CN115784985A - Preparation method of halquinol - Google Patents
Preparation method of halquinol Download PDFInfo
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- CN115784985A CN115784985A CN202211538896.XA CN202211538896A CN115784985A CN 115784985 A CN115784985 A CN 115784985A CN 202211538896 A CN202211538896 A CN 202211538896A CN 115784985 A CN115784985 A CN 115784985A
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Abstract
The invention relates to a preparation method of halquinol, belonging to the technical field of medicine synthesis. The preparation method of the halquinol comprises the following steps: mixing the mixed acid with 8-hydroxyquinoline, gradually adding aqueous hydrogen peroxide solution for reaction after cooling, and purifying after the reaction is finished; the mixed acid is the mixed acid of hydrochloric acid and protonic acid. According to the preparation method of the hamoquinoline, the acid used in chlorination of the 8-hydroxyquinoline is mixed acid, the content of each component of the obtained final product meets the quality requirement, and impurities are few; the post-treatment is simple without freezing and centrifuging, and the production cost is reduced; high atom utilization rate, high yield, easy control of reaction, stable process and easy large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of halquinol.
Background
The halquinol is widely applied in foreign countries, and is in the form of yellow white to yellow gray powder. The hamnolide comprises 5,7-dichloro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline and 7-chloro-8-hydroxyquinoline as effective components, wherein the 5,7-dichloro-8-hydroxyquinoline accounts for 57% -74%, the 5-chloro-8-hydroxyquinoline accounts for 23% -40%, and the 7-chloro-8-hydroxyquinoline does not exceed 4%. The anti-bacterial mechanism of the halquinol is that metal ions required by enzyme synthesis required by bacteria are blocked by chelating with ions such as iron, copper and zinc, and an auxiliary antibacterial drug inhibits the growth of harmful bacteria, regulates the microecological balance of intestinal tracts, can also act on gastrointestinal smooth muscles, reduces gastrointestinal peristalsis, improves the nutrient absorption efficiency, and has obvious curative effect when being used as a feed additive for resisting escherichia coli and salmonella.
The difficulty of directly preparing and synthesizing the mixture with the specific proportion of 5,7-dichloro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline and 7-chloro-8-hydroxyquinoline is higher, and the preparation method of the mixture with the specific proportion of 5,7-dichloro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline and 7-chloro-8-hydroxyquinoline is less. The invention patent with application publication number CN105693604 discloses a production process of halquinol, which is to chlorinate 8-hydroxyquinoline with hydrogen peroxide and hydrochloric acid, and has the advantages of low atom utilization rate, relatively low yield, high requirements of refrigerated centrifugation on production equipment conditions, and high production cost.
Disclosure of Invention
The invention aims to provide a preparation method of halquinol, which aims to solve the technical problem of how to directly prepare and synthesize a mixture with a specific proportion of 5,7-dichloro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline and 7-chloro-8-hydroxyquinoline in the prior art.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a preparation method of halquinol comprises the following steps: mixing the mixed acid with 8-hydroxyquinoline, gradually adding aqueous hydrogen peroxide solution for reaction after cooling, and purifying after the reaction is finished; the mixed acid is the mixed acid of hydrochloric acid and protonic acid.
The effective components of the product are mainly obtained by chlorination of 8-hydroxyquinoline, wherein an acid environment is needed during chlorination, and a chlorine source and the acid environment are directly provided by hydrochloric acid in a conventional reaction, but the method has the defects that the chlorine source is excessive while a certain acid environment is achieved, so that the proportion of the final product cannot meet the quality requirement due to transitional chlorination; the invention uses mixed acid, hydrochloric acid provides proper chlorine source, protonic acid provides acidic environment, excessive chlorine source is avoided, the content of each component of the obtained final product meets the quality requirement, the impurities are less, and the process is stable.
Preferably, the protonic acid is one or a mixture of sulfuric acid and phosphoric acid.
Preferably, the molar ratio of the 8-hydroxyquinoline to the hydrochloric acid to the protonic acid is 1:3-6:2-6.
Preferably, the mass fraction of the hydrochloric acid is 25 to 37 percent, and the mass fraction of the protonic acid is 30 to 60 percent.
Preferably, the mass fraction of hydrogen peroxide in the aqueous hydrogen peroxide solution is 20 to 35%.
Preferably, the molar ratio of the 8-hydroxyquinoline to the hydrogen peroxide in the aqueous solution is 1:2-4.
Preferably, the reaction temperature after the addition of the aqueous hydrogen peroxide solution is 10 to 30 ℃ and the reaction time is 2 to 4 hours.
Preferably, the purification method comprises the following steps: after the reaction is finished, adding an alkali solution gradually to adjust the pH value to 4-6, and filtering to obtain the catalyst.
Preferably, the alkali solution is one or more of sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution.
Preferably, the mass fraction of the alkali in the alkali solution is 10-50%.
The invention has the beneficial effects that:
in the preparation method of the hamoquinoline, the acid used in chlorination of the 8-hydroxyquinoline is mixed acid, the content of each component of the obtained final product meets the quality requirement, and impurities are few; the post-treatment is simple without freezing and centrifuging, and the production cost is reduced; high atom utilization rate, high yield, easy control of reaction, stable process and easy large-scale production.
Drawings
FIG. 1 is a gas chromatogram of hamoquinol from example 1.
Detailed Description
The present invention will be further described with reference to the following examples and accompanying drawings.
Example 1
The preparation method of the hamoquinoline comprises the following steps: adding hydrochloric acid, sulfuric acid and 8-hydroxyquinoline into a 2L reaction bottle, wherein the addition amount of the hydrochloric acid is 400g, and the mass fraction of the hydrochloric acid is 30%; the adding amount of the sulfuric acid is 360g, and the mass fraction of the sulfuric acid is 30%; the amount of 8-hydroxyquinoline added was 80g. After the hydrochloric acid, the sulfuric acid and the 8-hydroxyquinoline are added, stirring to dissolve the 8-hydroxyquinoline and cooling, and dropwise adding H with the mass fraction of 35% at the temperature of 20 DEG C 2 O 2 Aqueous solution of H 2 O 2 The amount of the added aqueous solution was 107g, and the reaction was incubated for 2 hours. And (2) dropwise adding a NaOH aqueous solution with the mass fraction of 30% into the reaction solution, adjusting the pH of the reaction solution to 4, filtering, drying the filtered solid to obtain 99g of solid powder, and detecting, wherein the content of the 5-chloro-8-hydroxyquinoline is 33.5%, the content of the 5,7-dichloro-8-hydroxyquinoline is 66.1%, and the molar yield is 89.3%.
Example 2
The preparation method of the hamoquinoline comprises the following steps: hydrochloric acid, sulfuric acid, phosphoric acid and 8-hydroxyquinoline are added into a 2L reaction bottle, the addition amount of the hydrochloric acid is 248g, and the mass fraction of the hydrochloric acid is 25%. The adding amount of the sulfuric acid is 134g, the adding amount of the phosphoric acid is 404g, and the mass fraction of the sulfuric acid and the phosphoric acid is 40%. The amount of 8-hydroxyquinoline added was 80g. After the hydrochloric acid, the acetic acid and the 8-hydroxyquinoline are added, stirring to dissolve the 8-hydroxyquinoline and cooling, and dropwise adding 30% by mass of H at 10 DEG C 2 O 2 Aqueous solution of H 2 O 2 The amount of the aqueous solution added was 187g, and the reaction was incubated for 3 hours. Adding 10% KOH aqueous solution in percentage by mass into the reaction solution dropwise, adjusting the pH of the reaction solution to 6, filtering, drying the solid obtained by filtering to obtain 101g of solid powder, and detecting, wherein the content of 5-chloro-8-hydroxyquinoline is 33.1%, the content of 5,7-dichloro-8-hydroxyquinoline is 66.3%, and the yield is 90.6%.
Example 3
The preparation method of the hamoquinoline comprises the following steps: adding hydrochloric acid, phosphoric acid and 8-hydroxyquinoline into a 2L reaction bottleThe loading amount is 271g, and the mass fraction of hydrochloric acid is 37%. The adding amount of the phosphoric acid is 539g, and the mass fraction of the phosphoric acid is 60%. The amount of 8-hydroxyquinoline added was 80g. After the hydrochloric acid, the phosphoric acid and the 8-hydroxyquinoline are added, stirring to dissolve the 8-hydroxyquinoline and cooling, and dropwise adding H with the mass fraction of 20% at the temperature of 30 DEG C 2 O 2 Aqueous solution of H 2 O 2 The addition of the aqueous solution was 374g, and the reaction was incubated for 4h. Na with the mass fraction of 50 percent is dripped into the reaction liquid 2 CO 3 Adjusting the pH value of the reaction solution to 5 by using an aqueous solution, filtering, and drying a solid obtained by filtering to obtain 100g of solid powder, wherein the content of the 5-chloro-8-hydroxyquinoline is 33.2 percent, the content of the 5,7-dichloro-8-hydroxyquinoline is 66.4 percent and the yield is 90.0 percent through detection.
Comparative example 1
10g of hydrochloric acid with the mass fraction of 8-hydroxyquinoline being 30% is placed in a reaction flask and stirred until the 8-hydroxyquinoline is completely dissolved. Cooling to 10 deg.C with ice brine, and adding 5g of H dropwise in 2H 2 O 2 Aqueous solution and reaction is carried out for 2h under the temperature of 10 ℃.
Then cooling and suction filtering are carried out, and the separated 5-chloro-8-hydroxyquinoline hydrochloride is extracted by hydrochloric acid of 3 multiplied by 20g and suction filtering is carried out. The separated 5-chloro-8-hydroxyquinoline hydrochloride was added to 40g of water and sufficiently stirred to give a suspended yellow solution, followed by dropwise addition of 28% ammonia water to neutralize the solution to a pH of =6.7, followed by suction filtration to obtain a white solid 5-chloro-8-hydroxyquinoline, which was then dried under vacuum in a yield of 82.4%.
Claims (10)
1. A preparation method of halquinol is characterized by comprising the following steps: mixing the mixed acid with 8-hydroxyquinoline, cooling, gradually adding aqueous hydrogen peroxide solution for reaction, and after the reaction is finished, purifying to obtain the compound; the mixed acid is the mixed acid of hydrochloric acid and protonic acid.
2. The method for preparing halquinol as claimed in claim 1, wherein the protonic acid is one or a mixture of sulfuric acid and phosphoric acid.
3. The method for preparing halquinol according to claim 1 or 2, wherein the molar ratio of 8-hydroxyquinoline to hydrochloric acid to protonic acid is 1:3 to 6:2 to 6.
4. The method for preparing halquinol as claimed in claim 1 or 2, wherein the mass fraction of the hydrochloric acid is 25% to 37%, and the mass fraction of the protonic acid is 30% to 60%.
5. The method for preparing hamquinolone according to claim 1, wherein the mass fraction of hydrogen peroxide in the aqueous hydrogen peroxide solution is from 20% to 35%.
6. The method of claim 1 or 5, wherein the molar ratio of 8-hydroxyquinoline to hydrogen peroxide in the aqueous hydrogen peroxide solution is 1:2-4.
7. The method for preparing halquinol according to claim 1, wherein the reaction temperature after the addition of the aqueous hydrogen peroxide solution is 10 to 30 ℃ and the reaction time is 2 to 4 hours.
8. The method for preparing halquinol as claimed in claim 1, wherein the purification method comprises: after the reaction is finished, adding an alkali solution gradually to adjust the pH value to 4-6, and filtering to obtain the catalyst.
9. The method for preparing halquinol according to claim 8, wherein the alkali solution is one or more of sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution.
10. The method for preparing halquinol according to claim 8 or 9, wherein the mass fraction of the alkali in the alkali solution is 10-50%.
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| CN202211538896.XA CN115784985A (en) | 2022-12-01 | 2022-12-01 | Preparation method of halquinol |
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| CN202211538896.XA CN115784985A (en) | 2022-12-01 | 2022-12-01 | Preparation method of halquinol |
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| CN202211538896.XA Pending CN115784985A (en) | 2022-12-01 | 2022-12-01 | Preparation method of halquinol |
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