CN112174884A - Preparation method of chloroquinate - Google Patents
Preparation method of chloroquinate Download PDFInfo
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- CN112174884A CN112174884A CN202011155773.9A CN202011155773A CN112174884A CN 112174884 A CN112174884 A CN 112174884A CN 202011155773 A CN202011155773 A CN 202011155773A CN 112174884 A CN112174884 A CN 112174884A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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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
- Y02P20/584—Recycling of catalysts
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Abstract
The invention provides a preparation method of chloroquinate, which comprises the following steps: under the catalytic action of metal manganese salt, hydrochloric acid and hydrogen peroxide are used as chlorinating agents to perform chlorination reaction on 8-hydroxy-2-methylquinoline, and then the chloroquinate is prepared. The method uses metal manganese salt as a catalyst, uses hydrochloric acid and hydrogen peroxide as reaction raw materials, improves chemical selectivity, has few byproducts, has strong reaction operability, does not need light protection and gas protection, obtains the product with the purity of more than 99.00 percent, and ensures the quality of the chloroquinate. The method does not use organic solvent in the reaction process, reduces the generation of waste liquid, avoids the pollution to the environment to the maximum extent, saves the cost, improves the quality, and is a green and environment-friendly process route suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of cloquindol.
Background
The cloquindol is a broad-spectrum bacteriostatic agent and has the following structure:
the chemical name is: 5, 7-dichloro-8-hydroxy-2-methylquinoline, molecular weight 228.07, is a yellow needle-like crystal with a slightly pungent odor. As early as the 50 s, it was extensively studied by many pharmaceutical facilities in Europe and found to have activity against antimicrobial pathogens such as fungi, infusorium, bacteria (G + and G-), chlamydia and mycoplasma, as broad-spectrum bacteriostats. Because the medicine is slightly soluble in water, pathogenic microorganisms generally enter pathogen cells through endocytosis, the pH value of the pathogen cells is changed, the pathogen metabolism is inhibited, and the like, the pathogen death is finally caused, and human epithelial cells have no phagocytic function on the chloroquinalder, so that the medicine has small adverse reaction on a human body when being externally used.
The chloroquinalder is prepared by Moringa Theramex pharmaceutical factory, and the published production method is that 8-hydroxy-2-methylquinoline is used as raw material, chlorine is used as chlorinated raw material, and the chloroquinalder is synthesized by one-step chlorination reaction. The equation is as follows:
the method has the disadvantages that chlorine is extremely toxic and has high requirements on safe production. The absorption efficiency of the chlorine is not easy to control, and in addition, the efficiency of the gas-liquid reaction is difficult to control, so that the amount of the chlorine participating in the reaction in the chlorination reaction is difficult to accurately control, the chlorine dosage is insufficient, the monochlorinated products are more, and the excessive chlorine can cause the increase of the trichloro-chlorinated products and the polychlorinated products. The reaction also needs to be strictly protected from light, otherwise, the chlorination reaction is also easy to occur at the methyl position. This presents difficulties in the purification of the final product.
At present, many documents and patents research on the synthesis process of the chloroquinate, but few reports on the research on the product quality of the chloroquinate exist.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing chloroquinate, which has high selectivity, less by-products and high reaction efficiency.
In order to solve the technical problem, the invention provides a preparation method of chloroquinate, which comprises the following steps:
under the catalytic action of metal manganese salt, hydrochloric acid and hydrogen peroxide are used as chlorinating agents to perform chlorination reaction on 8-hydroxy-2-methylquinoline, and then the chloroquinate is prepared.
The reaction equation for the above reaction is as follows:
preferably, the metal manganese salt is selected from one or more of manganese sulfate, manganese carbonate, manganese nitrate and manganese chloride. More preferably manganese sulfate.
It has been found that if only hydrogen peroxide and hydrochloric acid are added to the above reaction system, and no catalyst is added, the reaction mainly produces a mixture of 4-chloro product and 2-chloro product and other by-products, and the target 2, 4-dichloro product, i.e., chloroquinado, is hardly produced.
And when cuprous chloride is used as the catalyst, most of the chlorination products are 4-chloro-monochloro products, and the 2, 4-dichloro products are very few.
Magnesium chloride, calcium chloride, ferric sulfate, ferric chloride and the like are used as catalysts, all the products obtained by reaction are mixtures, the selectivity of 2, 4-dichloro products is poor, and the mixtures are difficult to refine.
According to the method, metal manganese salt (such as manganese sulfate, manganese carbonate, manganese nitrate and manganese chloride) is used as a catalyst, chloroquinate is generated through one-step chlorination reaction, the catalytic efficiency is highest, the selectivity is good, the reaction yield is greatly improved, a few monochloro byproducts are generated, the reaction efficiency can be improved, the reaction time is shortened, the post-treatment is simple, the purity of the prepared chloroquinate is over 99.00%, and the quality of the chloroquinate is guaranteed.
Preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the metal manganese salt is 100: 1-15; more preferably 100:8 to 12.
According to the invention, the preferable molar ratio of the 8-hydroxy-2-methylquinoline to the hydrochloric acid is 1: 5-10; more preferably 1:6 to 8.
Preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the hydrogen peroxide is 1: 2.5-10.0; more preferably 1:3.0 to 6.0.
Preferably, the mass concentration of the hydrochloric acid is 10-37%; more preferably 15% to 25%.
The source of the hydrogen peroxide is not particularly limited in the present invention, and the hydrogen peroxide may be a general commercially available hydrogen peroxide, and preferably a hydrogen peroxide having a mass content of 30% commercially available hydrogen peroxide.
Preferably, the temperature of the chlorination reaction is 25-90 ℃; more preferably 30 to 80 ℃, in some embodiments of the present invention, the reaction temperature may be 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃, or a temperature range in which any two temperatures are the upper limit value and the lower limit value, such as 40 to 50 ℃, 50 to 60 ℃, and more preferably 70 to 80 ℃.
Preferably, the chlorination reaction time is 3-12 h; further preferably 4 to 7 hours.
Preferably, the preparation method comprises the following steps:
A) mixing 8-hydroxy-2-methylquinoline, a metal manganese salt and hydrochloric acid;
B) and (3) heating to the reaction temperature, dropwise adding hydrogen peroxide into the reaction system, and carrying out chlorination reaction to obtain the cloquindol.
Preferably, the chlorination reaction is followed by refining, specifically:
after the reaction is finished, cooling the reaction system to 20-30 ℃, filtering to obtain a crude product, and refining the crude product by using a mixed solution of a good solvent and water to obtain a pure cloquindol product;
the good solvent is alcohol or acetonitrile.
In the present invention, the purification is preferably recrystallization purification.
Preferably, the alcohol is selected from one or more of methanol, ethanol and isopropanol. Ethanol is more preferred.
In the present invention, the mass ratio of the good solvent to the water is preferably 2 to 30:1, and more preferably 5 to 15: 1.
Compared with the prior art, the invention provides a preparation method of chloroquinate, which comprises the following steps: under the catalytic action of metal manganese salt, hydrochloric acid and hydrogen peroxide are used as chlorinating agents to perform chlorination reaction on 8-hydroxy-2-methylquinoline, and then the chloroquinate is prepared.
Compared with the prior art, the invention has the following beneficial effects:
(1) the method does not use organic solvent in the reaction process, thereby avoiding the pollution to the environment.
(2) The invention uses HCl and H2O2As a chlorination reaction raw material, under the catalysis of metal manganese salt, the method has the advantages of high reaction efficiency, good selectivity and less side reaction, increases the conversion rate and yield, and ensures the quality of the chloroquinate.
(3) The catalyst can be recycled, waste residues and waste liquid are not generated, the treatment cost of industrial three wastes is reduced, the environmental pollution is avoided, and the method is a green and environment-friendly process route.
(4) The method simplifies the process operation, has mild reaction temperature, does not need light protection and gas protection, has low requirement on reaction equipment, has strong reaction operability, ensures the production safety, and is a route suitable for industrial production.
Detailed Description
In order to further illustrate the present invention, the following examples are given to describe in detail the process for preparing chloroquinate provided by the present invention.
Example 1
Adding 80g of 20% HCl, 10g of 8-hydroxy-2-methylquinoline and 0.9g of manganese sulfate into a 250ml reaction bottle, stirring to dissolve, controlling the temperature to be 70-80 ℃, dropwise adding 30g of 30% hydrogen peroxide into the reaction liquid, and reacting for 5 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 8g of crude chloroquinate. Recrystallizing and refining with 100g ethanol and 10g water to obtain 6.6g of pure chloroquinader, with yield of 46.07% and HPLC purity of 99.95%.
Example 2
230g of 15 percent HCl, 20g of 8-hydroxy-2-methylquinoline and 1.6g of manganese carbonate are put into a 500ml reaction bottle, stirred and dissolved to be clear, the temperature is controlled to be 50-60 ℃, 150g of 30 percent hydrogen peroxide is dripped into the reaction liquid, and the reaction is finished for 7 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 15.2g of crude chloroquinate. Recrystallizing and refining with 280g acetonitrile and 35g water to obtain 10.84g of pure chloroquinader, the yield is 37.83 percent, and the HPLC purity is 99.13 percent.
Example 3
Adding 60g of 25% HCl, 10g of 8-hydroxy-2-methylquinoline and 1.2g of manganese sulfate into a 250ml reaction bottle, stirring to dissolve, controlling the temperature to be 30-40 ℃, dropwise adding 60g of 30% hydrogen peroxide into the reaction liquid, and reacting for 8 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 7.6g of crude chloroquinate. Recrystallizing and refining with 200g ethanol and 35g water to obtain 6g of the pure product of the chloroquinader, the yield is 41.88 percent, and the HPLC purity is 99.08 percent.
Example 4
Adding 250g of 25% HCl, 50g of 8-hydroxy-2-methylquinoline and 0.8g of manganese chloride into a 1L reaction bottle, stirring to dissolve, controlling the temperature to be 80-90 ℃, dropwise adding 125g of 30% hydrogen peroxide into the reaction solution, and reacting for 10 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 28g of crude chloroquinate. Recrystallizing with 550g isopropanol and 50g water, and refining to obtain 20g of pure chloroquinader with yield of 27.92% and HPLC purity of 98.83%.
Example 5
Adding 900g of 10% HCl, 100g of 8-hydroxy-2-methylquinoline and 15g of manganese nitrate into a 5L reaction bottle, stirring to dissolve, controlling the temperature to be 40-50 ℃, dropwise adding 800g of 30% hydrogen peroxide into the reaction liquid, and reacting for 7 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 75g of crude chloroquinate. Recrystallizing with 1200g methanol and 130g water, and refining to obtain 59.6g of pure chloroquinader with yield of 41.60% and HPLC purity of 99.38%.
Example 6
Putting 1000g of 37% HCl, 100g of 8-hydroxy-2-methylquinoline and 1g of manganese sulfate into a 5L reaction bottle, stirring to dissolve, controlling the temperature to be 25-30 ℃, dropwise adding 1000g of 30% hydrogen peroxide into the reaction liquid, and reacting for 12 hours after the addition. And (4) carrying out suction filtration on the reaction solution to obtain 59g of crude chloroquinader. Recrystallizing with 900g ethanol and 100g water, and refining to obtain 39.7g of pure chloroquinader with yield of 27.69% and HPLC purity of 99.19%.
Comparative example 1
Adding 80g of 20% HCl and 10g of 8-hydroxy-2-methylquinoline into a 250ml reaction bottle, stirring, dissolving, controlling the temperature to be 70-80 ℃, dropwise adding 30g of 30% hydrogen peroxide into the reaction solution, and reacting for 5 hours after the addition. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 0.5g of crude chloroquinate. Recrystallizing and refining with 10g ethanol and 1g water to obtain 0.35g of pure chloroquinader, with the yield of 2.44% and the HPLC purity of 99.42%.
Comparative example 2
Adding 80g of 20% HCl and 10g of 8-hydroxy-2-methylquinoline and 0.9g of cuprous chloride into a 250ml reaction bottle, stirring to dissolve, controlling the temperature to be 70-80 ℃, dropwise adding 30g of 30% hydrogen peroxide into the reaction solution, and reacting for 5 hours. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 5g of crude chloroquinate. Recrystallizing and refining with 100g ethanol and 10g water to obtain 3.2g of pure chloroquinader, with yield of 22.32% and HPLC purity of 98.84%.
Comparative example 3
Adding 80g of 20% HCl, 10g of 8-hydroxy-2-methylquinoline and 0.9g of calcium chloride into a 250ml reaction bottle, stirring to dissolve, controlling the temperature to be 70-80 ℃, dropwise adding 30g of 30% hydrogen peroxide into the reaction solution, and reacting for 1 h. And cooling the reaction liquid to 20-30 ℃, and performing suction filtration to obtain 2.2g of crude chloroquinate. Recrystallizing with 100g ethanol and 10g water, and refining to obtain 1.2g of pure chloroquinader with yield of 8.37% and HPLC purity of 98.51%.
Comparative example 4
Adding 80g of 20% HCl, 10g of 8-hydroxy-2-methylquinoline and 0.9g of manganese sulfate into a 250ml reaction bottle, stirring to dissolve, controlling the temperature to be 10-20 ℃, dropwise adding 30g of 30% hydrogen peroxide into the reaction liquid, and reacting for 1 h. And (4) carrying out suction filtration on the reaction solution to obtain 1.8g of crude chloroquinader. Recrystallizing and refining with 100g ethanol and 10g water to obtain 0.7g of pure chloroquinader, with yield of 4.88% and HPLC purity of 98.96%.
As can be seen from the above examples and comparative examples, the present invention uses a manganese metal salt as a catalyst, which greatly improves the yield and purity of chloroquinate.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A preparation method of chloroquinate comprises the following steps:
under the catalytic action of metal manganese salt, hydrochloric acid and hydrogen peroxide are used as chlorinating agents to perform chlorination reaction on 8-hydroxy-2-methylquinoline, and then the chloroquinate is prepared.
2. The method according to claim 1, wherein the metal manganese salt is selected from one or more of manganese sulfate, manganese carbonate, manganese nitrate and manganese chloride.
3. The preparation method according to claim 1, wherein the molar ratio of the 8-hydroxy-2-methylquinoline to the metal manganese salt is 100: 1-15;
the molar ratio of the 8-hydroxy-2-methylquinoline to the hydrochloric acid is 1: 5-10;
the molar ratio of the 8-hydroxy-2-methylquinoline to the hydrogen peroxide is 1: 2.5-10.0.
4. The preparation method according to claim 1, wherein the mass concentration of the hydrochloric acid is 10% to 37%;
the mass concentration of the hydrogen peroxide is 30%.
5. The method according to claim 1, wherein the temperature of the chlorination reaction is 25 to 90 ℃.
6. The preparation method according to claim 1, wherein the time of the chlorination reaction is 3-12 h.
7. The method of claim 1, comprising the steps of:
A) mixing 8-hydroxy-2-methylquinoline, a metal manganese salt and hydrochloric acid;
B) and (3) heating to the reaction temperature, dropwise adding hydrogen peroxide into the reaction system, and carrying out chlorination reaction to obtain the cloquindol.
8. The preparation method according to claim 1, characterized in that after the chlorination reaction, further refining is performed, specifically:
after the reaction is finished, cooling the reaction system to 20-30 ℃, filtering to obtain a crude product, and refining the crude product by using a mixed solution of a good solvent and water to obtain a pure cloquindol product;
the good solvent is alcohol or acetonitrile.
9. The method according to claim 8, wherein the alcohol is one or more selected from methanol, ethanol, and isopropanol.
10. The preparation method according to claim 8, wherein the mass ratio of the good solvent to the water is 2-30: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527199A (en) * | 2021-05-27 | 2021-10-22 | 北京斯利安药业有限公司 | Preparation method of chloroquinate |
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| DE1770018A1 (en) * | 1968-03-21 | 1972-04-06 | Ruetgerswerke Ag | Process for the preparation of 5-chloro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline |
| CN101402635A (en) * | 2008-11-20 | 2009-04-08 | 雅本化学（苏州）有限公司 | Process for producing 5-chlorine-7-aza indole |
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| CN110143919A (en) * | 2019-07-08 | 2019-08-20 | 北京金城泰尔制药有限公司 | The synthesis technology of Chlorquinaldol |
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- 2020-10-26 CN CN202011155773.9A patent/CN112174884B/en active Active
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| DE1770018A1 (en) * | 1968-03-21 | 1972-04-06 | Ruetgerswerke Ag | Process for the preparation of 5-chloro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline |
| CN101402635A (en) * | 2008-11-20 | 2009-04-08 | 雅本化学（苏州）有限公司 | Process for producing 5-chlorine-7-aza indole |
| CN108341776A (en) * | 2018-04-13 | 2018-07-31 | 北京朗依制药有限公司沧州分公司 | The technique for synthesizing Chlorquinaldol |
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| CN110878046A (en) * | 2019-11-01 | 2020-03-13 | 广西师范大学 | Rare earth complex constructed based on 2-methyl-5, 7-dichloro-8-hydroxyquinoline and preparation method and application thereof |
| CN111116467A (en) * | 2020-01-14 | 2020-05-08 | 北京金城泰尔制药有限公司 | Preparation method of chloroquinate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527199A (en) * | 2021-05-27 | 2021-10-22 | 北京斯利安药业有限公司 | Preparation method of chloroquinate |
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