CN111732539A - Chloroquine phosphate enantiomer crystal form and preparation method thereof - Google Patents
Chloroquine phosphate enantiomer crystal form and preparation method thereof Download PDFInfo
- Publication number
- CN111732539A CN111732539A CN202010714336.XA CN202010714336A CN111732539A CN 111732539 A CN111732539 A CN 111732539A CN 202010714336 A CN202010714336 A CN 202010714336A CN 111732539 A CN111732539 A CN 111732539A
- Authority
- CN
- China
- Prior art keywords
- chloroquine
- organic solvent
- side chain
- cooling
- phosphate
- Prior art date
- 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.)
- Pending
Links
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
A chloroquine phosphate enantiomer crystal form and a preparation method thereof. The invention provides (R)/(S) -chloroquine phosphate and a preparation method thereof, wherein the X-ray powder diffraction pattern of the provided (S) -chloroquine phosphate expressed by the angle of 2 theta is 10.4o、10.7o、15.6o、15.8o、17.8o、18.9o、21.3oAnd 23.9o±0.2oHas a characteristic peak; the provided (R) -chloroquine phosphate has an X-ray powder diffraction pattern expressed by a 2 theta angle of 10.3o、15.5o、15.7o、17.8oAnd 18.8o±0.2oHas characteristic peaks.
Description
Technical Field
The invention relates to (R)/(S) -chloroquine phosphate crystals and a preparation method thereof.
Background
The chemical name of Chloroquine Phosphate (Chloroquine Phosphate) is 7-chloro-4- (4-diethylamino-1-methylbutylamino) quinoline diphosphate, the chemical structure is shown as formula I, Chloroquine is free alkali of the Chloroquine, the Chloroquine has 1 chiral center and is S-Chloroquine (formula II) and R-Chloroquine (formula III) respectively.
Racemic chloroquine is used clinically to treat chloroquine-sensitive malarial falciparum, alternate-day abuse and tri-day abuse. And can be used for the inhibitory prevention of malaria symptoms. Can also be used for treating extraintestinal amebiasis, connective tissue disease, and light-sensitive diseases (such as erythema solare).
The patent CN105693605B discloses an asymmetric synthesis method of optically pure R/S-chloroquine, and because the pharmacological action and the pharmacokinetic property of S-chloroquine and R-chloroquine in human cancer cells and human bodies are obviously different, the deep research on the two isomers has important significance for the application of the medicaments in new fields, and the acquisition of stable crystal forms is an important link of research and development.
The S-chloroquine or the R-chloroquine can be respectively prepared by condensation reaction of a corresponding optically pure side chain S-chloroquine side chain or a R-chloroquine side chain and 4, 7-dichloroquinoline, and the S-chloroquine side chain or the R-chloroquine side chain can be prepared by splitting a (+/-) -chloroquine side chain and a corresponding chiral splitting reagent mandelic acid, for example, the splitting method disclosed in the patent CN107922404A needs to be subjected to repeated splitting and crystallization, and has the disadvantages of complex operation and low yield.
In order to solve the above problems, it is necessary to conduct research to improve the yield and stability of crystals.
Disclosure of Invention
The invention researches the preparation of (R)/(S) -chloroquine phosphate and the crystal form thereof, obtains a (R)/(S) -chloroquine side chain with high yield by adopting a resolution method, prepares the (R)/(S) -chloroquine by adopting the condensation reaction of the (R)/(S) -chloroquine side chain and 4, 7-dichloroquinoline, and obtains the (R)/(S) -chloroquine phosphate by reacting with phosphoric acid in an organic solvent.
The invention provides a preparation method of (S) -chloroquine phosphate, wherein the (S) -chloroquine phosphate is a crystal and is characterized in that the (S) -chloroquine phosphate is prepared by reacting with phosphoric acid in an organic solvent.
Preferably, the preparation method of the (S) -chloroquine phosphate is characterized in that S-chloroquine is dissolved in an organic solvent, a phosphoric acid solution is added under the condition of high temperature, the temperature is reduced, crystallization is carried out, cooling, filtration and drying are carried out, and the (S) -chloroquine phosphate is obtained;
wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;
wherein the weight volume ratio of the chloroquine to the organic solvent is 1: 3.5-4.5;
wherein the high temperature condition is 70-90 ℃;
wherein the molar ratio of the R-chloroquine to the phosphoric acid is 1: 2-3;
wherein the temperature for cooling and crystallization is 30-45 ℃, and preferably 30 ℃;
wherein the temperature reduction and crystallization heat preservation time is 0.5-2 h, preferably 1 h;
wherein the cooling and filtering temperature is 20-30 ℃, and preferably 25 ℃.
The (S) -chloroquine phosphate prepared by the method provided by the invention has the following X-ray diffraction pattern data:
the invention provides a preparation method of (R) -chloroquine phosphate, wherein the (R) -chloroquine phosphate is a crystal and is characterized in that the (R) -chloroquine is prepared by reacting with phosphoric acid in an organic solvent.
Preferably, the preparation method of the (R) -chloroquine phosphate is characterized by dissolving R-chloroquine in an organic solvent, adding a phosphoric acid solution under a high-temperature condition, cooling for crystallization, cooling and filtering, dissolving the obtained filter cake in water, heating, adding the organic solvent until the mixture is turbid, cooling to room temperature for crystallization, crystallizing at 5-10 ℃, filtering and drying to obtain the (R) -chloroquine phosphate;
wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;
wherein the weight volume ratio of the chloroquine to the organic solvent is 1: 3.5-4.5;
wherein the high temperature condition is 70-90 ℃;
wherein the molar ratio of the R-chloroquine to the phosphoric acid is 1: 2-3;
wherein the temperature for cooling and crystallization is 30-45 ℃, and preferably 30 ℃;
wherein the temperature reduction and crystallization heat preservation time is 0.5-2 h, preferably 1 h;
the room temperature is 20 ℃ to 30 ℃ as the room temperature is not particularly specified.
The (R) -chloroquine phosphate prepared according to the method provided by the invention has the following X-ray diffraction pattern data:
the XPRD test conditions of the invention are as follows:
the apparatus is a PANalyticalX' Pert3 powder X-ray diffractometer, targets Cu, K α, wavelengths K α 1: 1.54060 Å, K α 2: 1.54443 Å, tube pressure 40kV, tube flow 40mA, step length [ phi ], [o2θ]: 0.0260; time of scanning per step s]:37.9440。
Further, the invention provides a preparation method of (S) -chloroquine phosphate, which is characterized by comprising the following steps:
1) condensation reaction: reacting 4, 7-dichloroquinoline with an S-chloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH after the reaction is finished, extracting by adopting halogenated alkane, concentrating, adjusting the pH to be acidic, adjusting the pH of a water phase to be alkaline, extracting by adopting halogenated alkane, and concentrating to obtain R-chloroquine;
2) salt forming reaction: dissolving the R-chloroquine obtained in the step 1) in an organic solvent, adding a phosphoric acid solution under a high temperature condition, cooling and crystallizing, cooling and filtering, dissolving the obtained filter cake in water, heating, adding the organic solvent until the mixture is turbid, cooling to room temperature for crystallizing, crystallizing at the temperature of 5-10 ℃, filtering and drying to obtain the (R) -chloroquine phosphate.
Further, the invention provides a preparation method of (R) -chloroquine phosphate, which is characterized by comprising the following steps:
1) condensation reaction: reacting 4, 7-dichloroquinoline with an R-chloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH after the reaction is finished, extracting by adopting halogenated alkane, concentrating, adjusting the pH to be acidic, adjusting the pH of a water phase to be alkaline, extracting by adopting halogenated alkane, and concentrating to obtain R-chloroquine;
2) salt forming reaction: dissolving the R-chloroquine obtained in the step 1) in an organic solvent, adding a phosphoric acid solution under a high temperature condition, cooling and crystallizing, cooling and filtering, dissolving the obtained filter cake in water, heating, adding the organic solvent until the mixture is turbid, cooling to room temperature for crystallizing, crystallizing at the temperature of 5-10 ℃, filtering and drying to obtain the (R) -chloroquine phosphate.
The invention also provides a preparation method of the S-chloroquine side chain S- (+) -mandelate, which is characterized in that the chloroquine side chain is dissolved in an organic solvent, and L- (+) -mandelic acid is added for salification;
wherein the molar ratio of the L- (+) -mandelic acid to the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3, preferably 1: 2;
wherein the weight ratio of the chloroquine side chain to the organic solvent is 1: 1.5-3, preferably 1: 2;
wherein the organic solvent is C1-C4 monohydric alcohol, preferably isopropanol;
wherein the temperature of the salt forming reaction is room temperature.
Preferably, the method further comprises filtering and drying.
The S-chloroquine side chain S- (+) -mandelate or R-chloroquine side chain R- (-) -mandelate prepared by the method provided by the invention is neutralized in alkaline aqueous solution, extracted by dichloromethane, dried and concentrated to obtain the S/R-chloroquine side chain.
The (S) -chloroquine phosphate provided by the invention is derived from X-ray powder expressed by 2 theta angleThe injection spectrum is 10.4o、10.7o、15.6o、15.8o、17.8o、18.9o、21.3oAnd 23.9o±0.2oHas a characteristic peak; the (R) -chloroquine phosphate provided by the invention has an X-ray powder diffraction pattern expressed by a 2 theta angle of 10.3o、15.5o、15.7o、17.8oAnd 18.8o±0.2oHas characteristic peaks.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention: the term "XRPD" refers to powder X-ray diffraction;
the term "HPLC" refers to high performance liquid chromatography;
the temperature of the added materials is room temperature unless otherwise specified in the invention.
The S-chloroquine phosphate is the same as the S-chloroquine phosphate; the R-chloroquine phosphate and the R-chloroquine phosphate are the same; the chloroquine side chain is a racemate.
The optically pure chloroquine side chain mandelate is (R) -chloroquine side chain R- (-) -mandelate (the structural formula is shown in the formula V) or (S) -chloroquine side chain S- (+) -mandelate (the structural formula is shown in the formula IV);
the structural formula of the S-chloroquine side chain is shown as a formula VI, and the structural formula of the R-chloroquine side chain is shown as a formula VII.
The invention has the beneficial effects that: 1) obtaining S-chloroquine side chain S- (+) -mandelate or R-chloroquine side chain R- (+) -mandelate with high yield by adopting specific reaction conditions; 2) the (R)/(S) -chloroquine phosphate crystal is prepared by a simple and feasible preparation method, and is characterized by XRPD, so that the method is easy for industrial production and stable and reliable in quality.
Drawings
FIG. 1 XRPD spectrum of example 4(S) -chloroquine phosphate
FIG. 2 XRPD spectrum of example 6 (R) -chloroquine phosphate
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions.
The method for detecting the purity of the R/S-chloroquine and the salt thereof comprises the following steps:
the instrument comprises the following steps: preparing an ultraviolet detector and an electronic analytical balance by using a high performance liquid chromatograph;
a chromatographic column: octadecylsilane chemically bonded silica is used as a packed column;
flow rate: 1.0 ml/min; detection wavelength: 242 nm; sample introduction amount: 20 mu l of the mixture; column temperature: 35 ℃;
mobile phase A: acetonitrile: water: phosphoric acid (100: 900:2, V/V/V);
mobile phase B: acetonitrile: water: phosphoric acid (800: 200:1, V/V/V);
elution was performed with the following gradient:
the instrument related to the XPRD test of the invention is a PANALYTICAL X' Pert3 powder X-ray diffractometer, and the conditions are as follows: the instrument comprises the following steps: (ii) a Target: cu, Ka; wavelength K alpha 1: 1.54060A, K alpha 2: 1.54443A; pipe pressure: 40 kV; pipe flow: 40 mA; step size [ o2 θ ]: 0.0260; scanning time [ s ] per step: 37.9440.
EXAMPLE 1 preparation of (S) -chloroquine side chain S- (+) -mandelate
Weighing 72 g (0.48 mol) of chloroquine side chain into a 250 mL round-bottom flask, adding 150g of isopropanol, and stirring to dissolve; then 36.5 g (0.24 mol) of L-mandelic acid is weighed and added into the system, and stirred at room temperature, and a large amount of white solid is separated out; the white solid obtained is filtered by suction and then put into a vacuum drying oven at 50 ℃. Drying for 8h gave 68.8 g of a white solid (94.9% yield).
EXAMPLE 2 preparation of S-chloroquine side chain
Dissolving the (S) -chloroquine side chain S- (+) -mandelate prepared in example 1 in 200 mL of water, adding NaOH to adjust the pH value to 8-9, adding a proper amount of sodium chloride into the water phase, and extracting with dichloromethane; dried over anhydrous sodium sulfate and concentrated to give 35.3 g (1 eq, 0.251 mol) of a colourless oil.
EXAMPLE 3 preparation of (S) -chloroquine phosphate
All S-chloroquine side chains prepared in example 2 were transferred to a three-necked flask, and 44.8 g of 4, 7-dichloroquinoline (0.9 equivalent, 0.226mol), 6 mL of isopropanol were weighed and stirred with heating at 100 ℃. After reacting for 18 h, basically completely reacting the raw materials, stopping the reaction, and naturally cooling; adding NaOH solution to adjust the pH value to 12, and extracting and concentrating by DCM; the pH was adjusted to 2 with dilute HCl and the aqueous phase was made alkaline again, extracted with DCM and concentrated to give 72.4 g (75% by HPLC) of a yellow oil. 200 mL of absolute ethanol was added to dissolve the oil. Heating and refluxing at 80 ℃ for 15min to stabilize the temperature; 2 equivalents of phosphoric acid (0.34 mol, 17.7 mL) were added dropwise and stirred at 30 ℃ for 1 h. A large amount of white solid is separated out, heating is stopped, and the mixture is cooled to room temperature; filtering, and continuously cooling and crystallizing the obtained R-chloroquine phosphate. Filtering and drying to obtain 62 g R-chloroquine phosphate with purity of 99.5%.
EXAMPLE 4 preparation of (R) -chloroquine side chain R- (-) -mandelate
Weighing 72 g (0.48 mol) of chloroquine side chain into a 250 mL round-bottom flask, adding 150g of isopropanol, and stirring to dissolve; then 36.5 g (0.24 mol) of D-mandelic acid is weighed and added into the system, and stirred at room temperature, and a large amount of white solid is separated out; stirring for 3h to complete salification, suction filtering, and placing in a vacuum drying oven. 68.8 g of a white solid were obtained (yield 94.9%).
The measured specific photometric values were as follows, R-chloroquine side chain mandelate: = 56.1 ° (c = 1.0 g/100mL H2O).
EXAMPLE 5 preparation of R-chloroquine side chain
Dissolving the (R) -chloroquine side chain R- (-) -mandelate prepared in example 4 in 200 mL of water, adding NaOH to adjust the pH value to 11-12, adding a proper amount of sodium chloride into the water phase, and extracting with dichloromethane for three times; the combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 35.3 g (1 eq, 0.251 mol) of a colorless oil.
EXAMPLE 6 preparation of (R) -chloroquine phosphate
All the R-chloroquine side chains prepared in example 5 were transferred to a three-necked flask, and 44.8 g of 4, 7-dichloroquinoline (0.9 equivalent, 0.226mol), 10g of isopropanol, 100 g were weighedoC, heating and stirring. After reacting for 18 h, basically completely reacting the raw materials, stopping the reaction, and naturally cooling; adding NaOH solution to adjust the pH value to 12, and extracting and concentrating by DCM; the pH was adjusted to 2 with dilute HCl and the aqueous phase was made alkaline again, extracted with DCM and concentrated to give 72.4 g (75% by HPLC) of a yellow oil.
200 mL of absolute ethanol was added to dissolve the oil. Heating and refluxing at 80 ℃ for 15min to stabilize the temperature; 2 equivalents of phosphoric acid (0.34 mol, 17.7 mL) were added dropwise and stirred at 30 ℃ for 1 h. A large amount of white solid is separated out, heating is stopped, and the mixture is cooled to room temperature; dissolving the obtained R-chloroquine phosphate with 50 mL of water, heating the solution to 100 ℃ on a distillation device, dropwise adding absolute ethyl alcohol until the solution is just not turbid, stopping heating, cooling the solution to room temperature, and then putting the solution into a refrigerator to continuously cool and crystallize. Filtering and drying to obtain 62 g R-chloroquine phosphate with purity of 99.5%.
And (3) measuring the optical rotation: r-chloroquine phosphate: = 74.73 ° (c = 2.1 g/100mL H2O)。
Claims (10)
1. The (S) -chloroquine phosphate crystal is characterized in that the X-ray powder diffraction pattern of the crystal expressed by the 2 theta angle is 10.4o、10.7o、15.6o、15.8o、17.8o、18.9o、21.3oAnd 23.9o±0.2oHas characteristic peaks.
2. The (R) -chloroquine phosphate crystal is characterized in that the X-ray powder diffraction pattern of the crystal expressed by the 2 theta angle is 10.3o、15.5o、15.7o、17.8oAnd 18.8o±0.2oHas characteristic peaks.
3. A process for preparing a crystal according to claim 1, wherein (S) -chloroquine is prepared by reacting (S) -chloroquine with phosphoric acid in an organic solvent.
4. The method as claimed in claim 3, wherein the (S) -chloroquine phosphate is obtained by dissolving S-chloroquine in an organic solvent, adding a phosphoric acid solution under a high temperature condition, cooling for crystallization, cooling for filtration and drying.
5. The method according to claim 4, wherein the organic solvent is an alcohol solvent, and the weight volume ratio of the chloroquine to the organic solvent is 1: 3.5-4.5.
6. A process for preparing a crystal according to claim 2, wherein (R) -chloroquine is prepared by reacting (R) -chloroquine with phosphoric acid in an organic solvent.
7. The method as claimed in claim 6, wherein the (R) -chloroquine phosphate is obtained by dissolving R-chloroquine in an organic solvent, adding a phosphoric acid solution under a high temperature condition, cooling for crystallization, cooling and filtering, dissolving the obtained filter cake in water, heating, adding the organic solvent until turbidity exists, cooling to room temperature for crystallization, crystallizing at 5-10 ℃, filtering and drying.
8. The method according to claim 7, wherein the organic solvent is an alcohol solvent, and the weight-volume ratio of the chloroquine to the organic solvent is 1: 3.5-4.5.
9. A method for preparing optical pure chloroquine side chain mandelate is characterized in that chloroquine side chain is dissolved in organic solvent, and L- (+) -mandelic acid is added for salification or D- (-) -mandelic acid is added for salification;
the molar ratio of the salified L- (+) -mandelic acid or salified D- (-) -mandelic acid to the chloroquine side chain is 1: 1.9-2.3;
the weight ratio of the chloroquine side chain to the organic solvent is 1: 1.5-3;
the organic solvent is monohydric alcohol of C1-C4.
10. The method of claim 9, wherein the organic solvent is isopropanol.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010714336.XA CN111732539A (en) | 2020-07-23 | 2020-07-23 | Chloroquine phosphate enantiomer crystal form and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010714336.XA CN111732539A (en) | 2020-07-23 | 2020-07-23 | Chloroquine phosphate enantiomer crystal form and preparation method thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111732539A true CN111732539A (en) | 2020-10-02 |
Family
ID=72657267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010714336.XA Pending CN111732539A (en) | 2020-07-23 | 2020-07-23 | Chloroquine phosphate enantiomer crystal form and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111732539A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112225697A (en) * | 2020-10-16 | 2021-01-15 | 宁波大学 | Preparation method of enantiomer pure chloroquine and chloroquine phosphate |
CN115232015A (en) * | 2022-07-06 | 2022-10-25 | 暨明医药科技(苏州)有限公司 | Synthetic method of chloroquine chiral side chain |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111620815A (en) * | 2020-05-12 | 2020-09-04 | 南方科技大学 | Chiral chloroquine, hydroxychloroquine and derivatives thereof, and preparation method and application thereof |
CN111803501A (en) * | 2020-06-17 | 2020-10-23 | 南方科技大学 | Application of chiral chloroquine hydroxychloroquine or salt thereof as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity |
CN111909087A (en) * | 2020-06-15 | 2020-11-10 | 珠海润都制药股份有限公司 | Preparation method of chiral amino chloroquinoline |
CN113350343A (en) * | 2020-03-06 | 2021-09-07 | 华南理工大学 | Application of dextro-chiral chloroquine phosphate in preparing medicine for treating coronavirus |
-
2020
- 2020-07-23 CN CN202010714336.XA patent/CN111732539A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113350343A (en) * | 2020-03-06 | 2021-09-07 | 华南理工大学 | Application of dextro-chiral chloroquine phosphate in preparing medicine for treating coronavirus |
CN111620815A (en) * | 2020-05-12 | 2020-09-04 | 南方科技大学 | Chiral chloroquine, hydroxychloroquine and derivatives thereof, and preparation method and application thereof |
CN111909087A (en) * | 2020-06-15 | 2020-11-10 | 珠海润都制药股份有限公司 | Preparation method of chiral amino chloroquinoline |
CN111803501A (en) * | 2020-06-17 | 2020-10-23 | 南方科技大学 | Application of chiral chloroquine hydroxychloroquine or salt thereof as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity |
Non-Patent Citations (3)
Title |
---|
BATHAN L.DRAKE等: "Synthetic Antimalarials. The Preparation and Properties of 7-Chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline (SN-7618)", 《J.AM.CHEM.SOC.》, vol. 68, no. 7, pages 1216 * |
GIDEON BLAUER等: "Synthesis and optical properties of the chloroquine enantiomers and their complexes with ferriprotoporphyrin IX in aqueous solution", 《CHIRALITY》, vol. 10, pages 558 * |
GOTTFVIED BLASCHKE等: "Chloroquin-Enantiomere durch chromatographische -Racemattrennung und Synthese", 《CHEM. BER.》, pages 3 - 4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112225697A (en) * | 2020-10-16 | 2021-01-15 | 宁波大学 | Preparation method of enantiomer pure chloroquine and chloroquine phosphate |
CN115232015A (en) * | 2022-07-06 | 2022-10-25 | 暨明医药科技(苏州)有限公司 | Synthetic method of chloroquine chiral side chain |
CN115232015B (en) * | 2022-07-06 | 2024-01-02 | 暨明医药科技(苏州)有限公司 | Synthesis method of chloroquine chiral side chain |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR20180127428A (en) | Improved method for the manufacture of sugarmaxes | |
CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
CN111732539A (en) | Chloroquine phosphate enantiomer crystal form and preparation method thereof | |
CN111793026A (en) | Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form | |
CN104447600A (en) | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound | |
CN105693695A (en) | Delafloxacin meglumine salt crystal form, and preparation method thereof | |
TWI703163B (en) | Method for preparing sugammadex sodium and crystalline form thereof | |
CN113527202A (en) | Hydroxychloroquine sulfate crystal | |
CN110467580B (en) | Resolution method of Raxinard axis chiral enantiomer | |
CN105683186A (en) | An industrially applicable process for preparing high purity aclidinium bromide | |
KR100495107B1 (en) | Optical separation method of 3- (para-chlorophenyl) -glutaramide | |
CN102731265B (en) | Preparation method of high-purity propofol | |
CN111548310B (en) | Levosimendan sodium crystal form and preparation method thereof | |
CN112480165A (en) | A crystal form of polysubstituted diphenylethane phosphate sodium salt EBTP and preparation method thereof | |
CN114057640A (en) | Asymmetric synthesis method of optically pure (R)/(S) -hydroxychloroquine side chain | |
KR20230026411A (en) | Method for producing aromatic ether compounds | |
CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
EP2258676B1 (en) | Stable vinamidinium salt and nitrogen-containing heterocyclic ring synthesis using the same | |
TWI480281B (en) | Novel crystal form of tricyclic benzopyran compound and production method thereof | |
CN113121492A (en) | Vilandiolo intermediate, preparation method and application thereof | |
CN110818676A (en) | Crystal form of cyclohexane derivative | |
CN111943933B (en) | Preparation method of neratinib impurity D | |
RU2703286C1 (en) | (5-hydroxy-3,4-bis(hydroxymethyl)-6-methylpyridin-2-yl)methanesulphonic acid salt and a method for production thereof | |
RU2339631C1 (en) | Method of obtaining esomeprazole | |
WO2010079046A1 (en) | Process for the preparation of desvenlafaxine and pharmaceutically acceptable acid addition salts thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |