CN113105470A - Synthetic method and application of isosorbide mononitrate - Google Patents
Synthetic method and application of isosorbide mononitrate Download PDFInfo
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- CN113105470A CN113105470A CN202110278382.4A CN202110278382A CN113105470A CN 113105470 A CN113105470 A CN 113105470A CN 202110278382 A CN202110278382 A CN 202110278382A CN 113105470 A CN113105470 A CN 113105470A
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- isosorbide mononitrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the field of drug synthesis, and discloses a synthesis method and application of isosorbide mononitrate. The synthesis method of isosorbide mononitrate provided by the invention adopts a one-pot method, sorbitol is added into concentrated sulfuric acid, nitrate is added after dehydration and cyclization, nitration reaction is carried out, and zinc powder is added for reduction reaction, thus obtaining isosorbide mononitrate. The synthesis method has the advantages of simple process flow, high utilization rate of raw materials and production cost saving. The method is suitable for synthesizing isosorbide mononitrate, and the obtained isosorbide mononitrate is used for preparing isosorbide mononitrate for injection.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a synthesis method and application of isosorbide mononitrate, in particular to isosorbide mononitrate.
Background
Sorbitol mononitrate, chemical name: 1,4,3, 6-dianhydro-D-sorbitol-5-mononitrate, also known as 5-isosorbide mononitrate, is the main biologically active agent of isosorbide dinitrate in vivo, activating guanylate cyclase by releasing nitric oxide, relaxing vascular smooth muscle and dilating peripheral arteries and veins. The 5-isosorbide mononitrate is suitable for long-term treatment of coronary heart disease, prevention of angina pectoris and treatment of continuous angina pectoris after myocardial infarction, is widely applied to clinic since the eighties are on the market, and is generally popular with patients.
However, the process and purification steps for synthesizing 5-isosorbide mononitrate are complicated, the yield is low, and the cost is high, so that the industrial production is limited. There are three major routes currently of industrial value:
the first route employs an indirect nitration process, wherein patents US4371703, US4065488, CN 1618798A; yan Fuan et al, "study on the synthesis of isosorbide 5-mononitrate (I) (Wuhan chemical Proc., 1997,19 (1): 25-27)", Yan Fuan et al, "study on the synthesis of isosorbide 5-mononitrate (II) (Fine chemical engineering, 1998,15 (3): 50-53)", Liuhongxia "Synthesis of isosorbide acetate in ionic liquid (applied chemistry, 2008,25 (12): 1502-1504)" reported such methods, the chemical reaction formula of which is:
the route can be summarized as that isosorbide is used as a starting material, acetyl esterification is carried out for 2-bit protection, then 5-bit nitration is carried out, and finally 2-bit ethyl ester group is hydrolyzed to obtain 5-isosorbide mononitrate. However, the synthesis process of the route is long in route, and a part of routes adopt catalytic reaction of catalysts, so that the cost is overhigh. Meanwhile, the selective acylation process conditions are difficult to control, the generated by-products are difficult to remove, the product is difficult to purify, and the yield is difficult to improve between 50 and 60 percent;
the second line is a direct nitration process, wherein patents US3886186, JP5529996, German Pat. No. 2221080; czizmodia, L.D.Hayward "Photochem.Photobiol.4657 (1965)", L.D.Hayward "Synthesis of isosorbide-5-monate (Can.J.chem, 1967, (45): 2191)", Lucchi O.De. "chemical reduction of isosorbide-2, 5-dintrate (Gazzetta Chimica Italiana, 1897, (17): 173)" and the like report such a method, the chemical reaction formula of which is:
the process uses isosorbide as raw material, uses fuming nitric acid to directly nitrify, uses the resultant as mixture, and adopts column chromatography and other methods for post-treatment. However, the yield of the route is low, fuming nitric acid and volatile toxic gas are used in the nitration process, and column chromatography and other methods are adopted in post-treatment, so that the method is not suitable for industrial production;
the third line is a selective reduction method, and the patents are US4381400, EP0201067 and CN 1609108A; zhenghengzuan et al, "Synthesis of 5-isosorbide mononitrate (proceedings of Hebei university of science, 2002,23 (4): 25-27)", hydrargyrum "research progress of sodium borohydride in organic Synthesis (applied chemistry, 2002, 19 (5); 409-:
the disadvantage of the route is that the selective reducing agent and the catalyst are frequently used, which results in high cost.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a method for synthesizing isosorbide mononitrate by using cheap raw materials through a one-pot method, so as to achieve the purposes of simplifying the process route of isosorbide mononitrate and reducing the production cost.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a synthetic method of isosorbide mononitrate is characterized by adding sorbitol into concentrated sulfuric acid, carrying out dehydration and cyclization, cooling after reaction, adding nitrate, carrying out nitration reaction, adding a reducing agent for reduction reaction after reaction, pouring reaction liquid into ice water after reaction, adjusting pH to alkalescence by using alkali liquor, concentrating and drying to obtain the isosorbide mononitrate, wherein the chemical reaction formula is as follows:
the volume weight ratio of the concentrated sulfuric acid to the sorbitol is 1-1.5: 1; the weight ratio of the nitrate to the sorbitol is 1.5-2.5: 1; the weight ratio of the reducing agent to the sorbitol is 0.8-1.2: 1;
as another limitation of the invention, the nitrate is sodium nitrate, potassium nitrate, or calcium nitrate; the reducing agent is zinc powder, iron powder or magnesium strips; the alkali liquor is a 1N sodium hydroxide aqueous solution;
as a third limitation of the invention, the pressure of the dehydration ring is-0.6 to-0.8 MPa, the temperature is 120 to 150 ℃, and the time is 2 to 4 hours;
as a fourth limitation of the invention, the temperature of the nitration reaction is 0-5 ℃ and the time is 6-10 h;
as a fifth limitation of the invention, the temperature of the reduction reaction is 10-15 ℃ and the time is 7-9 h;
the invention also provides an application of the isosorbide mononitrate synthesized by the method for synthesizing the isosorbide mononitrate, and the isosorbide mononitrate is used for preparing the isosorbide mononitrate for injection.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) the method for synthesizing isosorbide mononitrate provided by the invention adopts a one-pot method, shortens the original synthesis route of isosorbide mononitrate, can fully utilize concentrated sulfuric acid, reduces the discharge amount of waste liquid, and simultaneously adopts cheaper sorbitol to replace isosorbide ester, thereby reducing the industrial production cost;
(2) according to the method for synthesizing isosorbide mononitrate, the single strong acid is used, so that the potential safety hazard caused by frequent replacement of the type of the strong acid is prevented, and the side reaction and the reaction interference of the residual strong acid on the next reaction in the process of treating the intermediate are avoided, so that the final product is influenced.
In conclusion, the method for synthesizing isosorbide mononitrate provided by the invention has the advantages of simple process flow, high utilization rate of raw materials and industrial production cost saving.
The method is suitable for synthesizing isosorbide mononitrate, and the synthesized isosorbide mononitrate is used for preparing isosorbide mononitrate for injection.
Drawings
The invention is described in further detail below with reference to the figures and the embodiments.
FIG. 1 is an HPLC of isosorbide mononitrate A1 of example 1 of the present invention;
FIG. 2 is a diagram showing the detection of isosorbide mononitrate for injection in example 7 of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the description of the preferred embodiment is only for purposes of illustration and understanding, and is not intended to limit the invention.
Example 1 method for synthesizing isosorbide mononitrate A1
The embodiment provides a method for synthesizing isosorbide mononitrate A1, which has a chemical reaction formula:
weighing 1.82kg sorbitol, adding into 2.73L concentrated sulfuric acid, stirring, reducing pressure to-0.8 MPa, heating to 150 deg.C, reacting for 2h, monitoring reaction progress by TLC, after the reaction is finished, naturally cooling to 40 ℃, further cooling the reaction solution to 0 ℃ by ice water bath, weighing 1.28kg of sodium nitrate, adding the sodium nitrate into the reaction solution in three batches, stirring for 10h, naturally heating to 15 ℃ after TLC monitoring reaction, adding 0.52kg of zinc powder, stirring at 15 deg.C for 9h, monitoring by TLC, stopping reaction, pouring the reaction solution into 5L ice water, adjusting the pH value to 7 by using 1N sodium hydroxide aqueous solution, adding 3L dichloromethane for extraction, repeatedly extracting for three times, combining organic phases, concentrating and drying to obtain 1.53kg of isosorbide mononitrate A1 (the yield is 80%, the purity is 99.6%, HPLC is shown in figure 1, and other data meet the requirements of pharmacopeia).
Example 2-5 Synthesis method of isosorbide mononitrate A2-A5
Table 1: process parameter table for synthesizing isosorbide mononitrate A2-A5
Other parameters were the same as in example 1.
Example 7 preparation of isosorbide mononitrate for injection
This example provides a method for preparing isosorbide mononitrate for injection by using any one of isosorbide mononitrate prepared in examples 1-6, which comprises injecting 8L of water for injection into a solution preparation tank, cooling to room temperature, weighing 1kg of isosorbide mononitrate and 0.2kg of mannitol respectively, and stirring for dissolution. Adding 2L of water for injection, stirring uniformly, adding 0.03g of activated carbon, stirring at room temperature for 30min, performing decarburization sampling detection by a 0.45-micron filter element (the detection result is shown in figure 2), filtering by two 0.22-micron filter elements, conveying to a filling chamber after the detection is qualified, filling and half-plugging, performing freeze-drying, and performing full-pressure plugging to obtain the isosorbide mononitrate for injection.
Although the present invention has been described in detail with reference to the above embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A method for synthesizing isosorbide mononitrate is characterized by comprising the following steps: adding sorbitol into concentrated sulfuric acid, performing dehydration and cyclization, cooling after the reaction is finished, adding nitrate, performing nitration reaction, adding a reducing agent for reduction reaction after the reaction is finished, pouring the reaction solution into ice water, adjusting the pH value to be alkalescent by using an alkali solution, concentrating and drying to obtain the isosorbide mononitrate, wherein the chemical reaction formula is as follows:
2. the method for synthesizing isosorbide mononitrate according to claim 1, wherein: the volume weight ratio of the concentrated sulfuric acid to the sorbitol is 1-1.5L: 1 kg; the weight ratio of the nitrate to the sorbitol is 1.5-2.5: 1; the weight ratio of the reducing agent to the sorbitol is 0.8-1.2: 1.
3. The method for synthesizing isosorbide mononitrate according to claim 1 or 2, wherein: the nitrate is sodium nitrate, potassium nitrate or calcium nitrate; the reducing agent is zinc powder, iron powder or magnesium strips; the alkali liquor is 1N sodium hydroxide aqueous solution.
4. The method for synthesizing isosorbide mononitrate according to claim 1 or 2, wherein: the pressure of the dehydration ring is-0.6 to-0.8 MPa, the temperature is 120 to 150 ℃, and the time is 2 to 4 hours.
5. The method for synthesizing isosorbide mononitrate according to claim 1 or 2, wherein: the temperature of the nitration reaction is 0-5 ℃ and the time is 6-10 h.
6. The method for synthesizing isosorbide mononitrate according to claim 1 or 2, wherein: the temperature of the reduction reaction is 10-15 ℃, and the time is 7-9 h.
7. The use of isosorbide mononitrate synthesized by the method of synthesizing isosorbide mononitrate according to any one of claims 1-6, wherein: the isosorbide mononitrate is used for preparing isosorbide mononitrate for injection.
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| CN202110278382.4A CN113105470A (en) | 2021-03-15 | 2021-03-15 | Synthetic method and application of isosorbide mononitrate |
| PCT/CN2021/118254 WO2022193577A1 (en) | 2021-03-15 | 2021-09-14 | Synthesis method for isosorbide mononitrate and application thereof |
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| CN202110278382.4A CN113105470A (en) | 2021-03-15 | 2021-03-15 | Synthetic method and application of isosorbide mononitrate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861211A (en) * | 2021-09-29 | 2021-12-31 | 北京京丰制药(山东)有限公司 | Preparation process of isosorbide dinitrate |
| WO2022193577A1 (en) * | 2021-03-15 | 2022-09-22 | 海南通用康力制药有限公司 | Synthesis method for isosorbide mononitrate and application thereof |
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- 2021-03-15 CN CN202110278382.4A patent/CN113105470A/en active Pending
- 2021-09-14 WO PCT/CN2021/118254 patent/WO2022193577A1/en active Application Filing
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022193577A1 (en) * | 2021-03-15 | 2022-09-22 | 海南通用康力制药有限公司 | Synthesis method for isosorbide mononitrate and application thereof |
| CN113861211A (en) * | 2021-09-29 | 2021-12-31 | 北京京丰制药(山东)有限公司 | Preparation process of isosorbide dinitrate |
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| WO2022193577A1 (en) | 2022-09-22 |
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