CN111635358B - Preparation method of hydroxychloroquine - Google Patents
Preparation method of hydroxychloroquine Download PDFInfo
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- CN111635358B CN111635358B CN202010602555.9A CN202010602555A CN111635358B CN 111635358 B CN111635358 B CN 111635358B CN 202010602555 A CN202010602555 A CN 202010602555A CN 111635358 B CN111635358 B CN 111635358B
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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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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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
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
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.
Description
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, can resist oxidation and blood fat, avoids large-amount aggregation of blood platelets, improves 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 wastewater is generated, and finally, the single impurity is controlled to be below 0.1 percent. 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 an initial raw 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 three-step reactions of hydrolysis, decarboxylation, and chlorination using 4-hydroxy-7-chloro-quinoline-3-carboxylic acid ethyl ester as a raw material in patent document (CN103626699A) 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 is subjected to condensation reaction with N, N-dimethylformamide methylal in N, N-dimethylformamide at 100 ℃, then acetic acid is added, and reduction is carried out by using 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 a 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.
Example 1
7-chloro-4-hydroxyquinoline p-methylbenzenesulfonate (333.0g, 1.0mol) and hydroxychloroquine side chain (182.7g, 1.05mol) were added to a eutectic solvent (200g) composed of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 80 ℃ for 9 hours with TLC detection.
The temperature is reduced to 25 ℃, ethyl acetate (300mL) is added, cold water (500mL) is added under full stirring, the mixture is kept stand for 2 hours, and ethyl acetate solution is separated, washed by water and concentrated to obtain a crude product. Recrystallization from isopropanol gave off-white crystals (289g) in 86% yield. The melting point is: 91-92 ℃.
The content of hydroxychloroquine by liquid chromatography analysis is 99.54%.
Preparation of hydroxychloroquine sulfate
Under the cooling of ice water, concentrated sulfuric acid (20g) is slowly added into an isopropanol (80g) solution, a hydroxychloroquinoline (70g,0.2mol) and isopropanol (100g) solution is slowly dripped into the concentrated sulfuric acid solution, the addition speed of sulfuric acid is controlled to control the temperature to be 0-10 ℃, the dripping is finished, the stirring is carried out for 2 hours, a precipitated solid is filtered, and the drying is carried out to obtain 83.3g of hydroxychloroquinoline sulfate (the yield is 96 percent), and the melting point is 239-241 ℃.
HPLC purity 99.73%, maximum individual impurity 0.08%.
Example 2
7-chloro-4-hydroxyquinoline p-methylbenzenesulfonate (33.3g, 0.1mol) and hydroxychloroquine side chain (17.4g, 0.1mol) were added to a eutectic solvent (50g) composed of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 85 ℃ for 8 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give the crude product. Recrystallization from isopropanol gave off-white crystals (30g) in 91% yield, melting point: 91-92 ℃.
The content of hydroxychloroquine analyzed by liquid chromatography was 99.62%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.79%, maximum single impurity 0.06%.
Example 3
7-chloro-4-hydroxychloroquine trifluoromethanesulfonate (32.7g, 0.1mol) and a hydroxychloroquine side chain (20.9g, 0.12mol) were added to a eutectic solvent (50g) consisting of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 70 ℃ for 5 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give the crude product. Recrystallization from isopropanol gave off-white crystals (32.3g) in 96% yield, melting point: 91-92 ℃.
The content of hydroxychloroquine by liquid chromatography analysis is 99.69%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.87%, maximum single impurity 0.04%.
Example 4
7-chloro-4-hydroxyquinoline p-methylbenzenesulfonate (33.3g, 0.1mol) and a hydroxychloroquine side chain (20.9g, 0.12mol) were added to a eutectic solvent (50g) composed of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 75 ℃ for 8 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give the crude product. Recrystallization from isopropanol gave off-white crystals (31g) in 93% yield, melting point: 91-92 ℃.
The content of hydroxychloroquine by liquid chromatography analysis is 99.65%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.81%, maximum single impurity 0.05%.
Example 5
7-chloro-4-hydroxyquinoline p-methylbenzenesulfonate (33.3g, 0.1mol) and hydroxychloroquine side chain (17.4g, 0.11 mol) were added to a eutectic solvent (50g) composed of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 90 ℃ for 8 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give the crude product. Recrystallization from isopropanol gave off-white crystals (30g) in 90% yield. The melting point is: 91-92 ℃.
The content of hydroxychloroquine analyzed by liquid chromatography was 99.62%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.78%, maximum single impurity 0.07%.
Example 6
7-chloro-4-hydroxychloroquine trifluoromethanesulfonate (32.7g, 0.1mol) and hydroxychloroquine side chain (17.4g, 0.1mol) were added to a eutectic solvent (50g) consisting of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 60 ℃ for 10 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give the crude product. Recrystallization from isopropanol gave off-white crystals (32.5g) in 97% yield, melting point: 91-92 ℃.
The content of hydroxychloroquine by liquid chromatography analysis is 99.73%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.89%, maximum single impurity 0.04%.
Example 7
7-chloro-4-hydroxyquinoline p-methylbenzenesulfonate (33.3g, 0.1mol) and hydroxychloroquine side chain (17.4g, 0.1mol) were added to a eutectic solvent (50g) composed of choline chloride and urea (molar ratio 1:2), and the mixture was reacted at 95 ℃ for 10 hours with TLC detection.
The temperature was reduced to 25 ℃, ethyl acetate (50mL) was added, cold water (100mL) was added with sufficient stirring, and after standing for 2 hours, the ethyl acetate solution was separated, washed with water, and concentrated to give a crude product. Recrystallization from isopropanol gave off-white crystals (32g) in 95% yield. The melting point is: 91-92 ℃.
The content of hydroxychloroquine by liquid chromatography analysis is 99.71%.
Preparation of hydroxychloroquine sulfate
Hydroxychloroquinoline sulfate is obtained according to the preparation procedure described in example 1, having a melting point of 239 ℃ to 241 ℃.
HPLC purity 99.82%, maximum single impurity 0.06%.
Example 8
The preparation of intermediate 7-chloro-4-hydroxyquinoline p-toluenesulfonate can be carried out as follows.
Firstly, preparing 4-chloro-2-nitroacetophenone by the following reaction principle:
1) dripping thionyl chloride (17.8g, 0.15mol)) into toluene (100mL) with 20.0g (0.1mol) of 4-chloro-2-nitrobenzoic acid at room temperature, heating to 60 ℃ for reaction for 6h after dripping, cooling to room temperature, and distilling the toluene under reduced pressure to obtain light yellow oily substance which is directly used for the next reaction;
2) at room temperature, dropwise adding triethylamine (20mL) into the product obtained in the previous step and an ethyl acetate (100mL) solution of mugwort acid (14.4g, 0.1mol), heating to 80 ℃, reacting for about 2 hours, detecting by TLC to finish the reaction, cooling, adjusting the pH value to 5-6 by hydrochloric acid, separating an organic phase, washing twice by saturated sodium bicarbonate and saturated salt water in sequence, drying by anhydrous sodium sulfate, concentrating to obtain a yellow oily substance, and directly using the yellow oily substance in the next reaction;
3) the product obtained in the step (2) was added to a solution of sulfuric acid (2mL) in acetic acid (40mL) and water (100mL), refluxed for about 3 hours, TLC detected that the reaction was complete, cooled to room temperature, adjusted to neutral with sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 17.1g of a yellow oily liquid with a yield of 86%.
Through structural analysis, the product is 4-chloro-2-nitroacetophenone:
1H NMR(CDCl3,500MHz):δ8.05(d,J＝2.0Hz,1H),7.69(dd,J 1＝8.0 Hz,J 2＝2.0Hz,1H),7.42(d,J＝8.0Hz,1H),2.55(s,3H)；
MS(EI):m/z＝199[M]+.
secondly, preparing quinoline 7-chloro-4-hydroxyquinoline p-methylbenzenesulfonic acid sulfonate according to the following reaction principle:
4) 4-chloro-2-nitroacetophenone (20.0g, 0.1mol) obtained in the above step and N, N-dimethylformamide formal (36g, 0.3mol) were dissolved in N, N-dimethylformamide (50 mL). The reaction was heated to 80 ℃ for 6 hours and the reaction was complete by TLC. After cooling to room temperature, pouring the reaction liquid into stirred ice water (200g), filtering, washing and drying the precipitated solid after 1 hour to obtain a condensation product (23g), and directly using the condensation product in the next reaction;
5) iron powder (11.2g, 0.2mol) was added in portions to the condensate (23g, 0.09mol) obtained in the above step (4) in acetic acid (60mL), and the mixture was heated to 90 ℃ with stirring for 4 hours of reaction, and the reaction was terminated by TLC. After cooling to room temperature, pouring the reaction solution into ice water (200g), filtering, washing and drying the precipitated solid after 1 hour to obtain a cyclized product (14g), and directly using the cyclized product in the next reaction;
the product is 7-chloro-4-hydroxyquinoline by structural analysis:
1H NMR(CDCl3,400MHz):δ6.65(d,J＝7.8Hz,1H),7.61(d,J＝8.0Hz, 1H),8.05(d,J＝8.0Hz,1H),8.12(s,1H),8.69(s,d,J＝7.8Hz,1H, 1H),11.24(s,1H).
MS(EI):m/z＝180[M+H]+.
6) to a solution of 7-chloro-4-hydroxyquinoline (17.9g, 0.1mol) and triethylamine (50g) in dichloromethane (120mL) at 0-10 deg.C was added dropwise a solution of p-toluenesulfonyl chloride (22.8g, 0.12mol) and dichloromethane (100 mL). After the addition was complete, the mixture was heated to 50 ℃ for 4 hours and the reaction was complete by TLC. The temperature is reduced to room temperature, the reaction solution is transferred into ice water (100g), stirred for 1 hour, separated, a dichloromethane layer is washed by sodium bicarbonate solution, concentrated, crystallized, filtered and dried to obtain 31g of an intermediate, and the yield is 94%.
The product is 7-chloro-4-hydroxyquinoline p-toluenesulfonate by structural analysis:
1H NMR(CDCl3,400MHz):δ2.37(s,3H),6.65(d,J＝7.8Hz,1H),6.96 (d,J＝8.0Hz,2H),7.61(d,J＝8.2Hz,1H),8.05(d,J＝8.2Hz,1H), 8.06(d,J＝8.0Hz,2H),8.12(s,1H),8.69(s,d,J＝7.8Hz,1H). MS(EI):m/z＝334[M+H]+.
example 9
The preparation of intermediate 7-chloro-4-hydroxyquinoline trifluoromethanesulfonate can be carried out according to the following procedure.
To a solution of 7-chloro-4-hydroxyquinoline (17.9g, 0.1mol) and triethylamine (50g) in dichloromethane (120mL) was added dropwise a solution of trifluoromethanesulfonyl chloride (16.8g, 0.1mol) and N, N-dimethylformamide (25mL) at 0-5 ℃. After the addition, the reaction was carried out at room temperature for 10 hours, and the reaction was terminated by TLC. The reaction solution was transferred to ice water (200g), stirred for 1 hour, separated, and the dichloromethane layer was washed with a sodium bicarbonate solution and concentrated to obtain 30g of an intermediate with a yield of 92%.
The product is 7-chloro-4-hydroxyquinoline trifluoromethanesulfonate by structural analysis:
1H NMR(CDCl3,400MHz):δ6.83(d,J＝7.8Hz,1H),7.64(d,J＝8.2 Hz,1H),8.07(d,J＝8.2Hz,1H),8.16(s,1H),8.89(s,d,J＝7.8Hz, 1H).
MS(EI):m/z＝328[M+H]+。
it should be understood that the detailed description of the present invention is only for illustrating the present invention and is not limited by the technical solutions described in the embodiments of the present invention, and those skilled in the art should understand that the present invention can be modified or substituted equally to achieve the same technical effects; as long as the use requirements are met, the method is within the protection scope of the invention.
Claims (5)
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 a target product; 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; the molar ratio of the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate to the hydroxychloroquine side chain is 1: 1-2; 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) taking 4-chloro-2-nitrobenzoic acid as a raw material, preparing acyl chloride through chlorination reaction, condensing with Meldrum's acid, and hydrolyzing 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.
2. The method for producing hydroxychloroquine as claimed in claim 1, wherein: in the step (1), the acyl chlorination reagent adopted in the chlorination reaction is thionyl chloride or oxalyl chloride.
3. The method for producing hydroxychloroquine as claimed in claim 2, 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.
4. The method for producing hydroxychloroquine as claimed in claim 2, 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.
5. The method for producing hydroxychloroquine as claimed in claim 2, wherein: in the step (2), 4-chloro-2-nitroacetophenone is subjected to condensation reaction with N, N-dimethylformamide methylal 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.
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