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-甲基喹啉和二氯海因的物料I,反应I,得到所述氯喹那多。本发明用二氯海因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: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol. The invention uses dichlorohydantoin 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 yield, has the purity of more than 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: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol.

2. The method according to claim 1, wherein the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1:0.48 to 1.0.

3. The method according to claim 1, wherein the molar ratio of 8-hydroxy-2-methylquinoline to Lewis acid is 1: 0.02-0.08.

4. 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, p-toluenesulfonic acid and titanium tetrachloride.

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 process according to claim 1, wherein the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin further comprises a solvent I; the solvent I is at least one selected from dichloromethane and chloroform.

7. The preparation method according to claim 6, wherein the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the solvent I is 1g (3-20) mL.

8. 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) and separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing the chloroquinate.

9. The method according to claim 8, wherein the acid is hydrochloric acid with a mass fraction of 25 to 38%.

10. The method according to claim 8, wherein the mass-to-volume ratio of the 8-hydroxy-2-methylquinoline to the acid is 1g: (1-1.5) 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 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, 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 method has the disadvantages 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.

The synthesis process of substituting chlorine with sodium hypochlorite as chloro material has the following reaction equation:

the process avoids the pollution of chlorine, but still uses hydrochloric acid with higher 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 problem, the invention provides a preparation method of chloroquinate, which takes 8-hydroxy-2-methylquinoline as a raw material to perform one-step chlorination reaction with dichlorohydantoin under the catalysis of Lewis acid to obtain the chloroquinate. 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: reacting the material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin in the presence of a catalyst Lewis acid to obtain the chloroquinadol.

The reaction equation for the above reaction is as follows:

optionally, the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1: 0.48-1.0.

Alternatively, the upper limit of the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is selected from 1: 0.49, 1: 0.50, 1: 0.51, 1: 0.52, 1: 0.53, 1: 0.54, 1:0.55, 1: 0.56, 1: 0.57, 1: 0.58, 1: 0.59, 1: 0.60, 1: 0.70, 1: 0.80, 1: 0.90 or 1: 1.00; the lower limit is selected from 1:0.48, 1: 0.49, 1: 0.50, 1: 0.51, 1: 0.52, 1: 0.53, 1: 0.54, 1:0.55, 1: 0.56, 1: 0.57, 1: 0.58, 1: 0.59, 1: 0.60, 1: 0.70, 1: 0.80 or 1: 0.90.

preferably, the molar ratio of the 8-hydroxy-2-methylquinoline to the dichlorohydantoin is 1: 0.55-0.75.

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: 0.04-0.06.

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 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 material I containing 8-hydroxy-2-methylquinoline and dichlorohydantoin 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 preparation method comprises:

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

B) adding dichlorohydantoin into the intermediate product A, heating to the reaction temperature, and carrying out chlorination reaction to prepare 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 concentrated hydrochloric acid, and reacting II to obtain an intermediate product I; (2) and separating out a material II containing the intermediate product I and inorganic base to obtain a material III containing 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, 1g: 1.26: 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, 1g: 1.56: 1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.24mL, 1g:1.35mL, 1g:1.35mL, 1g:1.44mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1.44mL, 1g:1.44mL, 1.35mL, 1g:1.35mL, 1.44mL, 1.35mL, 1g:1.44mL, 1.35mL, 1g:1.35mL, 1.44mL, 1g:1.35mL, 1.44mL, 1g:1.44mL, 1.35mL, 1.44mL, 1g:1.44mL, 1g:1.44mL, 1.35mL, 1.44mL, 1g:1.44mL, 1., 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:1.17mL1g: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:1.27mL1g:1.28mL, 1g:1.29mL, 1g:1.30mL, 1g:1.31mL, 1g:1.32mL, 1g:1.33mL, 1g:1.34mL, 1g:1.35mL, 1g:1.36mL, 1g:1.37mL1g:1.38mL, 1g:1.39mL, 1g:1.40mL, 1g:1.41mL, 1g:1.42mL, 1g:1.43mL, 1g:1.44mL, 1g:1.45mL, 1g:1.46mL, 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.

Optionally, the upper pH limit of the feed II containing the intermediate product I and an inorganic base is selected from 3.0, 3.5, 4.0, 4.5 or 5.0; the lower limit is selected from 2.5, 3.0, 3.5, 4.0 or 4.5.

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

Optionally, the post-processing step further comprises: and mixing the material III containing the chloroquinate with the solution II, and refining to obtain the chloroquinate.

Optionally, the solvent II comprises an organic solvent and water; the organic solvent is at least one selected from methanol, ethanol and acetonitrile.

Preferably, the organic solvent is selected from 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-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 dichlorohydantoin to replace chlorine as the raw material of the chlorination reaction, has good selectivity, reduces side reaction, improves the quality yield, ensures the quality of the chloroquinate, and reduces the pollution to the environment, and the purity is over 99.00 percent.

(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 following examples are given to describe in detail the process for preparing chloroquinate provided by the present invention.

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: moles of product chloroquinadol/moles 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 ℃, 7.8g of dichlorohydantoin is added, and the temperature is kept at 32-41 ℃ for reaction for 7 hours.

And 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 2.8, precipitating 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 8.7g of the pure product of the chloroquinader, the yield is 60.32 percent, and the HPLC purity is 99.23 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 15.3g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.

And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, 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 ethanol and 30mL of water to obtain 19.0g of the pure product of the chloroquinader, wherein the yield is 65.85% and the HPLC purity is 99.43%.

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 ℃, 7.7g of dichlorohydantoin is added, and the temperature is kept at 32-41 ℃ for reaction for 9 hours.

And 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 99.71 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 ℃, 37.3g of dichlorohydantoin is added, and the mixture is reacted for 9 hours at the temperature of 32-41 ℃.

And cooling the reaction liquid to 20-30 ℃, filtering, dripping 55mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 600mL of water, stirring to dissolve, slowly adding ammonia water until the pH value is 5.0, 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 43.5g of the pure product of the chloroquinader, the yield is 60.34 percent, and the HPLC purity is 99.45 percent.

Example 5

Putting 200g of 8-hydroxy-2-methylquinoline, 1800mL of dichloromethane and 9.5g of aluminum chloride into a 5L reaction bottle, stirring, cooling to 20-30 ℃, adding 156g of dichlorohydantoin, and carrying out heat preservation reaction for 10h at 32-41 ℃.

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 to dissolve, slowly adding ammonia water until the pH value is 4.5, 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 198.7g of the pure product of the chloroquinader, wherein the yield is 68.98% and the HPLC purity is 99.57%.

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 15.2g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.

And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, 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 15.4g of the pure product of the chloroquinader, wherein the yield is 53.30 percent, and the HPLC purity is 99.27 percent.

Example 7

Putting 20g of 8-hydroxy-2-methylquinoline, 200mL of chloroform and 1.1g of boron trifluoride tetrahydrofuran solution into a 500mL reaction flask, stirring, cooling to 20-30 ℃, adding 15.5g of dichlorohydantoin, and carrying out heat preservation reaction at 32-41 ℃ for 8 hours.

And cooling the reaction liquid to 20-30 ℃, filtering, dripping 20mL of concentrated hydrochloric acid into the filtrate to precipitate, filtering, adding 200mL of water, stirring to dissolve, 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 ethyl alcohol and 30mL of water to obtain 17.5g of a pure product of the chloroquinader, wherein the yield is 60.84 percent, and the HPLC purity is 99.70 percent.

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