitrate
In conclusion, a large amount of isosorbide 2-mononitrate and isosorbide dinitrate are mixed in the product by using the nitration method in the prior art, so that difficulty is brought to purification, and pressure on environmental protection is brought. The direct nitration route is short, but the selective nitration of the nitrating agent is difficult, so that the development of a high-selectivity nitration method is urgently needed to solve the problems.
Disclosure of Invention
The invention aims to provide a method for selectively nitrifying to obtain high-purity 5-isosorbide mononitrate in the process of nitrifying isosorbide aiming at the defects of the prior art.
Through intensive research and exploration, the inventor finds that selective nitrification effect is poor when the TMSCl and the nitrate are used as nitrating agents to nitrify the isosorbide under the action of the aluminum trichloride. The inventor further researches and discovers that after isosorbide is mixed and reacted with TMSCl and a proper amount of alkali for a certain time, nitrate and aluminum trichloride are added for nitration. By controlling factors such as nitration temperature, the proportion and the dosage of TMSCl and nitrate and the like, the high-purity isosorbide mononitrate can be obtained. The post-treatment is simple, after the reaction is completed, water is added for quenching, the pH value is adjusted to be neutral, the filtration is carried out, the filtrate is separated, the water phase organic solvent is extracted, the organic phase is dried and concentrated to be dried to obtain the product, the purity of the product is greatly improved, the aim of the invention is achieved, and the inventor further researches and verifies the reaction conditions influenced by reaction reagents, reaction temperature and the like.
Specifically, the invention is realized by the following technical scheme:
mixing and stirring isosorbide, TMSCl and a proper amount of organic base at a low temperature for a period of time, controlling the temperature, adding aluminum trichloride and nitrate to selectively nitrify 5-hydroxyl on the isosorbide, keeping the temperature low until the reaction is finished, pouring the reaction solution into ice water, adjusting the pH value to be neutral, filtering out precipitates, splitting phases, extracting and separating liquid by using an organic solvent for a water phase, adding a drying agent into the organic phase, drying the organic phase, decoloring the active carbon, and concentrating under reduced pressure until the organic phase is dry to obtain the high-purity 5-isosorbide mononitrate;
the reaction formula is as follows:
the mass ratio of the isosorbide to the TMSCl is as follows: 1: 0.5-1.5; preferably: 1:1.12.
The alkali is one or more of triethylamine, pyridine, diethylamine, propylamine, isopropylamine and diisobutylamine; triethylamine is preferred.
The stirring reaction is carried out for a period of time as follows: 0.2 h-2 h; the preferred reaction time is 0.5 h.
The mass ratio of the isosorbide to the organic base is as follows: 1: 1.0-1.1; preferably: 1:1.0.
The nitrate is one or a combination of sodium nitrate and potassium nitrate.
The mass ratio of the isosorbide to the nitrate is as follows: 1: 1.0-1.5; preferably: 1:1.1.
The mass ratio of the isosorbide to the aluminum trichloride is 1: 0.1-0.5; preferably: 1:0.18.
The organic solvent is one or more of ethyl acetate, methyl acetate, dichloromethane, trichloromethane and the like.
The volume ratio of the mass of the activated carbon to the organic solvent is as follows: 1: 20-100 g/ml; preferably: 1:50, g/ml.
The reaction temperature is as follows: -20 ℃ to 10 ℃; preferably: -10 ℃ to 5 ℃.
Compared with the prior art, the invention has the following technical effects:
(1) nitrate and TMSCl (trimethylchlorosilane) system are used as nitrating agents, the reaction condition is mild, the generated 5-isosorbide mononitrate has high purity and high selectivity, the generated silicon ether can be recycled through liquid separation, the operation is simple, and the environmental pollution is small.
(2) After the reaction is finished, purified water is added into the reaction liquid, and the post-treatment can not generate more 'three wastes'.
(3) The product yield can reach more than 90 percent; and the product is not purified by column chromatography, salifying and the like.
(4) The obtained product does not need to be refined; after the organic phase is extracted and dried, active carbon is decolorized and directly concentrated to be dry, so that a qualified finished product can be obtained, and the product loss caused by multiple refining is avoided.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Example 1:
adding 46g of isosorbide, 32g of triethylamine and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to obtain suspension, cooling to-5 deg.C, stirring for 0.5 hr, adding 8.3g aluminum trichloride, adding 26.78g sodium nitrate solid in batches, keeping temperature not higher than 0 deg.C during the addition process, stirring, holding at-5 deg.C for 2 hr, detecting by HPLC, reacting completely, pouring the reaction solution into 400ml ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting a water phase with 200mL, 100mL and 100mL of ethyl acetate, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 8.0g of activated carbon into the filtrate, heating and decoloring for 30min, filtering the activated carbon, and concentrating the solution under reduced pressure until the solution is dry to obtain 57.6g of solid, wherein the purity is 99.84% by HPLC detection, and the yield is 96.0%.
Example 2:
adding 46g of isosorbide, 32g of triethylamine and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to obtain suspension, cooling to-5 deg.C, stirring for 0.5 hr, adding 8.3g aluminum trichloride, adding 31.82g potassium nitrate solid in batches, keeping temperature not higher than 0 deg.C during the addition process, stirring, holding at-5 deg.C for 2 hr, detecting by HPLC, reacting completely, pouring the reaction solution into 400ml ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting a water phase with 200mL, 100mL and 100mL of ethyl acetate, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 4.0g of activated carbon into the filtrate, heating and decoloring for 30min, filtering the activated carbon, and concentrating the solution under reduced pressure until the solution is dry to obtain 57g of solid, wherein the purity is 99.74% by HPLC detection, and the yield is 95.0%.
Example 3:
adding 46g of isosorbide, 23g of diethylamine and 69g of trimethylchlorosilane into a three-necked bottle, stirring to obtain suspension, cooling to-5 deg.C, stirring for 0.2 hr, adding 8.3g aluminum trichloride, adding 40.17g sodium nitrate solid in batches, keeping temperature not higher than 0 deg.C during the addition process, stirring, maintaining at-5 deg.C for 2 hr, detecting by HPLC, reacting completely, pouring the reaction solution into 400ml ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting a water phase with 200mL, 100mL and 100mL of ethyl acetate, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 8.0g of activated carbon into the filtrate, heating and decoloring for 30min, filtering the activated carbon, and concentrating the solution under reduced pressure until the solution is dry to obtain 54.2g of a solid, wherein the purity is 99.70% by HPLC (high performance liquid chromatography) detection, and the yield is 90.3%.
Example 4:
adding 46g of isosorbide, 32g of triethylamine and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to form a suspension, cooling to about 10 ℃, stirring for reacting for 2 hours, adding 23g of aluminum trichloride, then adding 31.82g of potassium nitrate solid in batches, keeping the temperature not higher than 10 ℃ in the adding process, continuing stirring, keeping the temperature for reacting for 2 hours at about 10 ℃, detecting by HPLC (high performance liquid chromatography) until the reaction is complete, pouring the reaction liquid into 400mL of ice water, adjusting the pH value to be neutral by using a potassium hydroxide solution, carrying out suction filtration, separating the filtrate, extracting the water phase by using 200mL, 100mL and 100mL of ethyl acetate in sequence, combining the organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4 hours, carrying out suction filtration, adding 17.6g of activated carbon into the filtrate, heating for decoloration for 30 minutes, filtering the activated carbon, concentrating the solution under reduced pressure until the solution is dry to obtain 57g of a solid, detecting by HPLC, wherein the purity is 99.74%, and the yield is 95.0%.
Example 5:
adding 46g of isosorbide, 35.2g of triethylamine and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to obtain suspension, cooling to-20 deg.C, stirring for 0.5 hr, adding 8.3g aluminum trichloride, adding 26.78g sodium nitrate solid in batches, keeping temperature not higher than 0 deg.C during the addition process, stirring, holding at-20 deg.C for 2 hr, detecting by HPLC, reacting completely, pouring the reaction solution into 400ml ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting water phase with 200mL, 100mL and 100mL of dichloromethane, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 17.6g of activated carbon into the filtrate, heating and decoloring for 30min, filtering the activated carbon, and concentrating the solution under reduced pressure until the solution is dry to obtain 56.1g of solid, wherein the purity is 99.72% according to HPLC detection, and the yield is 93.5%.
Example 6:
adding 46g of isosorbide, 35.2g of triethylamine and 23.0g of trimethylchlorosilane into a three-necked bottle, stirring to obtain suspension, cooling to-5 deg.C, stirring for 0.5 hr, adding 8.3g aluminum trichloride, adding 31.82g potassium nitrate solid in batches, keeping temperature not higher than 0 deg.C during the addition process, stirring, holding at-5 deg.C for 2 hr, detecting by HPLC, reacting completely, pouring the reaction solution into 400ml ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting a water phase with 200mL, 100mL and 100mL of chloroform, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 8.0g of activated carbon into the filtrate, heating and decoloring for 30min, filtering the activated carbon, and concentrating the solution under reduced pressure until the solution is dry to obtain 54.8g of solid, wherein the purity is 99.78% by HPLC detection, and the yield is 91.3%.
Example 7:
adding 46g of isosorbide, 24.9g of pyridine and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to form a suspension, cooling to about-5 ℃, stirring for reaction for 0.5h, adding 8.3g of aluminum trichloride, then adding 47.7g of potassium nitrate solid in batches, keeping the temperature not higher than 0 ℃ in the adding process, continuing stirring, keeping the temperature about-5 ℃ for reaction for 2h after the adding is finished, detecting by HPLC (high performance liquid chromatography), completely reacting, pouring the reaction solution into 400mL of ice water, adjusting the pH value to be neutral by using a potassium hydroxide solution, performing suction filtration, separating filtrate, sequentially extracting an aqueous phase by using 200mL, 100mL and 100mL of methyl acetate, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 8.0g of activated carbon into the filtrate, heating for decoloration for 30min, filtering the activated carbon, concentrating the solution under reduced pressure to dryness to obtain 55.2g of solid, wherein the purity is 99.71% by HPLC, and the yield is 92.0%.
Example 8: (comparative example)
Adding 46g of isosorbide and 51.5g of trimethylchlorosilane into a three-necked bottle, stirring to form suspension, cooling to about-5 ℃, stirring for reaction for 0.5h, adding 8.3g of aluminum trichloride, then adding 26.78g of sodium nitrate solid in batches, keeping the temperature not higher than 0 ℃ in the adding process, continuing stirring, keeping the temperature about-5 ℃ for reaction for 2h after the adding is finished, detecting by HPLC (high performance liquid chromatography), completely reacting, pouring the reaction liquid into 400mL of ice water, adjusting the pH value of a potassium hydroxide solution to be neutral, performing suction filtration, separating filtrate, sequentially extracting a water phase by using 200mL, 100mL and 100mL of ethyl acetate, combining organic phases, adding 20g of anhydrous magnesium sulfate, drying for 4h, performing suction filtration, adding 8.0g of activated carbon into the filtrate, heating for decoloration for 30min, filtering the activated carbon, concentrating the solution under reduced pressure to be dry to obtain 32.4g of solid, detecting the purity by HPLC to be 99.50%, and the yield to be 54.0%.
Claims (3)
1. A preparation method of 5-isosorbide mononitrate is characterized by comprising the following steps:
mixing and stirring isosorbide, TMSCl (trimethyl chlorosilane) and a proper amount of organic base at a low temperature for reacting for a period of time, controlling the temperature, adding aluminum trichloride and nitrate to selectively nitrify 5-hydroxyl on the isosorbide, keeping the temperature low until the reaction is finished, pouring the reaction liquid into ice water, adjusting the pH value to be neutral, filtering out precipitates, separating phases, extracting and separating liquid by using an organic solvent for a water phase, adding a drying agent into the organic phase for drying, decoloring by using activated carbon, and concentrating under reduced pressure until the organic phase is dry to obtain the high-purity 5-isosorbide mononitrate;
the reaction formula is as follows:
the mass ratio of the isosorbide to TMSCl (trimethyl chlorosilane) is as follows: 1: 0.5-1.5;
the alkali is one or more of triethylamine, pyridine, diethylamine, propylamine, isopropylamine and diisobutylamine;
the mass ratio of the isosorbide to the organic base is as follows: 1: 1.0-1.1;
the nitrate is one or a combination of sodium nitrate and potassium nitrate;
the mass ratio of the isosorbide to the nitrate is as follows: 1: 1.0-1.5;
the mass ratio of the isosorbide to the aluminum trichloride is 1: 0.1-0.5;
the reaction temperature is as follows: -20 ℃ to 10 ℃; the stirring reaction is carried out for a period of time as follows: 0.2-2 h.
2. The method according to claim 1, wherein the organic solvent is one or more of ethyl acetate, methyl acetate, dichloromethane, and chloroform.
3. The preparation method according to claim 1, wherein the ratio of the mass of the activated carbon to the volume of the organic solvent is: 1: 20-100 g/ml.
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| GB2358859B (en) * | 2000-02-01 | 2003-10-15 | Archimica Ltd | Synthesis of isosorbide-5-mononitrate and substituted analogues thereof |
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