阅读说明：本技术 一种氯喹那多的制备方法 (Preparation method of chloroquinate ) 是由 阮长浩 廖俊凯 张书彬 郑莎 易斌 于 2021-05-27 设计创作，主要内容包括：本发明提供了一种氯喹那多的制备方法,所述制备方法包括：在催化剂路易斯酸存在的条件下,含有8-羟基-2-甲基喹啉和次氯酸叔丁酯的物料,反应I,得到所述氯喹那多。本发明用次氯酸叔丁酯替代氯气作为反应原料,选择性好,副产物少,反应操作性强,不用避光和气体保护,提高了质量和收率,纯度在99.00％以上,保证了氯喹那多的质量。本发明反应过程中减少了废液的生成,最大限度的避免了对环境的污染,节约了成本,提高了质量,是一条绿色环保适合工业化生产的工艺。(The invention provides a preparation method of chloroquinate, which comprises the following steps: and (2) reacting the materials containing 8-hydroxy-2-methylquinoline and tert-butyl hypochlorite in the presence of a catalyst Lewis acid to obtain the cloquindol. The invention uses tert-butyl hypochlorite to replace chlorine as a reaction raw material, has good selectivity, few byproducts and strong reaction operability, does not need light shielding and gas protection, improves the quality and the yield, has the purity of over 99.00 percent, and ensures the quality of the chloroquinalder. The method reduces the generation of waste liquid in the reaction process, avoids the pollution to the environment to the maximum extent, saves the cost, improves the quality, and is a green and environment-friendly process suitable for industrial production.)

1. A preparation method of chloroquinate, which is characterized by comprising the following steps: and (2) reacting the material I containing 8-hydroxy-2-methylquinoline and tert-butyl hypochlorite in the presence of a catalyst Lewis acid to obtain the chloroquinate.

2. The production method according to claim 1, wherein the Lewis acid is at least one member selected from the group consisting of aluminum trichloride, ferric trichloride, boron trifluoride, zinc chloride and titanium tetrachloride.

3. The preparation method according to claim 1, wherein the molar ratio of the 8-hydroxy-2-methylquinoline to the tert-butyl hypochlorite is 1: 1.80-3.50;

preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the lewis acid is 1: 0.02-0.08.

4. The method according to claim 1, wherein the material I containing 8-hydroxy-2-methylquinoline and tert-butyl hypochlorite further comprises a solvent I; the solvent I is at least one selected from dichloromethane and chloroform;

preferably, the mass-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is 1g (3-20) mL.

5. The method according to claim 1, wherein the conditions of reaction I are: the reaction temperature is 20-60 ℃, and the reaction time is 5-14 hours.

6. The method of claim 1, further comprising a post-treatment step; the post-processing step comprises:

(1) mixing the mixed system obtained after the reaction I with acid, and reacting II to obtain an intermediate product I;

(2) separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing the chloroquinate;

(3) and mixing the material III containing the chloroquinate with the solution II, and refining to obtain the chloroquinate.

7. The method according to claim 6, wherein the acid is selected from hydrochloric acid with a mass fraction of 25% to 38%;

preferably, the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the acid is 1g: (1-1.5) ml.

8. The method according to claim 6, wherein the conditions of the reaction II are as follows: the temperature is 20-30 ℃;

preferably, the inorganic base is selected from at least one of ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonium bicarbonate.

9. The preparation method according to claim 6, wherein the pH of the material II containing the intermediate product I and the inorganic base is 2.5-5.0;

preferably, the solvent II comprises an organic solvent and water; the organic solvent is at least one of methanol, absolute ethyl alcohol and acetonitrile.

10. The preparation method according to claim 9, wherein the volume ratio of the organic solvent to the water is 2-20: 1;

preferably, the mass-volume ratio of the material III containing the chloroquinate to the organic solvent is 1g (6-20) mL.

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, has a slightly pungent odor, and has antimicrobial activity against fungi, trichomonads, bacteria (G + and G-), chlamydia, mycoplasma, etc. 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 chloroquinaldehyd, 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, hydrochloric acid is used as solvent, chlorine is used as chlorinated raw material, and the chloroquinalder is synthesized by one-step chlorination reaction. The equation is as follows:

the red Tong is prepared from 8-hydroxy-2-methylquinoline as a raw material, formic acid instead of hydrochloric acid, and chloroquinate is synthesized by one-step chlorination reaction under the condition of introducing chlorine gas.

The method has the defects that chlorine is extremely toxic, has high requirements on safety production and is easy to cause environmental pollution. The reaction rate of the gas-liquid reaction is difficult to control, so that the dosage of the chlorine participating in the reaction is difficult to accurately control, the dosage of the chlorine is insufficient, the monochloro product is more, and the trichloro product and the polychlorinated product are increased due to excessive chlorine. The reaction also needs to be strictly protected from light, otherwise, the chlorination reaction is also easy to occur at the methyl position. The whole reaction has low conversion rate, more impurities and difficult purification.

At present, a synthesis process using sodium hypochlorite to replace chlorine as a chlorinated raw material is disclosed, and the reaction equation formula is as follows:

the process avoids the pollution of chlorine, but still uses hydrochloric acid with larger volatility, and the sodium hypochlorite solution has large dosage, can dissolve part of generated products in the reaction process, so that the yield is reduced, the generated waste liquid is more, and the cost for treating the waste liquid is increased.

Therefore, there is a need to develop a green and environment-friendly process for synthesizing chloroquinate.

Disclosure of Invention

In order to solve the technical problems, the invention provides a preparation method of cloquindol, which takes 8-hydroxy-2-methylquinoline as a raw material, tert-butyl hypochlorite as a chlorinated raw material and Lewis acid as a catalyst to generate the cloquindol through one-step chlorination reaction. The preparation method has the advantages of high reaction efficiency, good selectivity, less monochloro by-products, reaction time saving and simpler post-treatment. And has higher selectivity, and the purity of the prepared chloroquinate is over 99.00 percent.

According to one aspect of the present application, there is provided a preparation method of chloroquinate, the preparation method comprising: and (3) reacting the material containing 8-hydroxy-2-methylquinoline and tert-butyl hypochlorite in the presence of a catalyst Lewis acid to obtain the chloroquinate.

The reaction equation for the above reaction is as follows:

optionally, the lewis acid is selected from at least one of aluminum chloride, ferric trichloride, boron trifluoride, zinc chloride, and titanium tetrachloride.

Preferably, the lewis acid is selected from aluminium chloride.

Optionally, the molar ratio of the 8-hydroxy-2-methylquinoline to the tert-butyl hypochlorite is 1: 1.80-3.50.

Alternatively, the upper limit of the molar ratio of the 8-hydroxy-2-methylquinoline to the tert-butyl hypochlorite is selected from 1: 1.81, 1: 1.82, 1: 1.83, 1: 1.84, 1: 1.85, 1: 1.86, 1: 1.87, 1: 1.88, 1: 1.89, 1: 1.90, 1: 1.91, 1: 1.92, 1: 1.93, 1: 1.94, 1:1.95, 1: 1.96, 1: 1.97, 1: 1.98, 1: 1.99, 1: 2.00, 1: 2.01, 1: 2.02, 1:2.03, 1: 2.04, 1: 2.05, 1: 2.06, 1: 2.07, 1: 2.08, 1: 2.09, 1: 2.10, 1: 2.11, 1: 2.12, 1: 2.13, 1: 2.14, 1: 2.15, 1: 2.16, 1: 2.17, 1: 2.18, 1: 2.19, 1: 2.20, 1: 2.30, 1: 2.40, 1: 2.50, 1: 2.60, 1: 2.70, 1: 2.80, 1: 2.90, 1: 3.00, 1: 3.10, 1: 3.20, 1: 3.30, 1: 3.40 or 1: 3.50; the lower limit is selected from 1:1.80, 1: 1.81, 1: 1.82, 1: 1.83, 1: 1.84, 1: 1.85, 1: 1.86, 1: 1.87, 1: 1.88, 1: 1.89, 1: 1.90, 1: 1.91, 1: 1.92, 1: 1.93, 1: 1.94, 1:1.95, 1: 1.96, 1: 1.97, 1: 1.98, 1: 1.99, 1: 2.00, 1: 2.01, 1: 2.02, 1:2.03, 1: 2.04, 1: 2.05, 1: 2.06, 1: 2.07, 1: 2.08, 1: 2.09, 1: 2.10, 1: 2.11, 1: 2.12, 1: 2.13, 1: 2.14, 1: 2.15, 1: 2.16, 1: 2.17, 1: 2.18, 1: 2.19, 1: 2.20, 1: 2.30, 1: 2.40, 1: 2.50, 1: 2.60, 1: 2.70, 1: 2.80, 1: 2.90, 1: 3.00, 1: 3.10, 1: 3.20, 1: 3.30 or 1: 3.40.

preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the tert-butyl hypochlorite is 1: 1.95-2.15.

Further preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the tert-butyl hypochlorite is 1: 2.03-2.08.

Alternatively, the molar ratio of 8-hydroxy-2-methylquinoline to lewis acid is 1: 0.02-0.08.

Alternatively, the upper limit of the molar ratio of the 8-hydroxy-2-methylquinoline to the lewis acid is selected from 1: 0.03, 1:0.04, 1: 0.05, 1: 0.06, 1: 0.07 or 1: 0.08; the lower limit is selected from 1: 0.02, 1: 0.03, 1:0.04, 1: 0.05, 1: 0.06 or 1: 0.07.

preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the Lewis acid is 1: 0.04-0.07.

Optionally, the material I containing 8-hydroxy-2-methylquinoline and tert-butyl hypochlorite also comprises a solvent I; the solvent I is at least one selected from dichloromethane and chloroform.

Optionally, the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is 1g (3-20) mL.

Alternatively, the upper limit of the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is selected from 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, or 1g:20 mL; the lower limit is selected from the group consisting of 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL, 1g:11mL, 1g:12mL, 1g:13mL, 1g:14mL, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, and 1g:19 mL.

Preferably, the mass-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent is 1g (5-10) mL.

Optionally, the conditions of reaction I are: the reaction temperature is 20-60 ℃, and the reaction time is 5-14 h.

Preferably, the reaction temperature is 32-41 ℃.

Preferably, the reaction time is 7-9 h.

Optionally, the preparation method comprises:

A) mixing 8-hydroxy-2-methylquinoline, Lewis acid and a solvent to obtain an intermediate product A;

B) and adding tert-butyl hypochlorite into the intermediate product A, heating to the reaction temperature, and carrying out chlorination reaction to obtain the cloquindol.

Optionally, the preparation method further comprises a post-treatment step; the post-processing step comprises:

(1) mixing the mixed system obtained after the reaction I with acid, and reacting II to obtain an intermediate product I;

(2) separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing the chloroquinate;

(3) and mixing the material III containing the chloroquinate with the solution II to obtain the chloroquinate.

Optionally, the acid is selected from hydrochloric acid with a mass fraction of 25% to 38%.

Preferably, the acid is selected from hydrochloric acid with the mass fraction of 30-38%.

Optionally, the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the acid is 1g: (1-1.5) ml.

Alternatively, the upper limit of the mass to volume ratio of the 8-hydroxy-2-methylquinoline to the acid is selected from 1g: 1.01mL, 1g: 1.02mL, 1g: 1.03mL, 1g:1.04mL, 1g:1.05mL, 1g:1.06mL, 1g:1.07mL, 1g:1.08mL, 1g:1.09mL, 1g:1.10mL, 1g:1.11mL, 1g:1.12mL, 1g:1.13mL, 1g:1.14mL, 1g:1.15mL, 1g:1.16mL, 1g:1.17mL, 1. g:1.18mL, 1g:1.19mL, 1g:1.20mL, 1g:1.21mL, 1g:1.22mL, 1g:1.23mL, 1g:1.24mL, 1g:1.25mL, 1g:1.26mL, 1g:1.27mL, 1.32: 1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.24mL, 1g:1.32mL, 1g:1.42mL, 1g:1.34mL, 1.32mL, 1g:1.32mL, 1g:1.34mL, 1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.47mL1g:1.48mL, 1g:1.49mL or 1g:1.50 mL; the lower limit is selected from 1g: 1.00mL, 1g: 1.01mL, 1g: 1.02mL, 1g: 1.03mL, 1g:1.04mL, 1g:1.05mL, 1g:1.06mL, 1g:1.07mL, 1g:1.08mL, 1g:1.09mL, 1g:1.10mL, 1g:1.11mL, 1g:1.12mL, 1g:1.13mL, 1g:1.14mL, 1g:1.15mL, 1g:1.16mL, 1g:1.17mL, 1. g:1.18mL, 1g:1.19mL, 1g:1.20mL, 1g:1.21mL, 1g:1.22mL, 1g:1.23mL, 1g:1.24mL, 1g:1.25mL, 1g:1.26mL, 1g:1.27mL, 1.32: 1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.24mL, 1g:1.32mL, 1g:1.42mL, 1g:1.34mL, 1.32mL, 1g:1.32mL, 1g:1.34mL, 1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.32mL, 1g:1.47mL1g:1.48mL or 1g:1.49 mL.

Alternatively, the conditions of reaction II are: the temperature is 20-30 ℃.

Optionally, the reaction II is performed under normal temperature and pressure.

Optionally, the inorganic base is selected from at least one of ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.

Preferably, the inorganic base is selected from aqueous ammonia.

Optionally, the pH of the material II containing the intermediate product I and the inorganic base is 2.5-5.0.

Preferably, the pH of the material II containing the intermediate product I and the inorganic base is 3.0-3.5.

Alternatively, the upper pH limit of feed II containing intermediate I and inorganic base is selected from 3.0, 3.2, 3.5, 3.8, 4.0, 4.2, 4.5, or 5.0; the lower limit is selected from 2.5, 3.0, 3.2, 3.5, 3.8, 4.0, 4.2 or 4.5. Optionally, the solvent II comprises an organic solvent and water; the organic solvent is at least one of methanol, absolute ethyl alcohol and acetonitrile.

Preferably, the organic solvent is selected from anhydrous ethanol.

Optionally, the volume ratio of the organic solvent to the water is 2-20: 1.

Preferably, the volume ratio of the organic solvent to the water is 6-9: 1.

Optionally, the mass-to-volume ratio of the material III containing the chloroquinate to the organic solvent is 1g (6-20) mL.

Preferably, the mass-volume ratio of the material III containing the chloroquinate to the organic solvent is 1g (7-12) mL.

Specifically, the post-processing includes: after the reaction is finished, cooling the reaction system to 20-30 ℃, filtering to remove the catalyst, dripping concentrated hydrochloric acid into the filtrate, precipitating, and filtering to obtain the cloquindol hydrochloride. And adding the solid into water, stirring to dissolve, slowly adding inorganic base, separating out the solid, filtering, leaching and drying to obtain a crude product. And refining the crude product by using a mixed solution of an organic solvent and water to obtain the chloroquinate.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention uses tert-butyl hypochlorite to replace chlorine gas as the raw material of the chlorination reaction, has good selectivity, reduces side reaction, improves quality and yield, has purity of over 99.00 percent, ensures the quality of the chloroquinalder and reduces the pollution to the environment.

(2) The invention uses dichloromethane or chloroform as solvent, which can be recycled, thus reducing the generation of waste liquid and the cost for treating the waste liquid; the catalyst Lewis acid is used, so that the generation of a mixture of a 4-chlorine product, a 2-chlorine product and a target product 2, 4-dichloro product can be avoided, and the problem that qualified chloroquinate cannot be obtained in the post-treatment stage is also avoided; in the post-treatment of the invention, the product is salified and separated out by dripping concentrated hydrochloric acid, thereby avoiding the generation and increase of impurities in the long-time concentration process, reducing the production energy consumption and reducing the production time.

(3) 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 process for preparing chloroquinate provided by the present invention is described in detail below with reference to examples.

The raw materials in the examples of the present application were all purchased commercially, unless otherwise specified. If not stated, the test method adopts the conventional method, and the instrument setting adopts the setting recommended by the manufacturer.

The purity of chloroquinate was determined by HPLC.

HPLC：Waters 2998

The method for calculating the yield comprises the following steps: the moles of product chloroquinadol per mole of 8-hydroxy-2-methylquinoline x 100%.

Example 1

10g of 8-hydroxy-2-methylquinoline, 50mL of dichloromethane and 0.35g of aluminum chloride are put into a 250mL reaction bottle, stirred and cooled to 20-30 ℃, 14.2g of tert-butyl hypochlorite is added, and the reaction is carried out for 7 hours at the temperature of 32-41 ℃.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 15mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 150mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.0, precipitating to obtain a solid, filtering, leaching, and drying to obtain a crude product.

The crude product is refined by 160mL of absolute ethyl alcohol and 20mL of water to obtain 9.1g of the pure product of the chloroquinader, the yield is 63.28 percent, and the HPLC purity is 99.58 percent.

Example 2

Adding 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.0g of aluminum chloride into a 500mL reaction bottle, stirring, cooling to 20-30 ℃, adding 28.0g of tert-butyl hypochlorite, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.5, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

Refining the crude product with 280mL of absolute ethyl alcohol and 30mL of water to obtain 19.7g of the pure product of the chloroquinader, wherein the yield is 68.86 percent, and the HPLC purity is 99.65 percent.

Example 3

10g of 8-hydroxy-2-methylquinoline, 80mL of dichloromethane and 0.5g of aluminum chloride are put into a 250mL reaction bottle, stirred and cooled to 20-30 ℃, 14g of tert-butyl hypochlorite is added, and the temperature is kept at 32-41 ℃ for reaction for 9 hours.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 12mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 100mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 4.0, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

The crude product is refined by using 100mL of acetonitrile and 10mL of water to obtain 9.5g of the pure product of the chloroquinader, the yield is 66.05 percent, and the HPLC purity is 99.70 percent.

Example 4

50g of 8-hydroxy-2-methylquinoline, 750mL of dichloromethane and 2.5g of aluminum chloride are put into a 1L reaction bottle, stirred and cooled to 20-30 ℃, 68g of tert-butyl hypochlorite is added, and the temperature is kept at 32-41 ℃ for reaction for 9 hours.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 55mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 600mL of water, stirring for dissolving, slowly adding ammonia water until the pH value is 2.5, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

The crude product is refined by 1600mL of methanol and 200mL of water to obtain 44.3g of the pure product of the chloroquinader, the yield is 61.89 percent, and the HPLC purity is 99.52 percent.

Example 5

200g of 8-hydroxy-2-methylquinoline, 1800mL of dichloromethane and 9.5g of aluminum chloride are put into a 5L reaction bottle, stirred and cooled to 20-30 ℃, 285g of tert-butyl hypochlorite is added, and the mixture is reacted for 10 hours at 32-41 ℃ under the condition of heat preservation.

And cooling the reaction liquid to 20-30 ℃, filtering, dripping 250mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 2200mL of water, stirring for dissolving, slowly adding ammonia water until the pH value is 3.8, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

Refining the crude product with 280mL of absolute ethanol and 30mL of water to obtain 203.0g of the pure product of the chloroquinader, wherein the yield is 70.86 percent, and the HPLC purity is 99.68 percent.

Example 6

Adding 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.2g of ferric chloride into a 500mL reaction bottle, stirring, cooling to 20-30 ℃, adding 28.0g of tert-butyl hypochlorite, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 3.2, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

Refining the crude product with 280mL of absolute ethanol and 30mL of water to obtain 17.4g of the pure product of the chloroquinader, wherein the yield is 60.59 percent, and the HPLC purity is 99.60 percent.

Example 7

20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.1g of boron trifluoride tetrahydrofuran solution are put into a 500mL reaction bottle, stirred and cooled to 20-30 ℃, 28.0g of tert-butyl hypochlorite is added, and the temperature is kept at 32-41 ℃ for reaction for 8 hours.

Cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate, precipitating, filtering, adding 200mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 4.2, precipitating a solid, filtering, leaching, and drying to obtain a crude product.

Refining the crude product with 280mL of absolute ethanol and 30mL of water to obtain 18.0g of the pure product of the chloroquinader, wherein the yield is 62.72 percent, and the HPLC purity is 99.65 percent.

As can be seen from the above examples, the method of the invention adopts Lewis acid as a catalyst and tert-butyl hypochlorite as a chlorinated raw material, thereby greatly improving the yield and purity of the chloroquinalder.

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.