阅读说明：本技术 一种羟氯喹的制备方法 (Preparation method of hydroxychloroquine ) 是由 宋也 于 2020-06-29 设计创作，主要内容包括：本发明属于医药和化工技术领域,具体涉及羟氯喹的制备方法,该方法系将喹啉中间体7-氯-4-羟基喹啉磺酸酯与羟氯喹侧链在低共熔溶剂中进行缩合反应,即得目的产物；所述喹啉中间体7-氯-4-羟基喹啉磺酸酯的制备方法：(1)以4-氯-2-硝基苯甲酸为原料,经氯化反应,制得酰氯,再与麦氏酸缩合,水解得到4-氯-2-硝基苯乙酮；(2)4-氯-2-硝基苯乙酮通过与N,N-二甲基甲酰胺甲缩醛的缩合反应、硝基还原环化、羟基保护反应,即得喹啉中间体7-氯-4-羟基喹啉磺酸酯。本发明原料易得,反应条件温和,不易发生副反应,避免了高温生产条件,降低了风险,中间体稳定性好,得到的羟氯喹产率高、纯度好,有利于规模化生产。(The invention belongs to the technical field of medicine and chemical industry, and particularly relates to a preparation method of hydroxychloroquine, wherein a quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate and a hydroxychloroquine side chain are subjected to condensation reaction in a eutectic solvent to obtain a target product; the preparation method of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate comprises the following steps: (1) 4-chloro-2-nitrobenzoic acid is taken as a raw material, chlorination reaction is carried out to prepare acyl chloride, and the acyl chloride is condensed with Meldrum's acid and hydrolyzed to obtain 4-chloro-2-nitroacetophenone; (2) the condensation reaction, the nitro reduction cyclization and the hydroxyl protection reaction of the 4-chloro-2-nitroacetophenone and N, N-dimethylformamide methylal are carried out to obtain the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate. The method has the advantages of easily obtained raw materials, mild reaction conditions, difficult side reaction, avoidance of high-temperature production conditions, reduction of risks, good stability of the intermediate, high yield and good purity of the obtained hydroxychloroquine, and contribution to large-scale production.)

1. The preparation method of hydroxychloroquine is characterized in that condensation reaction is carried out on quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate and hydroxychloroquine side chain in eutectic solvent to obtain the target product.

2. The method for producing hydroxychloroquine as claimed in claim 1, wherein: the eutectic solvent is a composition of choline chloride and urea, and the mixing molar ratio of the choline chloride to the urea is 1: 2.

3. The method for producing hydroxychloroquine as claimed in claim 2, wherein: the molar ratio of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate to the hydroxychloroquine side chain is 1: 1-2.

4. The method for producing hydroxychloroquine as claimed in claim 3, wherein: the reaction temperature of the condensation reaction is 20-120 ℃.

5. The method for producing hydroxychloroquine as claimed in claim 4, wherein: the preparation method of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate comprises the following steps:

(1) 4-chloro-2-nitrobenzoic acid is taken as a raw material, chlorination reaction is carried out to prepare acyl chloride, and the acyl chloride is condensed with Meldrum's acid and hydrolyzed to obtain 4-chloro-2-nitroacetophenone;

(2) and (2) carrying out condensation reaction, nitro reduction cyclization and hydroxyl protection reaction on the 4-chloro-2-nitroacetophenone obtained in the step (1) and N, N-dimethylformamide methylal to obtain a quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

6. The method for producing hydroxychloroquine as claimed in claim 5, wherein: in the step (1), the acyl chlorination reagent adopted in the chlorination reaction is thionyl chloride or oxalyl chloride.

7. The method for producing hydroxychloroquine as claimed in claim 6, wherein: in the step (1), the prepared acyl chloride is condensed with Meldrum's acid under the action of triethylamine, and is refluxed in an aqueous solution of acetic acid, and hydrolyzed to obtain the 4-chloro-2-nitroacetophenone.

8. The method for producing hydroxychloroquine as claimed in claim 6, wherein: in the step (2), 4-chloro-2-nitroacetophenone and N, N-dimethylformamide methylal are subjected to condensation reaction in N, N-dimethylformamide at 100 ℃, acetic acid is added, and the mixture is reduced by zinc powder to obtain 7-chloro-4-hydroxyquinoline; the 7-chloro-4-hydroxyquinoline is subjected to condensation reaction with p-toluenesulfonyl chloride under the action of triethylamine to prepare quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

9. The method for producing hydroxychloroquine as claimed in claim 6, wherein: in the step (2), 4-chloro-2-nitroacetophenone and N, N-dimethylformamide methylal are subjected to condensation reaction in N, N-dimethylformamide at 100 ℃, then acetic acid is added, and the mixture is reduced by zinc powder or iron powder to obtain 7-chloro-4-hydroxyquinoline; the 7-chloro-4-hydroxyquinoline is subjected to condensation reaction with trifluoromethyl sulfonyl chloride under the action of triethylamine to prepare quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

Technical Field

The invention belongs to the technical field of medicines and chemical engineering, and particularly relates to a preparation method of hydroxychloroquine.

Background

Hydroxychloroquine is a 4-aminoquinoline derivative, and the sulfate thereof, namely hydroxychloroquine sulfate, is used in clinical application.

Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate) has a chemical name of 2- [ [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino ] -ethanol Sulfate and a CAS number of 747-36-4, and has a chemical structural formula as follows:

hydroxychloroquine sulfate was successfully developed by Winthrop company, and first introduced into the United states in 1956, and then introduced into France, Denmark, Japan, Germany, Finland and other countries and regions. The American FDA approves the hydroxychloroquine sulfate tablet at 29/5 of 1998 to treat lupus erythematosus and rheumatoid arthritis. Compared with other similar medicines, the traditional Chinese medicine composition has advantages in safety, can improve arthritis symptoms of patients, resist oxidation and blood fat, avoid large-scale aggregation of blood platelets, improve the overall sensitivity of insulin on the basis of accelerating the insulin secretion rate of the patients by reducing the blood sugar level of the patients, and has positive effects on treating dermatomyositis, lichen planus, AIDS and the like.

The research in recent years shows that hydroxychloroquine has better inhibiting effect on various malignant tumors, can inhibit the growth of human breast cancer cells MCF-7 and MDA-MB-231 and regulate the protein acetylation process of the tumor cells MCF-7; can also inhibit the activity of chronic lymphocytic leukemia cells, and induce cancer cell apoptosis by activating Caspase-3 (Caspase-3) and regulating the ratio of BCL-2 protein and Bax protein; can also increase the permeability of lysosome and mitochondria, thereby inducing apoptosis. As an autophagy inhibitor, hydroxychloroquine inhibits the growth of tumor cells by inhibiting autophagy of tumor cells, destroying the metabolism of tumor cells.

The recent clinical research results show that hydroxychloroquine sulfate has the activity of inhibiting the new coronavirus in vitro, becomes one of effective medicaments of antiviral medicaments in the treatment of the new coronary pneumonia, can inhibit the new coronavirus from invading human cells, can be used as an immunosuppressant to relieve the immune storm caused by the virus in a patient body, and reduces the harm to the patient.

In the early preparation methods related to the preparation of hydroxychloroquine sulfate, U.S. patent (US2546658) discloses the following reaction sequence:

the process uses phenol as solvent and 2, 4-dichloroquinoline as raw material, and prepares the product by condensation reaction with amino side chain. The reaction time is long (18h), the yield is low (18.6 percent), and phenol has great harm to personnel and environment. And the product has low quality due to more impurities and high content, and cannot ensure clinical application.

As an improvement on the above patent contents, canadian patent (CA2561987) discloses a process for the preparation of hydroxychloroquine sulfate:

prepared by condensation reaction of 2, 4-dichloroquinoline and an amino side chain in isopropanol at 120-130 ℃, and the yield is 80%. In the method, the purification process of the product is very complicated, the post-treatment process is complicated for removing impurities, a large amount of waste water is generated, and finally, the single impurity is controlled below 0.1%. Complicated operation, high cost and long time, and is not beneficial to industrial production.

In patent WO2005062723a2, a method for synthesizing hydroxychloroquine sulfate is disclosed, wherein the reaction process of the method is as follows:

in the method, KI is used as a catalyst, so that the reaction temperature is reduced, but the reaction time is too long (50h), the energy consumption is high, the production cost is increased, the generation of impurities is increased, and the industrial production is not facilitated; in the post-treatment process, the product is firstly made into phosphate, and then the product is dissociated out by the alkalization of ammonium hydroxide, so that the operation is complicated, a large amount of phosphorus-containing wastewater is generated, and the wastewater treatment pressure is increased; particularly, the final product is prepared by column chromatography, has complex operation and high cost, and is not suitable for industrialized mass production.

In patent US5314894, a method for synthesizing hydroxychloroquine sulfate is also disclosed, the reaction process of which is as follows:

in the method, high-boiling point N-ethyldiisopropylamine is used as both a catalyst and a reaction solvent, but the solvent is difficult to recover, solvent residues are easy to influence the purification of the product, the condensation reaction time is long (48 h), and the yield is low (45.9%). The final product is purified by column chromatography, and the method has the disadvantages of complex operation and high cost, and is not suitable for industrial mass production.

In recent years, in domestic patent reports on hydroxychloroquine (CN102050781B, CN103724261B, CN104230803B and CN109456266A), 4, 7-dichloroquinoline is used as a starting material, and is condensed with a hydroxychloroquine side chain under the action of alkali (such as sodium ethoxide, N-diisopropylethylamine and aluminum oxide-loaded villiaumite or quaternary ammonium salt) to obtain the hydroxychloroquine, so that the product purity is effectively improved (over 99.5 percent), impurities are controlled (the single impurity is less than or equal to 0.1 percent), the reaction temperature is still higher (120-130 ℃), the reaction time is longer (12-24 hours), and the production cost is higher.

In addition, in a recently reported patent document (CN107266323A), a method for synthesizing hydroxychloroquine sulfate is disclosed, wherein the reaction process of the method is as follows:

the method comprises the steps of taking 4-amino-7-chloroquinoline as a raw material, obtaining an active intermediate-sulfamide through sulfonation reaction of p-methylbenzenesulfonyl chloride, then carrying out condensation reaction with a chloro side chain under the action of tetrabutylammonium bromide, and then hydrolyzing and acidifying under the action of sulfuric acid to obtain hydroxychloroquine sulfate. The technological process improves the synthetic side chain of the hydroxychloroquine, and enables the final condensation reaction to be carried out at a lower temperature (60-65 ℃), but the 4-amino-7-chloroquinoline raw material is expensive and difficult to source, so that the final preparation cost of the hydroxychloroquine is higher.

The above routes have the disadvantages of long reaction time, high reagent toxicity, complex operation, environmental pollution, high production cost, poor product quality and the like, are difficult to meet the green production requirements of safety and environmental protection, lack of market competitiveness and are not suitable for industrial production. Particularly, with the increase of productivity, the environmental protection cost rises sharply. Therefore, it is very necessary to further improve the production method of hydroxychloroquinoline in order to obtain a simple, highly selective, highly pure, and low-cost preparation method.

On the other hand, 4, 7-dichloroquinoline is obtained by a three-step reaction of 4-hydroxy-7-chloro-quinoline-3-carboxylic acid ethyl ester as a raw material in patent document (CN103626699A) through hydrolysis, decarboxylation and chlorination as a quinoline intermediate 4, 7-dichloroquinoline in the hydroxychloroquine synthesis process. The process involves the use of phosphorus oxychloride with high temperature (230-250 ℃) and high toxicity, so that the production cost is high and the safety risk is high.

As an improvement of the above-mentioned method for producing 4, 7-dichloroquinoline, a method for producing 4, 7-dichloroquinoline using 4-hydroxy-7-chloroquinoline as a raw material and triphosgene as a chlorinating reagent is disclosed in a recently reported patent document (CN 110627716A). However, the reaction process inevitably results in the release of hydrogen chloride and phosgene, so that the risk of corrosion of equipment and environmental pollution is still high.

It is noted that the existing methods for preparing 4, 7-dichloroquinoline involve 4-hydroxy-7-chloroquinoline and use it as the initial starting material. Patent document CN1847226A discloses a method for synthesizing the raw materials, which is completed by condensation and cyclization using diethyl ethoxymethylene malonate and m-chloroaniline as starting materials, as follows:

in the preparation process, the cyclization stage inevitably generates the following position isomers (Zhongguo, Li Chengzhou, Xuangui, Tianrui, Zhongnan pharmacy, 2006, 4(1), 28-29) due to the difference of reaction selectivity, and the reaction process is as follows:

in the above reaction principles, it can be seen that: the 4, 7-dichloroquinolino synthesis process required for the preparation of hydroxychloroquine chloride inevitably contains a production pathway for the isomer 4, 5-dichloroquinoline. The presence of this impurity, which undoubtedly puts a great strain on the production process of hydroxychloroquine, will also affect the final quality of the product. Although further purification of this product is possible by some purification means (CN109928925A, CN103626699A), it is also difficult to ensure high quality of 4, 7-dichloroquinoline, the intermediate required for the preparation of hydroxychloroquine chloride.

The organic solvent used in large amount in the chemical production process not only causes environmental pollution, but also has high cost and difficult recovery, and is not beneficial to industrial application, so the development of nontoxic and cheap green solvent is a very important subject for the chemical industry.

The Deep Eutectic Solvent (DES) is a novel Solvent developed in recent years, and compared with the traditional organic Solvent, the DES has the advantages of difficult volatilization, nonflammability, easy storage, no toxicity, good chemical stability, designability, recycling, simple synthesis process and environmental protection. Thus, eutectic solvents are considered as "Green solvents" instead of organic solvents (Green chem.,2012,14: 285-289; chem. Soc. Rev.,2012,41: 7108-7946; chemical evolution, 2014,26: 784-795; organic chemistry, 2016,36: 480-489; modern chemical engineering, 2018,39: 53-57).

At present, eutectic solvents attract high attention of researchers in various countries in the world, and show good application prospects in the fields of separation processes, chemical reactions, functional materials, electrochemistry and the like.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides the preparation method of the high-purity hydroxychloroquine, which has the advantages of simple and convenient operation process, easily obtained raw materials, low cost and contribution to large-scale production.

In order to solve the technical problem, the invention is realized as follows:

a preparation method of hydroxychloroquine comprises the step of carrying out condensation reaction on a quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate and a hydroxychloroquine side chain in a eutectic solvent to obtain a target product.

As a preferable scheme, the eutectic solvent is a composition of choline chloride and urea, and the mixing molar ratio of the choline chloride to the urea is 1: 2.

Furthermore, the molar ratio of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate to the hydroxychloroquine side chain is 1: 1-2.

Further, the reaction temperature of the condensation reaction is 20-120 ℃.

The preparation method of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate comprises the following steps:

(1) 4-chloro-2-nitrobenzoic acid is taken as a raw material, chlorination reaction is carried out to prepare acyl chloride, and the acyl chloride is condensed with Meldrum's acid and hydrolyzed to obtain 4-chloro-2-nitroacetophenone;

(2) and (2) carrying out condensation reaction, nitro reduction cyclization and hydroxyl protection reaction on the 4-chloro-2-nitroacetophenone obtained in the step (1) and N, N-dimethylformamide methylal to obtain a quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

Further, in step (1) of the present invention, the acid chloride reagent used in the chlorination reaction is thionyl chloride or oxalyl chloride.

Further, in the step (1), the prepared acyl chloride is condensed with the Meldrum's acid under the action of triethylamine, and is refluxed in an aqueous solution of acetic acid, and hydrolyzed to obtain the 4-chloro-2-nitroacetophenone.

Further, in the step (2), 4-chloro-2-nitroacetophenone and N, N-dimethylformamide methylal are subjected to condensation reaction in N, N-dimethylformamide at 100 ℃, acetic acid is added, and reduction is carried out with zinc powder to obtain 7-chloro-4-hydroxyquinoline; the 7-chloro-4-hydroxyquinoline is subjected to condensation reaction with p-toluenesulfonyl chloride under the action of triethylamine to prepare quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

Further, in the step (2), 4-chloro-2-nitroacetophenone and N, N-dimethylformamide methylal are subjected to condensation reaction in N, N-dimethylformamide at 100 ℃, acetic acid is added, and the mixture is reduced by zinc powder or iron powder to obtain 7-chloro-4-hydroxyquinoline; the 7-chloro-4-hydroxyquinoline is subjected to condensation reaction with trifluoromethyl sulfonyl chloride under the action of triethylamine to prepare quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate.

The invention relates to a preparation method of hydroxychloroquine, in particular to a method for preparing hydroxychloroquine by condensing quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate and a hydroxychloroquine side chain in a eutectic solvent.

Wherein the eutectic solvent involved in the condensation reaction is a composition of choline chloride and urea, and the mixing molar ratio of the choline chloride to the urea is 1: 2.

The molar ratio of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate to the hydroxychloroquine side chain is 1: 1-2, preferably 1.05-1.5; the reaction temperature is 20-120 ℃, preferably 60-100 ℃.

The preparation of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate is realized according to the following process: firstly, 4-chloro-2-nitrobenzoic acid is taken as a raw material, and is subjected to chlorination, condensation with Meldrum's acid and hydrolysis to obtain 4-chloro-2-nitroacetophenone; then the intermediate is obtained through condensation reaction with N, N-dimethylformamide methylal, reduction cyclization of nitro and hydroxyl protection reaction.

Wherein, in the chlorination reaction step of the 4-chloro-2-nitrobenzoic acid, the acyl chlorination reagent is one of thionyl chloride and oxalyl chloride.

The acyl chloride is condensed with Meldrum's acid under the action of triethylamine, and then reflows in an aqueous solution of acetic acid, and is hydrolyzed to obtain 4-chloro-2-nitroacetophenone.

Then 4-chloro-2-nitroacetophenone reacts with N, N-dimethylformamide methylal in N, N-dimethylformamide at the temperature of 100 ℃, acetic acid is added, and the mixture is reduced by zinc powder or iron powder to obtain 7-chloro-4-hydroxyquinoline.

And finally, under the action of triethylamine, preparing quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate through condensation reaction of 7-chloro-4-hydroxyquinoline and p-toluenesulfonyl chloride.

Compared with other methods, the preparation method provided by the invention has the advantages that the raw materials are cheap and easy to obtain, the reaction conditions are mild, side reactions are not easy to occur, high-temperature production conditions are avoided, the risk is reduced, the stability of the intermediate is good, the yield of the prepared hydroxychloroquine is high, the purity is good, and the large-scale production is facilitated.

Compared with the prior art, the invention has the following advantages:

1) the preparation method of hydroxychloroquine provided by the invention can meet the high-purity quality requirement in the field of medicine production.

2) The hydroxychloroquine intermediate 7-chloro-4-hydroxyquinoline sulfonate and the preparation method thereof provided by the invention can effectively prevent the generation of isomers, thereby meeting the production requirement of high-purity hydroxychloroquine.

Detailed Description

The present invention will be illustrated by the following specific examples, but is not limited thereto.