CN112920114A - Synthetic method of hydroxychloroquine sulfate - Google Patents
Synthetic method of hydroxychloroquine sulfate Download PDFInfo
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- 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
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Abstract
The invention provides a preparation method of hydroxychloroquine sulfate 2- ((4- ((7-chloro-4-quinolyl) amino) pentyl) ethylamino) -ethanol sulfate. The method has the advantages of cheap and easily obtained raw materials, short reaction steps, high yield, simple overall process, strong operability, environmental friendliness and the like, reduces the cost, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to preparation of hydroxychloroquine sulfate for treating malaria, rheumatoid arthritis and systemic lupus erythematosus.
Background
Hydroxychloroquine is a 4-aminoquinone compound with the chemical name of 2- ((4- ((7-chloro-4-quinolyl) amino) amyl) ethylamino) -ethanol, and the chemical structure is as follows:
hydroxychloroquine was successfully developed by Winthrop in 1951 for malaria treatment and systemic lupus erythematosus in 1955. In 1998, the FDA in the united states approved hydroxychloroquine for the treatment of rheumatoid arthritis, lupus erythematosus. 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 by reducing the blood sugar level of the patients, and has positive effects in treating dermatomyositis, lichen planus, AIDS and the like.
The preparation method of the disclosed hydroxychloroquine has a plurality of patent reports, mainly comprising the following routes:
1) patent US2546658 discloses a method for synthesizing hydroxychloroquine:
the method adopts phenol as a solvent, mixes the compounds shown in the formula I and the formula II, adds potassium iodide, stirs for 18 hours at the temperature of 125-.
This method has three distinct disadvantages: the method uses a large amount of phenol as a reaction solvent, and the phenol has toxicity and corrosivity and is harmful to human bodies, and the waste liquid containing the phenol increases the difficulty in treating three wastes and is not environment-friendly; secondly, the phenol is solid at normal temperature (melting point 42 ℃), and the operation is complicated during the enlarged production because the phenol needs to be heated and dissolved for feeding when in use; and thirdly, a hydroxychloroquine side chain (formula II) is adopted as a raw material, and the existing preparation route of the side chain has complicated steps and high cost, and is not beneficial to controlling the product cost.
2) Patent CA2561987a1 discloses a method for synthesizing hydroxychloroquine:
the method comprises the steps of mixing compounds shown in the formula I and compounds shown in the formula II by using isopropanol as a solvent, stirring for 20-24h at the temperature of 120-130 ℃, adding water and methyl isobutyl ketone, regulating the pH value to be 10-11, then separating liquid, sequentially treating an obtained organic layer with acetic anhydride and lithium hydroxide monohydrate, salifying and purifying with sulfuric acid and methanol, and dissociating sodium hydroxide to obtain a crude hydroxychloroquine product.
This method has two significant disadvantages: firstly, a hydroxychloroquine side chain (formula II) is adopted as a raw material, and the existing preparation route of the side chain has complicated steps and high cost, and is not beneficial to controlling the product cost; secondly, the reaction time is as long as 20-24h, so that the production cost is increased, and the impurity content is easily increased.
3) Patent WO2010027150 discloses a method for synthesizing hydroxychloroquine:
the method mixes the compounds of formula I and formula II, pressurizes to 5-20bar under the protection of inert gas, and reacts at 100-120 ℃. Extracting the obtained reaction liquid with dilute hydrochloric acid and chloroform, alkalizing the obtained water phase with sodium hydroxide, extracting with chloroform, and recrystallizing with dichloromethane to obtain the crude product of hydroxychloroquine.
This method has three significant drawbacks: firstly, a hydroxychloroquine side chain (formula II) is adopted as a raw material, and the existing preparation route of the side chain has complicated steps and high cost, and is not beneficial to controlling the product cost; secondly, the reaction is carried out under a pressurization condition, so that the requirement on equipment is high, and certain danger exists in the amplification production; and thirdly, a II-type solvent with high toxicity is adopted as an extraction solvent, so that the harm to people and the environment is great.
In addition, the hydroxychloroquine side chain (formula II) is adopted in the method for synthesizing hydroxychloroquine, and the existing published preparation route is complicated and expensive. For example, patent WO2019165337a1 discloses a process for the preparation of compounds of formula II:
the intermediate of the method has no ultraviolet absorption, is mostly liquid, is difficult to detect and purify, and simultaneously adopts a pressurizing condition to carry out reaction, has higher requirement on equipment, has certain danger in amplification production, and has high cost of finished products.
Patent WO2005062723a2 discloses another process for the preparation of compounds of formula II:
the method is the same as the method disclosed in the patent WO2019165337A1, and has the defects that the intermediate has no ultraviolet absorption, is mostly liquid, is difficult to detect and purify, adopts a pressurized condition to carry out reaction, has higher requirements on equipment, has certain danger in amplification production, is expensive in finished product cost and the like.
In conclusion, the existing technology for preparing hydroxychloroquine sulfate has the problems of high raw material cost, long reaction time, high energy consumption, high environmental pollution and the like, so that a new process which is environment-friendly, controllable in cost and high in industrial value is urgently needed to be found.
Disclosure of Invention
The invention provides a synthetic route of hydroxychloroquine sulfate, wherein the route comprises the following steps:
step (1), mixing 4, 7-dichloroquinoline (formula I) and 5-methyl-2-pyrrolidone (formula II) in a solvent, adding alkali and a catalyst, and reacting at 50-200 ℃ until the raw materials are completely consumed. And extracting, concentrating and refining the obtained reaction liquid to obtain the compound shown in the formula III.
In some embodiments, the solvent of step (1) is selected from one or more of water, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide.
In some embodiments, the catalyst of step (1) is selected from any one of palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium, 1 '-bisdiphenylphosphinoferrocene palladium dichloride and dichloromethane complexes thereof, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, or a combination thereof.
In some embodiments, the base in step (1) is selected from any one of triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, potassium carbonate, sodium carbonate and cesium carbonate.
In some embodiments, during step (1), the compound of formula I and the compound of formula II are at a temperature of 80-150 ℃ to produce the compound of formula III.
And (2) reacting the compound shown in the formula III with N-ethyl-2-hydroxyethylamine at the temperature of 0-150 ℃ to prepare the compound shown in the formula IV under the condition of solvent or no solvent.
In some embodiments, the compound of formula III is reacted with N-ethyl-2-hydroxyethylamine under the action of aluminum trichloride to produce the compound of formula IV.
In some embodiments, the solvent in step (2) is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, or tetrahydrofuran.
In further embodiments, compounds of formula IV are prepared by reacting a compound of formula III with N-ethyl-2-hydroxyethylamine in the presence of aluminum trichloride in the presence or absence of a solvent at a temperature of 0-150 ℃, wherein the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, toluene, or tetrahydrofuran.
And (3) in the presence of a solvent, reacting the compound shown in the formula IV with a reducing agent at the temperature of-20-120 ℃, and salifying the obtained product with sulfuric acid to obtain the compound shown in the formula V.
In some embodiments, the solvent of step (3) is selected from one or more of dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, or ethylene glycol dimethyl ether.
In some embodiments, the reducing agent described in step (3) is selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, lithium aluminum hydride, sodium borohydride/I2Sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride, sodium borohydride/trifluoroacetic acid or sodium borohydride/sulfuric acid; preferably, the reducing agent is selected from sodium borohydride/boron trifluoride etherate, borane-tetrahydrofuran complex or sodium borohydride/sulfuric acid.
In some embodiments, during step (3), the compound of formula IV is reacted with a reducing agent at a temperature of 0-80 ℃.
By means of the scheme, compared with the prior art, the invention has the following advantages: the invention provides a preparation method of hydroxychloroquine sulfate, which has the advantages of cheap and easily obtained raw materials, short reaction steps, high yield, simple overall process, strong operability, environmental friendliness and the like, reduces the cost, and is suitable for large-scale industrial production.
Detailed Description
The preparation process described in the present invention is further illustrated by the following examples, which include, but are not limited to.
The following examples are intended only to illustrate specific embodiments of the present invention, so as to enable those skilled in the art to more fully understand the present invention, but not to limit the present invention in any way. In the embodiments of the present invention, technical means or methods which are not specifically described are conventional in the art.
The chemicals used in the following examples are all commercially available chemicals.
EXAMPLE 1 preparation of the Compound of formula III
Formula 4, 7-dichloroquinoline (19.8g,100.0mmol), 5-methyl-2-pyrrolidone (14.9g, 150.0mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (578mg,1.0mmol), palladium acetate (224 mg,1.0mmol) and cesium carbonate (48.8g,150.0mmol) were mixed in 1, 4-dioxane (150ml) at room temperature, replaced with nitrogen three times, and warmed to reflux under nitrogen. And stopping the reaction after TLC detection of the completion of the consumption of the raw materials, and cooling to room temperature. Ethyl acetate (300ml) and water (300ml) were added to the system, stirred for a while, separated, and the aqueous phase was extracted once more with ethyl acetate (150ml), and the organic phases were combined. The organic phase was washed once with water (200ml) and saturated sodium chloride (200ml) in this order, and concentrated to dryness under reduced pressure to give a yellow viscous liquid. The resulting viscous liquid was recrystallized from dichloromethane (20ml) and n-hexane (40ml) to give 16.2g of a yellow solid, yield 62%, i.e. the compound of formula III.
EXAMPLE 2 preparation of the Compound of formula III
Formula 4, 7-dichloroquinoline (3.9g,20.0mmol), 5-methyl-2-pyrrolidone (3.0g,30.0mmol), 1' -bisdiphenylphosphinoferrocene palladium dichloride dichloromethane complex (163mg,0.2mmol) and cesium carbonate (9.8g,30.0mmol) were mixed in 1, 4-dioxane (30ml) at room temperature, replaced with nitrogen three times, and warmed to reflux under nitrogen protection. And stopping the reaction after TLC detection of the completion of the consumption of the raw materials, and cooling to room temperature. Ethyl acetate (40ml) and water (40ml) were added to the system, stirred for a while, separated, and the aqueous phase was extracted once more with ethyl acetate (40ml), and the organic phases were combined. The organic phase was washed once with water (40ml) and saturated sodium chloride (40ml) in that order, and concentrated to dryness under reduced pressure to give a yellow viscous liquid. The resulting viscous liquid was recrystallized from dichloromethane (5ml) and n-hexane (10ml) to give 2.7g of a yellow solid in 53% yield, i.e. the compound of formula III.
EXAMPLE 3 preparation of the Compound of formula III
Formula 4, 7-dichloroquinoline (3.9g,20.0mmol), 5-methyl-2-pyrrolidone (3.0g,30.0mmol), bis (triphenylphosphine) palladium dichloride (140mg,0.2mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (96mg,0.2mmol) and triethylamine (3.0g,30.0mmol) were mixed in toluene (30ml) at room temperature, replaced with nitrogen three times, and heated to 100 ± 5 ℃ under nitrogen protection and stirred. And stopping the reaction after TLC detection of the completion of the consumption of the raw materials, and cooling to room temperature. Water (30ml) was added to the system, stirred for a while, separated, the aqueous phase was extracted once more with toluene (30ml), and the organic phases were combined. The organic phase was washed once with water (30ml) and saturated sodium chloride (30ml) successively and concentrated to dryness under reduced pressure to give a yellow viscous liquid. The resulting viscous liquid was recrystallized from dichloromethane (5ml) and n-hexane (10ml) to give 2.6g of a yellow solid in 51% yield, i.e. the compound of formula III.
EXAMPLE 4 preparation of the Compound of formula IV
The compound of formula III (2.6g,10.0mmol) and N-ethylethanolamine (4.5g,50.0mmol) were mixed at room temperature, warmed to 80 ℃ and stirred. And stopping the reaction after TLC detection of the consumption of the raw materials is finished, and cooling to room temperature to obtain orange mucus. Recrystallization from isopropanol (4ml) and n-hexane (10ml) gave 2.2g of a yellow solid in 63% yield, a compound of formula IV.
EXAMPLE 5 preparation of the Compound of formula IV
Mixing aluminum trichloride (1.7g,13.0mmol) and dichloromethane (20ml) at room temperature, cooling to 0 ℃ under the protection of nitrogen, and stirring; the compound of formula III (2.6g,10.0mmol) and N-ethylethanolamine (2.7g,25.0 mmol) were added to the system and stirred with an internal temperature of 0-5 ℃. After TLC detection, the reaction was quenched with water (30ml), the pH of the system was adjusted to 7-8 with aqueous sodium hydroxide (1N), stirred for a while, the aqueous layer was discarded after liquid separation, and the organic layer was concentrated to dryness under reduced pressure to give an orange viscous liquid. Recrystallization from isopropanol (4ml) and n-hexane (10ml) gave 2.6g of a yellow solid in 74% yield, a compound of formula IV.
EXAMPLE 6 preparation of the Compound of formula V
The compound of formula IV (1.0g,3.0mmol) was dissolved in dichloromethane (5ml) at room temperature, cooled to 0 ℃ and protected with nitrogen. To the above system was added dropwise borane-tetrahydrofuran complex (1N in THF,4.5ml,4.5mmol), the internal temperature was maintained at 0-5 ℃ during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 0-5 ℃. TLC detection of complete consumption of starting material and quenching of the reaction with methanol (5 ml). The reaction mixture was concentrated to dryness under reduced pressure, ethyl acetate (10ml) and water (10ml) were then added thereto, followed by stirring for a while, liquid separation, discarding of the aqueous layer, washing of the organic layer once with a saturated aqueous sodium chloride solution (10ml), and concentration to dryness under reduced pressure. Methanol (10ml) was added to the system, and a methanol solution of sulfuric acid (0.2ml of H) was added dropwise thereto with stirring2SO4in 2ml of MeOH), a white solid separated out after a while, stirred at room temperature for 2h, filtered, the filter cake washed with methanol (5ml), dried to give 1.0g of a white solid, yield 77%, i.e. the compound of formula V.
EXAMPLE 7 preparation of the Compound of formula V
The compound of formula IV (1.0g,3.0mmol) was dissolved in tetrahydrofuran (10ml) at room temperature, cooled to 0 ℃ and protected with nitrogen. Lithium aluminum hydride (1N in THF,4.5ml,4.5mmol) was added dropwise to the above system, the internal temperature was maintained at 0-5 ℃ during the addition, and after the addition, the temperature was raised to about 20 ℃ and stirred. TLC detection of complete consumption of starting material quenched the reaction with water (5ml) to give a viscous reaction solution. Anhydrous magnesium sulfate (2.0g) was added to the reaction solution, and the mixture was stirred until more white solid precipitated from the reaction solution, followed by filtration, and the filter cake was washed once with tetrahydrofuran (10ml), and the filter cake was discarded. The filtrate was concentrated to dryness under reduced pressure, ethyl acetate (15ml) and water (15ml) were added thereto, stirred for a while, separated, the aqueous layer was discarded, the organic layer was washed once with a saturated aqueous sodium chloride solution (10ml), and concentrated to dryness under reduced pressure. Methanol (10ml) was added to the system, and a methanol solution of sulfuric acid (0.2ml of H) was added dropwise thereto with stirring2SO4in 2ml of MeOH), a white solid separated out after a while, stirred at room temperature for 2h, filtered, the filter cake washed with methanol (5ml) and dried to obtain 805mg of a white solid, the yield of which is 62%, i.e. the compound of formula V.
EXAMPLE 8 preparation of the Compound of formula V
The compound of formula IV (1.0g,3.0mmol) was dissolved in tetrahydrofuran (5ml) at room temperature and cooled to 0 ℃. Adding boron trifluoride diethyl etherate (634mg,4.5mmol) into the system, stirring for a moment, adding sodium borohydride (568mg,15.0mmol) in batches, keeping the internal temperature at 0-5 ℃ in the process, and heating to about 20 ℃ after the addition is finished, and stirring. TLC detection raw material consumption, using water (5ml) quenching reaction, decompression concentration to dry, adding ethyl acetate (10ml) and water (10ml), stirring for a moment, separating, discarding the water layer, organic layer with saturated sodium chloride aqueous solution (10ml) washing once, decompression concentration to dry. Methanol (10ml) was added to the system, and a methanol solution of sulfuric acid (0.2ml of H) was added dropwise thereto with stirring2SO4in 2ml of MeOH), precipitating a white solid after a while, stirring at room temperature for 2h, carrying out suction filtration, washing the filter cake with methanol (5ml), and drying to obtain 1.1g of a white solid with a yield of 85%, namely the compound of the formula V.
The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matters disclosed in the specification including the abstract and all methods and steps disclosed herein may be combined in any combination, except combinations where the features and/or steps are mutually exclusive. Each feature disclosed in this specification, including the abstract, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.
Claims (10)
1. A process for the preparation of hydroxychloroquine sulfate, characterized in that: the method comprises the following steps:
wherein, in the process of the step (1), the compound of the formula III is prepared from the compound of the formula I and the compound of the formula II in the presence of a solvent and a catalyst and a base at the temperature of 50-200 ℃;
wherein, in the process of the step (2), the compound of the formula III and N-ethyl-2-hydroxyethylamine react at the temperature of 0-150 ℃ to prepare the compound of the formula IV under the condition of solvent or no solvent;
wherein, in the process of the step (3), the compound shown in the formula IV reacts with a reducing agent at the temperature of minus 20-120 ℃ in the presence of a solvent, and the obtained product forms a salt with sulfuric acid to obtain the compound shown in the formula V.
2. The process of claim 1, wherein the solvent in step (1) is selected from one or more of water, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide.
3. The process of claim 1 wherein the catalyst is selected from any one or combination of palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium, 1 '-bisdiphenylphosphinoferrocene palladium dichloride and its dichloromethane complex, 2-dicyclohexylphosphine-2', 4',6' -triisopropylbiphenyl or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene.
4. The method of claim 1, wherein the base in step (1) is selected from any one of triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, potassium carbonate, sodium carbonate, cesium fluoride or potassium phosphate.
5. The process of claim 1, wherein during step (1), the compound of formula I and the compound of formula II are at a temperature of 80-150 ℃ to produce the compound of formula III.
6. The process of claim 1, wherein in step (2), the compound of formula III is reacted with N-ethyl-2-hydroxyethylamine under the action of aluminum trichloride to produce the compound of formula IV.
7. The process of claim 1 or 6, wherein the solvent in step (2) is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, toluene or tetrahydrofuran.
8. The process of claim 1, wherein the solvent in step (3) is selected from one or more of dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, or ethylene glycol dimethyl ether.
9. The method of claim 1, wherein said step (3) is performed byThe reducing agent is selected from borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, lithium aluminum hydride, sodium borohydride/I2Sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride, sodium borohydride/trifluoroacetic acid or sodium borohydride/sulfuric acid; preferably, the reducing agent is selected from sodium borohydride/boron trifluoride etherate, borane-tetrahydrofuran complex or sodium borohydride/sulfuric acid.
10. The process of claim 1, wherein during step (3), the compound of formula IV is reacted with a reducing agent at a temperature of 0-80 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017033128A1 (en) * | 2015-08-25 | 2017-03-02 | Novartis Ag | Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors |
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
| CN109280029A (en) * | 2018-12-11 | 2019-01-29 | 上海应用技术大学 | A kind of preparation method of hydroxychloroquine sulfate |
| CN109456266A (en) * | 2018-11-12 | 2019-03-12 | 南京天际联盟医药科技有限公司 | The novel preparation method of hydroxychloroquine sulfate |
| CN111635358A (en) * | 2020-06-29 | 2020-09-08 | 北京成宇化工有限公司 | Preparation method of hydroxychloroquine |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017033128A1 (en) * | 2015-08-25 | 2017-03-02 | Novartis Ag | Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors |
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
| CN109456266A (en) * | 2018-11-12 | 2019-03-12 | 南京天际联盟医药科技有限公司 | The novel preparation method of hydroxychloroquine sulfate |
| CN109280029A (en) * | 2018-12-11 | 2019-01-29 | 上海应用技术大学 | A kind of preparation method of hydroxychloroquine sulfate |
| CN111635358A (en) * | 2020-06-29 | 2020-09-08 | 北京成宇化工有限公司 | Preparation method of hydroxychloroquine |
Non-Patent Citations (1)
| Title |
|---|
| SARA SZYMKUC等: "Computer-assisted planning of hydroxychloroquine’s syntheses commencing from inexpensive substrates and bypassing patented routes.", 《CHEMRXIV》 * |
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