CN113512001A - Preparation method of hydroxychloroquine - Google Patents
Preparation method of hydroxychloroquine Download PDFInfo
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- CN113512001A CN113512001A CN202110888753.0A CN202110888753A CN113512001A CN 113512001 A CN113512001 A CN 113512001A CN 202110888753 A CN202110888753 A CN 202110888753A CN 113512001 A CN113512001 A CN 113512001A
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- Prior art keywords
- hydroxychloroquine
- reaction
- preparation
- dichloroquinoline
- triethanolamine
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960004171 hydroxychloroquine Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 12
- XUVXSSOPXQRCGL-UHFFFAOYSA-N 2-[4-aminopentyl(ethyl)amino]ethanol Chemical compound OCCN(CC)CCCC(C)N XUVXSSOPXQRCGL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 8
- 208000012839 conversion disease Diseases 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 2
- 238000007344 nucleophilic reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- -1 sodium alkoxide Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RSYOSUMAMNFKSM-UHFFFAOYSA-N 2-[(7-chloroquinolin-4-yl)amino]ethanol Chemical compound ClC1=CC=C2C(NCCO)=CC=NC2=C1 RSYOSUMAMNFKSM-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- 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
Abstract
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of hydroxychloroquine. The method has the advantages that the nucleophilic reaction is promoted by adding the organic amine, the reaction time is shortened, the reaction conversion rate is improved, the impurity content is reduced, the product quality is improved, other organic solvents and catalysts are avoided, high-pressure reaction conditions are avoided, the reaction conditions are mild, the post-treatment is simple, the process controllability is strong, and the method is suitable for industrial production. A preparation method of hydroxychloroquine comprises the following steps: hydroxychloroquine is prepared by reacting 4, 7-dichloroquinoline with 2- [ (4-aminopentyl) (ethyl) amino ] ethanol in triethanolamine.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of hydroxychloroquine.
Background
The chemical name of the hydroxychloroquine is 2- [ {4- [ (7-chloro-4-quinolyl) amino ] pentyl } (ethyl) amino ] ethanol, and the chemical structure is shown as the formula (I).
Hydroxychloroquine sulfate was successfully developed by Winthrop company, first introduced into the United states in 1956, and 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.
The synthetic route of the hydroxychloroquine is single, the prior conventional technology adopts the mother nucleus 4, 7-dichloroquinoline and the side chain 2- [ (4-amino amyl) (ethyl) amino ] ethanol for reaction, and the methods reported by domestic and foreign documents optimize the reaction process on the basis.
The patent W02010027150 discloses a preparation method of hydroxychloroquine sulfate, wherein 4, 7-dichloroquinoline and 2- [ (4-aminopentyl) (ethyl) amino ] ethanol are subjected to a pressure reaction under the condition of no solvent, a pressure kettle is used for promoting the condensation reaction under the pressure condition, the industrialization requirement on equipment is high, great potential safety hazard is caused in application, no solvent is used, materials become thick in the reaction process, the reaction conversion rate is influenced, and the aftertreatment is difficult.
Patent CN102050781B discloses a preparation method of hydroxychloroquine sulfate, which comprises the steps of taking ethanol as a solvent, conducting condensation reaction in a mode of heating and gradually raising the temperature to evaporate the solvent, gradually evaporating the solvent for 7-12 hours at 120-125 ℃, and continuously keeping the temperature for reaction for 13-18 hours. The method has long reaction time, uncontrollable solvent evaporating mode and great operation difficulty, and does not solve the problems of low reaction conversion rate and difficult treatment of subsequent material viscosity.
Patent CN104230803B discloses a method for preparing hydroxychloroquine by using sodium alkoxide as a catalyst in an organic solvent, wherein the use of sodium alkoxide can participate in the reaction, bring new impurities into the reaction, and affect the product quality.
Patent CN109456266A reports a method for preparing hydroxychloroquine by using self-made villiaumite as a catalyst, and the method uses a large amount of auxiliary materials and reagents and has large three wastes.
The hydroxychloroquine prepared by the existing technical means has the problems of harsh reaction conditions, low reaction conversion rate, poor product quality, large three wastes, difficulty in viscosity post-treatment and the like. For the above reasons, the present invention needs to find a solvent and a simple and effective catalyst to solve the problems of the prior art.
Disclosure of Invention
The invention aims to provide a preparation method of hydroxychloroquine, which aims to solve the problems in the background technology.
A preparation method of hydroxychloroquine comprises the following steps: reacting 4, 7-dichloroquinoline with 2- [ (4-aminopentyl) (ethyl) amino ] ethanol in triethanolamine to prepare hydroxychloroquine;
preferably, the reaction temperature is 120-140 ℃, and the reaction time is 4-10 h.
Preferably, the molar ratio of the 4, 7-dichloroquinoline to the triethanolamine is 1: 0.5-1.5.
Preferably, the molar ratio of 4, 7-dichloroquinoline to 2- [ (4-aminopentyl) (ethyl) amino ] ethanol is from 1: 1 to 1.5.
Preferably, after the crude hydroxychloroquine is obtained, the crude hydroxychloroquine is recrystallized from a mixed solvent of ethyl acetate and isopropanol.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the preparation method of hydroxychloroquine, provided by the invention, the nucleophilic reaction is promoted by adding organic amine, so that the reaction conversion rate and the reaction rate are improved, the impurity content is reduced, and the product quality is improved;
(2) the preparation method of hydroxychloroquine provided by the invention avoids the use of other organic solvents and catalysts, and reduces three wastes;
(3) the preparation method of hydroxychloroquine provided by the invention has the advantages of mild reaction conditions, high safety, short reaction time, high productivity and suitability for industrialization;
(4) according to the preparation method of hydroxychloroquine, triethanolamine serves as both an acid-binding agent and a solvent, so that the viscosity of a reaction solution is reduced, the reaction conversion rate is improved, the impurity content is reduced, a single impurity of a product is less than or equal to 0.1%, the purity of the product is more than or equal to 99.5%, and the product quality is improved;
(5) according to the preparation method of hydroxychloroquine, provided by the invention, triethanolamine can be used as an acid-binding agent to promote nucleophilic substitution reaction, so that the reaction conversion rate and the reaction rate are improved, and meanwhile, the characteristics of good stability, high boiling point and the like of the triethanolamine can be used as a good solvent in the reaction;
(6) according to the preparation method of hydroxychloroquine, new impurities can be brought in due to the use of triethanolamine, the triethanolamine and the residual ethanolamine and diethanolamine in the triethanolamine can react with 4, 7-dichloroquinoline, but impurities generated by the reaction of the 4, 7-dichloroquinoline and the ethanolamine/diethanolamine are not detected in actual situations.
Drawings
FIG. 1 is an HPLC chromatogram of the compound of formula (I) obtained in example 1;
FIG. 2 is an HPLC chromatogram of the reaction product 2- [ (7-chloro-4-quinolinyl) amino ] ethanol of 4, 7-dichloroquinoline and ethanolamine;
FIG. 3 is an HPLC chromatogram of the reaction product 2- [ (7-chloro-4-quinolinyl) (2-hydroxyethyl) amino ] ethanol of 4, 7-dichloroquinoline and diethanolamine;
FIG. 4 is an HPLC chromatogram of the reaction product 2- [ { [ (7-chloro-4-quinolinyl) oxy ] ethyl } (2-hydroxyethyl) amino ] ethanol of 4, 7-dichloroquinoline and triethanolamine;
FIG. 5 is a 1H-NMR spectrum of the compound of formula (I) obtained in example 1;
FIG. 6 is a 13C-NMR spectrum of the compound of formula (I) obtained in example 1;
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: preparation of hydroxychloroquine
Under the protection of nitrogen, 3kg (15.15mol) of 4, 7-dichloroquinoline, 3.15kg (18.18mol) of 2- [ (4-aminopentyl) (ethyl) amino ] ethanol and 2.03kg (13.64mol) of triethanolamine are added into a 10L reaction kettle, the temperature is slowly raised to 130-140 ℃, and the reaction is carried out for 8 hours under the heat preservation; cooling to 70-80 ℃, adding 7% sodium hydroxide aqueous solution to adjust the Ph of the reaction solution to 12-13, adding ethyl acetate for extraction, washing the organic phase with water, recovering ethyl acetate under reduced pressure, adding 9kg ethyl acetate into the concentrate, heating to 50-70 ℃ for dissolution, cooling to 25-35 ℃, keeping the temperature, stirring for crystallization for 12h, continuously cooling to 5-10 ℃, crystallizing for 6 h, and filtering to obtain a crude product of the compound shown in the formula (I).
Recrystallizing the crude hydroxychloroquine product by using a mixed solution of ethyl acetate and isopropanol, filtering and drying to obtain 4.15kg of a refined compound of the formula (I) with the yield of 83 percent.
Table 1: HPLC detection result of hydroxychloroquine
Through liquid phase analysis, impurities possibly brought by the reaction of the triethanolamine and the 4, 7-dichloroquinoline are not detected in the product.
Example 2: preparation of hydroxychloroquine
Under the protection of nitrogen, 3kg (15.15mol) of 4, 7-dichloroquinoline, 3.15kg (18.18mol) of 2- [ (4-aminopentyl) (ethyl) amino ] ethanol and 2.03kg (13.64mol) of triethanolamine are added into a 10L reaction kettle, the temperature is slowly raised to 120-130 ℃, and the reaction is carried out for 10 hours under the heat preservation; cooling to 70-80 ℃, adding 7% sodium hydroxide aqueous solution to adjust the Ph of the reaction solution to 12-13, adding ethyl acetate for extraction, washing the organic phase with water, recovering ethyl acetate under reduced pressure, adding 9kg ethyl acetate into the concentrate, heating to 50-70 ℃ for dissolution, cooling to 25-35 ℃, keeping the temperature, stirring for crystallization for 12h, continuously cooling to 5-10 ℃, crystallizing for 6 h, and filtering to obtain a crude product of the compound shown in the formula (I).
Recrystallizing the crude hydroxychloroquine product by using a mixed solution of ethyl acetate and isopropanol, filtering and drying to obtain 4.1kg of a refined compound product of the formula (I), wherein the yield is 82%.
Example 3: preparation of hydroxychloroquine
Under the protection of nitrogen, 3kg (15.15mol) of 4, 7-dichloroquinoline, 3.15kg (18.18mol) of 2- [ (4-aminopentyl) (ethyl) amino ] ethanol and 2.03kg (13.64mol) of triethanolamine are added into a 10L reaction kettle, the temperature is slowly raised to 130-140 ℃, and the reaction is carried out for 8 hours under the heat preservation; cooling to 70-80 ℃, adding 7% sodium hydroxide aqueous solution to adjust the Ph of the reaction solution to 12-13, adding ethyl acetate for extraction, washing the organic phase with water, recovering ethyl acetate under reduced pressure, adding 9kg ethyl acetate into the concentrate, heating to 50-70 ℃ for dissolution, cooling to 25-35 ℃, keeping the temperature, stirring for crystallization for 12h, continuously cooling to 5-10 ℃, crystallizing for 6 h, and filtering to obtain a crude product of the compound shown in the formula (I).
Recrystallizing the crude hydroxychloroquine product by using a mixed solution of ethyl acetate and isopropanol, filtering and drying to obtain 4.2kg of a refined compound product of the formula (I), wherein the yield is 84%.
Example 4: preparation of hydroxychloroquine
Under the protection of nitrogen, 3kg (15.15mol) of 4, 7-dichloroquinoline, 3.94kg (22.73mol) of 2- [ (4-aminopentyl) (ethyl) amino ] ethanol and 3.38kg (22.73mol) of triethanolamine are added into a 10L reaction kettle, the temperature is slowly raised to 130-140 ℃, and the reaction is carried out for 8 hours under the heat preservation; cooling to 70-80 ℃, adding 7% sodium hydroxide aqueous solution to adjust the Ph of the reaction solution to 12-13, adding ethyl acetate for extraction, washing the organic phase with water, recovering ethyl acetate under reduced pressure, adding 9kg ethyl acetate into the concentrate, heating to 50-70 ℃ for dissolution, cooling to 25-35 ℃, keeping the temperature, stirring for crystallization for 12h, continuously cooling to 5-10 ℃, crystallizing for 6 h, and filtering to obtain a crude product of the compound shown in the formula (I).
Recrystallizing the crude hydroxychloroquine product by using a mixed solution of ethyl acetate and isopropanol, filtering and drying to obtain 4.15kg of a refined compound of the formula (I) with the yield of 83 percent.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. The preparation method of hydroxychloroquine is characterized by comprising the following steps: hydroxychloroquine is prepared by reacting 4, 7-dichloroquinoline with 2- [ (4-aminopentyl) (ethyl) amino ] ethanol in triethanolamine.
2. A method for preparing hydroxychloroquine according to claim 1, wherein: the reaction temperature is 120-140 ℃, and the reaction time is 4-10 hours.
3. A method for preparing hydroxychloroquine according to claim 1, wherein: the mol ratio of the 4, 7-dichloroquinoline to the triethanolamine is 1: 0.5-1.5.
4. A method for preparing hydroxychloroquine according to claim 1, wherein: the molar ratio of 4, 7-dichloroquinoline to 2- [ (4-aminopentyl) (ethyl) amino ] ethanol is 1: 1-1.5.
5. A method for preparing hydroxychloroquine as claimed in claim 1, comprising the steps of: after the crude product of the hydroxychloroquine is obtained, the crude product of the hydroxychloroquine is recrystallized by a mixed solvent of ethyl acetate and isopropanol.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050781A (en) * | 2010-12-21 | 2011-05-11 | 重庆康乐制药有限公司 | Industrial preparation method of hydroxychloroquine sulfate |
| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| 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 |
| CN108689929A (en) * | 2018-07-05 | 2018-10-23 | 上海中西三维药业有限公司 | A kind of preparation method of hydroxychloroquine and its sulfate |
| CN111606851A (en) * | 2020-05-29 | 2020-09-01 | 珠海润都制药股份有限公司 | Industrial preparation method of hydroxychloroquine sulfate with high purity and high yield |
| CN113185459A (en) * | 2021-04-23 | 2021-07-30 | 江西国药有限责任公司 | Hydroxychloroquine sulfate and preparation method thereof |
-
2021
- 2021-08-04 CN CN202110888753.0A patent/CN113512001A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050781A (en) * | 2010-12-21 | 2011-05-11 | 重庆康乐制药有限公司 | Industrial preparation method of hydroxychloroquine sulfate |
| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| 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 |
| CN108689929A (en) * | 2018-07-05 | 2018-10-23 | 上海中西三维药业有限公司 | A kind of preparation method of hydroxychloroquine and its sulfate |
| CN111606851A (en) * | 2020-05-29 | 2020-09-01 | 珠海润都制药股份有限公司 | Industrial preparation method of hydroxychloroquine sulfate with high purity and high yield |
| CN113185459A (en) * | 2021-04-23 | 2021-07-30 | 江西国药有限责任公司 | Hydroxychloroquine sulfate and preparation method thereof |
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Application publication date: 20211019 |