CN113185459A - Hydroxychloroquine sulfate and preparation method thereof - Google Patents
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Abstract
The invention discloses hydroxychloroquine sulfate and a preparation method thereof, which relate to the technical field of pharmaceutical chemistry and comprise the following steps: mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain, heating and condensing under the action of an organic base catalyst, adding water for separating liquid, and cooling and crystallizing to obtain hydroxychloroquine; dissolving hydroxychloroquine in ethyl acetate and ethanol water solution, heating to dissolve and clarify, dripping concentrated sulfuric acid, cooling to crystallize, filtering, and drying to obtain hydroxychloroquine sulfate. The invention has the advantages that the solvent-free reaction is used, the catalyst is added, the high pollution is avoided, the reaction process is accelerated, and the operation is simple; meanwhile, the HPLC purity of the obtained refined hydroxychloroquine product is not less than 96.50%, the maximum single impurity content is less than 0.10%, the yield can reach 85%, the HPLC purity of hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity content is less than 0.10%, and the yield can reach 90%.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to hydroxychloroquine sulfate and an industrial preparation method thereof.
Background
Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate) has the chemical name of 2- [ [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino ] -ethanol Sulfate. The product is successfully developed by Winthrop company, is firstly marketed in the United states in 1956, and is marketed in 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.
U.S. Pat. No. 4, 2546658A discloses a method for synthesizing hydroxychloroquine sulfate, which is reported in 1951, by reacting 4, 7-dichloroquinoline with 5- (N-ethyl-N-2-hydroxyethanediylamino) -2-pentanamine (hereinafter referred to as hydroxychloroquine side chain compound) using phenol as a solvent, and the reaction process is as follows:
phenol, however, is toxic and corrosive to the skin and is converted to sodium phenolate after post-treatment. Sodium phenolate-containing wastewater is one of the most harmful and difficult to treat in industrial wastewater, has great environmental pollution and causes pressure on three-waste treatment; the melting point of the phenol is 42 ℃, the phenol can be fed only after being melted into liquid, the operation is complex, the industrial production is difficult, and the reaction yield is less than 20 percent.
CN103724261B also discloses a method for preparing hydroxychloroquine sulfate, which comprises the step of gradually raising the temperature to 120-130 ℃ under the protection of inert gas by adopting a solvent-free reaction, and reacting for 13-24 hours to prepare a crude hydroxychloroquinoline. The crude hydroxychloroquinoline directly salifies with dilute sulphuric acid alcohol solution to prepare hydroxychloroquinoline sulfate, and the reaction process is as follows:
but the reaction does not use a catalyst, so that the reaction rate is slower; in the single-phase reaction, 4, 7-dichloroquinoline is seriously sublimated, the utilization rate is low, and the reaction is not facilitated. And water and concentrated sulfuric acid are added at a higher temperature, so that the method has high danger and is not beneficial to industrial production.
CN109280029A also discloses a method for preparing hydroxychloroquine sulfate, in the patent, 4, 7-dichloroquinoline and a hydroxychloroquine side chain are mixed, heated and condensed under the conditions of no solvent and no catalyst to obtain hydrochloride, sodium alkoxide/potassium is used for neutralization, the hydroxychloroquine is obtained after filtration, concentration, pulping and crystallization, and the hydroxychloroquine is salified by sulfuric acid, wherein the reaction process is as follows:
the hydroxychloroquine sulfate is obtained by the method through three steps of reaction, the reaction time is long compared with two steps, and the production cost is increased. The potassium/sodium alkoxide used is toxic, its vapor, mist, dust are irritating and corrosive, and it is not easy to store and deliquesce and burn.
In the preparation methods of hydroxychloroquine sulfate disclosed above, certain disadvantages exist, or the preparation methods are not environment-friendly, or the preparation methods are complicated in process and long in production time, and are not beneficial to industrial production. Therefore, it is necessary to solve the above problems and further improve the synthetic process of hydroxychloroquine sulfate in order to obtain a more effective, simpler and more environmentally friendly industrial preparation method of high-purity hydroxychloroquine sulfate.
Disclosure of Invention
The invention aims to at least solve one of the technical problems in the prior art and provides hydroxychloroquine sulfate and an industrial preparation method thereof.
The technical solution of the invention is as follows:
a preparation method of hydroxychloroquine sulfate comprises the following steps:
(1) mixing 4, 7-dichloroquinoline and a hydroxychloroquine side chain, heating for dissolving, heating and condensing under the action of an organic base catalyst, adding water for separating liquid, cooling for crystallization, filtering, and drying in vacuum to obtain hydroxychloroquine;
(2) dissolving hydroxychloroquine in ethyl acetate and ethanol, heating to dissolve and clarify, dripping concentrated sulfuric acid, cooling to crystallize, filtering, and vacuum drying to obtain hydroxychloroquine sulfate.
In a specific embodiment of the invention, in the step (1), the organic base catalyst is selected from one or more of triethylamine, ethanolamine and pyridine;
in a specific embodiment of the invention, in the step (1), the molar ratio of the 4, 7-dichloroquinoline to the hydroxychloroquine side chain to the base catalyst is 1:0.8-1.3: 0.8-1.3;
in a specific embodiment of the invention, in the step (1), the mass ratio of the 4, 7-dichloroquinoline to the water is 1: 1-6;
in a specific embodiment of the invention, in the step (1), the reaction temperature is 80-130 ℃, and the reaction time is 13-40 h;
in a specific embodiment of the invention, in the step (1), when water is added and separated, the temperature is kept to be not lower than 85 ℃, a lower organic layer is discarded, a water layer is cooled to room temperature, heat is preserved for crystallization for 1 hour, the temperature is reduced to 0-10 ℃, and heat is preserved for crystallization for 1 hour;
in a specific embodiment of the invention, in the step (1), the HPLC purity of hydroxychloroquine is not less than 96.50%, the maximum single impurity content is less than 0.10%, and the yield is more than 85%.
In a specific embodiment of the present invention, in the step (2), the molar ratio of hydroxychloroquine to sulfuric acid is 1:0.8 to 1.3;
in a specific embodiment of the invention, in the step (2), the mass ratio of hydroxychloroquine to ethyl acetate to ethanol is 1:1-3: 4-8;
in a specific embodiment of the invention, in the step (2), the reaction temperature is 60-70 ℃, and the reaction time is 2-4 h;
in a specific embodiment of the invention, in the step (2), during cooling crystallization, the reaction solution is cooled to 20-30 ℃ firstly, kept at the temperature for crystallization for 1h, and then cooled to 0-10 ℃ and kept at the temperature for crystallization for 1 h;
in a specific embodiment of the invention, in the step (2), the HPLC purity of hydroxychloroquine sulfate is greater than or equal to 98.00%, the maximum single impurity content is less than 0.10%, and the yield is greater than 90%.
Hydroxychloroquine sulfate is prepared by the preparation method of the hydroxychloroquine sulfate.
The invention has at least one of the following beneficial effects:
compared with the prior art, the invention has the advantages that:
1. the invention uses the solvent-free reaction, avoids using toxic solvents such as phenol and the like, simultaneously uses the organic base as the catalyst, avoids high pollution, accelerates the reaction process, carries out the reaction under normal pressure, and has simple operation.
2. When the method is used for crystallization, separation and purification, water is added for liquid separation, and the temperature is reduced for crystallization to obtain the hydroxychloroquine, so that an organic solvent is avoided, pollution and consumption are reduced, the operation is simple and rapid, the HPLC purity of the obtained hydrochloroquine is not less than 96.50%, the maximum single impurity content is less than 0.10%, and the yield can reach 85%.
3. The hydroxychloroquine salt is dissolved and clarified in ethyl acetate and ethanol at a high temperature, and then sulfuric acid is dropwise added, so that impurities can be effectively removed, the purity is improved, the crystal form, the granularity and the properties are good, the HPLC purity of the hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity is less than 0.10%, and the yield can reach 90%.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but the present invention is not limited to the following examples.
The preparation method of hydroxychloroquine sulfate is characterized by comprising the following steps:
(1) and (3) synthesis of hydroxychloroquine: mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain (namely 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine), heating and condensing under the action of an organic base catalyst, adding water for separating liquid, cooling and crystallizing to obtain the hydroxychloroquine, wherein the HPLC purity of the hydroxychloroquine is more than or equal to 96.50%, and the maximum single impurity content is less than 0.10%. Wherein the mol ratio of the 4, 7-dichloroquinoline to the hydroxychloroquine side chain to the alkali catalyst is 1:0.8-1.3: 0.8-1.3; the mass ratio of the 4, 7-dichloroquinoline to the water is 1: 1-6; the reaction temperature is 80-130 ℃, and the reaction time is 13-40 h; the organic base catalyst is selected from one or more of triethylamine, ethanolamine and pyridine; adding water, separating, keeping the temperature not lower than 85 deg.C, removing lower organic layer, keeping water layer, cooling water layer to room temperature, keeping temperature, crystallizing for 1 hr, cooling to 0-10 deg.C, and keeping temperature, and crystallizing for 1 hr.
(2) And (3) synthesizing hydroxychloroquine sulfate: and (2) dissolving the hydroxychloroquine synthesized in the step (1) in ethyl acetate and ethanol water solution, heating to dissolve and clarify, dropwise adding concentrated sulfuric acid, cooling to crystallize, filtering and drying to obtain hydroxychloroquine sulfate, wherein the HPLC purity of the hydroxychloroquine sulfate is more than or equal to 98.00%, and the maximum single impurity content is less than 0.10%. Wherein, the molar ratio of the hydroxychloroquine to the sulfuric acid is 1: 0.8-1.3; the mass ratio of the hydroxychloroquine to the ethyl acetate to the ethanol is 1:1-3: 4-8; the reaction temperature is 60-70 ℃, and the reaction time is 2-4 h; when the temperature is reduced for crystallization, the reaction liquid is firstly reduced to 20-30 ℃, the temperature is kept for crystallization for 1h, then the temperature is reduced to 0-10 ℃, and the temperature is kept for crystallization for 1 h.
Example 1
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 70.0g, adding 0.8eq (0.51mol) of triethylamine (29.8g), heating to 80 ℃, reacting for 40h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 100g of water, separating phases, keeping a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 0 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain about 144.5g of hydroxychloroquine, wherein the yield is 85.20%, the HPLC purity is 96.59%, and the maximum single impurity content is 0.08%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of hydroxychloroquine into a 1000mL four-neck flask, adding 50mL of ethyl acetate and 250mL of ethanol, heating, stirring and dissolving, dropwise adding 11.7g of concentrated sulfuric acid when the mixture is completely dissolved, stirring for 2 hours after the addition, cooling, crystallizing, carrying out suction filtration, leaching a filter cake twice by using 50mL of ethyl acetate, and carrying out vacuum drying to obtain 58.6g of hydroxychloroquine sulfate, wherein the yield is 90.71%, the HPLC purity is 98.25%, and the maximum single impurity content is 0.07%.
Example 2
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 79.0g, adding 0.9eq ethanolamine (28.3g), heating to 90 ℃, reacting for 30h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 200g of water, carrying out phase separation, retaining a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 2 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain about 146.4g of hydroxychloride, wherein the yield is 86.32%, the HPLC purity is 97.24%, and the maximum single impurity content is 0.07%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of refined hydroxychloroquine into a 1000mL four-neck flask, adding 100mL of ethyl acetate and 300mL of ethanol, heating, stirring and dissolving, dropwise adding 13.2g of concentrated sulfuric acid when the solution is completely dissolved, stirring for 2 hours after the addition is finished, cooling, crystallizing, carrying out suction filtration, leaching a filter cake twice by using 50mL of ethyl acetate, and carrying out vacuum drying to obtain 58.3g of hydroxychloroquine sulfate, wherein the yield is 90.25%, the HPLC purity is 98.79%, and the maximum single impurity content is 0.06%.
Example 3
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 88.0g (0.57mol), adding 1.0eq pyridine (39.2g), heating to 100 ℃, reacting for 20h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 300g water, separating phases, keeping a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 4 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and drying a filter cake in vacuum to obtain about 149.3g of hydroxychloroquine, wherein the yield is 88.03%, the HPLC purity is 96.83%, and the maximum single impurity content is 0.09%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of refined hydroxychloroquine into a 1000mL four-neck flask, adding 150mL of ethyl acetate and 350mL of ethanol, heating, stirring and dissolving, dropwise adding 14.7g of concentrated sulfuric acid when the solution is completely dissolved, stirring for 2 hours after the addition is finished, cooling, crystallizing, carrying out suction filtration, leaching a filter cake twice by using 50mL of ethyl acetate, and carrying out vacuum drying to obtain 60.0g of hydroxychloroquine sulfate, wherein the yield is 92.88%, the HPLC purity is 98.44%, and the maximum single impurity content is 0.07%.
Example 4
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 97.0g (0.60mol), adding 1.1eq triethylamine (40.9g), heating to 110 ℃, reacting for 30h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 400g of water, separating phases, keeping a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 6 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and drying a filter cake in vacuum to obtain about 146.4g of hydroxychloroquine, wherein the yield is 86.32%, the HPLC purity is 97.73%, and the maximum single impurity content is 0.05%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of refined hydroxychloroquine into a 1000mL four-neck flask, adding 50mL of ethyl acetate and 400mL of ethanol, heating, stirring and dissolving, dropwise adding 16.2g of concentrated sulfuric acid when the solution is completely dissolved, stirring for 2 hours after the addition is finished, cooling, crystallizing, carrying out suction filtration, leaching a filter cake twice by using 50mL of ethyl acetate, and carrying out vacuum drying to obtain 59.4g of hydroxychloroquine sulfate, wherein the yield is 91.95%, the HPLC purity is 98.96%, and the maximum single impurity content is 0.04%.
Example 5
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 106.0g, adding 1.2eq ethanolamine (37.8g), heating to 120 ℃, reacting for 36h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 500g of water, carrying out phase separation, retaining a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 8 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain 145.0g of hydroxychloroquine, wherein the yield is 85.50%, the HPLC purity is 96.55%, and the maximum single impurity content is 0.09%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of refined hydroxychloroquine into a 1000mL four-neck flask, adding 100mL of ethyl acetate and 450mL of ethanol, heating, stirring and dissolving, dropwise adding 17.7g of concentrated sulfuric acid when the solution is completely dissolved, stirring for 2 hours after the addition is finished, cooling, crystallizing, carrying out suction filtration, leaching a filter cake twice by using 50mL of ethyl acetate, and carrying out vacuum drying to obtain 58.2g of hydroxychloroquine sulfate, wherein the yield is 90.09%, the HPLC purity is 98.16%, and the maximum single impurity content is 0.07%.
Example 6
(1) And (3) synthesis of hydroxychloroquine:
in a 500mL three-necked flask, 4, 7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 115.0g, adding 1.3eq of pyridine (51.0g), heating to 130 ℃, reacting for 16h, monitoring by HPLC until the content of 4, 7-dichloroquinoline is less than 2.5%, adding 600g of water, separating phases, retaining a water phase, cooling to room temperature, carrying out heat preservation and crystallization, cooling to 10 ℃, carrying out heat preservation and crystallization, carrying out suction filtration, and drying a filter cake in vacuum to obtain 148.4g of hydroxychloroquine, wherein the yield is 87.50%, the HPLC purity is 96.60%, and the maximum single impurity content is 0.09%.
(2) And (3) synthesizing hydroxychloroquine sulfate:
adding 50.0g of refined hydroxychloroquine into a 1000mL four-neck flask, adding 150mL of ethyl acetate and 500mL of ethanol, heating, stirring and dissolving, dropwise adding 18.2g of concentrated sulfuric acid when the solution is completely dissolved, stirring for 2 hours after the addition is finished, cooling, crystallizing, filtering, leaching a filter cake twice by using 50mL of ethyl acetate, and drying in vacuum to obtain 58.5g of hydroxychloroquine sulfate, wherein the yield is 90.56%, the HPLC purity is 98.02%, and the maximum single impurity content is 0.09%.
Comparative example 1
In the synthetic process of the hydroxychloroquine in the step (1), organic alkali is not added as a catalyst; the rest is the same as example 1.
About 63.5g of hydroxychloroquine is obtained, the yield is 37.44%, the HPLC purity is 90.3%, and the maximum single impurity content is 0.13%;
the hydroxychloroquine sulfate obtained was about 55.8g, yield 86.38%, HPLC purity 96.8%, maximum single impurity content 0.10%.
Comparative example 2
Step (1) same as example 1;
in the step (2), during the synthesis of hydroxychloroquine sulfate, ethanol is not added, and the ethanol is replaced by equal amount of ethyl acetate; the rest is the same as example 1.
About 40.6g of hydroxychloroquine sulfate was obtained in 55.88% yield, 97.24% HPLC purity, and 0.07% maximum single impurity content.
Comparative example 3
Step (1) same as example 1;
in the step (2), during the synthesis of hydroxychloroquine sulfate, ethyl acetate is not added, and the ethyl acetate is replaced by equal amount of ethanol; the rest is the same as example 1.
About 56.7g of hydroxychloroquine sulfate was obtained in 87.78% yield, 96.2% HPLC purity, maximum single impurity content of 0.18%.
Comparing the results of examples 1-6 with the results of comparative example 1, it can be seen that the hydroxychloroquine prepared in examples 1-6 has significantly higher yield and purity than comparative example 1 (step 1 without catalyst), the maximum single impurity content is significantly lower than that of comparative example 1 (step 1 without catalyst), the purity of the hydroxychloroquine sulfate prepared is also greater than that of comparative example 1 (step 1 without catalyst), and the maximum single impurity content is also significantly lower than that of comparative example 1 (step 1 without catalyst).
Comparing the results of examples 1-6 with the results of comparative example 2, it can be seen that the hydroxychloroquine sulfate prepared in examples 1-6 has a yield and purity significantly higher than that of comparative example 2 (no ethanol is added in step 2), and the maximum content of single impurities is also significantly lower than that of comparative example 2 (no ethanol is added in step 2).
Comparing the results of examples 1-6 with the results of comparative example 3, it can be seen that the hydroxychloroquine sulfate prepared in examples 1-6 has a purity significantly higher than that of comparative example 3 (no ethyl acetate is added in step 2) and a maximum single impurity content significantly lower than that of comparative example 2 (no ethyl acetate is added in step 2).
Therefore, whether the catalyst is added in the step (1) or not can obviously influence the reaction progress, and whether the ethanol and the ethyl acetate are added in the step (2) or not can obviously influence the purity of the hydroxychloroquine and the hydroxychloroquine sulfate.
It should be noted that the above embodiments are only intended to illustrate the technical solution of the present invention and not to limit, and the present invention has been described by referring to the preferred embodiments of the present invention, but changes in form or detail can be made without departing from the crystal form and scope of the present invention.
Claims (10)
1. The preparation method of hydroxychloroquine sulfate is characterized by comprising the following steps:
(1) mixing 4, 7-dichloroquinoline and a hydroxychloroquine side chain, heating for dissolving, heating and condensing under the action of an organic base catalyst, adding water for separating liquid, cooling for crystallization, filtering, and drying in vacuum to obtain hydroxychloroquine;
(2) dissolving hydroxychloroquine in ethyl acetate and ethanol, heating to dissolve and clarify, dripping concentrated sulfuric acid, cooling to crystallize, filtering, and drying to obtain hydroxychloroquine sulfate.
2. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (1), the molar ratio of 4, 7-dichloroquinoline to hydroxychloroquine side chain to organic base catalyst is 1:0.8-1.3: 0.8-1.3; the organic base catalyst is selected from one or more of triethylamine, ethanolamine and pyridine.
3. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (1), the mass ratio of 4, 7-dichloroquinoline to water is 1: 1-6.
4. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (1), said reaction temperature is 80-130 ℃ and reaction time is 13-40 h; adding water, keeping the temperature not lower than 85 deg.C, removing the organic layer, cooling the water layer to room temperature, maintaining the temperature for crystallization for 1 hr, cooling to 0-10 deg.C, and maintaining the temperature for crystallization for 1 hr.
5. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (1), said hydroxychloroquine has an HPLC purity of not less than 96.50%, a maximum single impurity content of less than 0.10%, and a yield of more than 85%.
6. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (2), the molar ratio of hydroxychloroquine to concentrated sulfuric acid is 1: 0.8-1.3.
7. The preparation method of hydroxychloroquine sulfate according to claim 1, wherein in step (2), the mass ratio of hydroxychloroquine to ethyl acetate to ethanol is 1:1-3: 4-8.
8. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (2), said reaction temperature is 60-70 ℃, and the reaction time is 2-4 h; and during cooling crystallization, the reaction liquid is cooled to 20-30 ℃, kept for crystallization for 1h, then cooled to 0-10 ℃, and kept for crystallization for 1 h.
9. The method for preparing hydroxychloroquine sulfate according to claim 1, wherein in step (2), the HPLC purity of hydroxychloroquine sulfate is greater than or equal to 98.00%, the maximum single impurity content is less than 0.10%, and the yield is greater than 90%.
10. Hydroxychloroquine sulfate, characterized in that it is prepared by the method of any one of claims 1 to 9.
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