CN113354581A - Preparation method and application of chiral chloroquine and phosphate thereof - Google Patents
Preparation method and application of chiral chloroquine and phosphate thereof Download PDFInfo
- Publication number
- CN113354581A CN113354581A CN202010150710.8A CN202010150710A CN113354581A CN 113354581 A CN113354581 A CN 113354581A CN 202010150710 A CN202010150710 A CN 202010150710A CN 113354581 A CN113354581 A CN 113354581A
- Authority
- CN
- China
- Prior art keywords
- chloroquine
- solvent
- chiral
- solid
- resolving agent
- 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.)
- Granted
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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a preparation method and application of chiral chloroquine and phosphate thereof. In a resolution solvent, salifying and crystallizing a chloroquine racemate and a resolving agent, performing primary recrystallization, dissociating the crystals in an alkaline solution, filtering and separating the resolving agent, extracting with an organic solvent, drying and concentrating the organic phase to respectively obtain corresponding (R)/(S) -chloroquine, and further salifying the obtained product with phosphoric acid in the solvent to respectively obtain corresponding (R)/(S) -chloroquine phosphate. By adopting the method, after primary crystallization, the ee value of the optical purity of the finished product can be more than 80 percent, and the product with higher purity can be obtained by primary recrystallization. The method has the advantages of good crystalline form, easy filtration and separation, simple and convenient resolution operation, no need of complicated purification processes such as column separation and the like, high optical purity of the product, high yield, repeated use of the resolving agent, low production cost and good industrial application prospect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method and application of chiral chloroquine and phosphate thereof.
Background
Chloroquine (Chloroquine) was used clinically since 1944 for treating malaria such as falciparum malaria and vivax malaria sensitive to Chloroquine; can also be used for treating extraintestinal amebiasis, has antirheumatic effect and the like, and has been used for over 75 years in clinical application. Chloroquine has immunomodulatory activity in addition to antiviral activity, which may synergistically enhance its antiviral action in vivo. Recent studies have shown that chloroquine has a high inhibitory activity in vitro against a virus causing the novel coronavirus pneumoniveCoVID-19 (2019-nCoV).
The side chain of chloroquine contains a chiral carbon, all dosage forms of chloroquine clinically applied at present are racemates, and the stereo structure of chiral drugs has a close relationship with the biological activity thereof. Usually one enantiomer has good biological activity, the other has weak or no activity, and even has toxic and side effects. There are a lot of monographs and papers about the difference in the pharmaceutical effects of stereoisomers and racemates, for example, ibuprofen, a commonly used antipyretic analgesic in daily life, mainly plays a role in the S configuration, and the R configuration is completely inactive. The international association of pharmaceutical ingredients in london in 1997 has agreed that the racemate drug or the mixture of diastereomers which has been developed and marketed can be converted into a single active enantiomer for development, which policy undoubtedly extends the patentable scope of chiral drugs and prolongs the patentable life of drugs. Therefore, the chiral conversion of the racemic modification medicine is necessary in the pharmaceutical industry and clinical treatment, and the development of a new preparation method of optical pure chloroquine has positive significance for the application of the medicine in new fields.
The preparation method of chiral chloroquine phosphate is less, 4-amino-7-chloroquine and 5-diethylamino-2-pentanone are used as initial raw materials in CN201610133079.4, and under the catalysis of chiral acid, the optically pure chloroquine is obtained through asymmetric reduction ammoniation reaction, the ee value of the obtained (S) -chloroquine is 92%, the synthetic route is short, but the product is obtained by separating through a column in the method, and industrialization is difficult to realize. There are reports of methods for separating chiral isomers of chloroquine phosphate by HPLC or electrophoresis by adding different cyclodextrin chiral separating agents such as sulfobutyl ether-beta-cyclodextrin, but such methods can only be applied as analytical means.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of chiral chloroquine.
The invention aims to provide a preparation method of chiral chloroquine phosphate.
The invention also aims to provide the application of the preparation method of the chiral chloroquine phosphate and the phosphate thereof.
The purpose of the invention is realized by the following technical scheme: a preparation method of chiral chloroquine comprises the following steps:
(1) mixing chloroquine racemate, a resolving agent and a resolving agent solvent, heating for dissolving, preserving heat, cooling, standing until crystals are separated out, and carrying out solid-liquid separation to obtain a solid and a liquid; the resolving agent is (R) - (-) -binaphthol phosphate or (S) - (+) -binaphthol phosphate;
(2) adding the solid obtained in the step (1) into an alkaline solution and an organic solvent for reaction to obtain a reaction solution A containing a corresponding reaction product; adding water and an extraction solvent into the reaction solution A, and uniformly mixing to obtain a reaction solution B, wherein the reaction solution B contains a resolving agent salt and corresponding chiral chloroquine; performing solid-liquid separation, drying the obtained solid, recovering corresponding resolving agent salt, performing phase separation on the obtained liquid, washing the obtained organic phase material with water, and removing water and an organic solvent to obtain corresponding chiral chloroquine;
(3) adding the liquid obtained in the step (1) into an alkaline solution for reaction to obtain a reaction liquid C containing chiral chloroquine with another configuration; and (3) recovering the solvent in the reaction liquid C, adding water and the extraction solvent into the product after the solvent is removed, uniformly mixing, carrying out phase separation, washing the obtained organic phase material with water, and then removing the water and the organic solvent to obtain the chiral chloroquine with the other configuration.
The preparation method of the chiral chloroquine further comprises (1-2) a recrystallization step, and the specific steps between the step (1) and the step (2) are as follows: and (2) mixing the solid obtained in the step (1) with a crystallization solvent, heating to dissolve, cooling, standing until crystals are separated out, and performing solid-liquid separation to obtain the solid, namely the further purified chiral chloroquine.
The crystallization solvent in the step (1-2) is preferably a mixture of at least two of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, acetone, diethyl ether, isopropyl ether, tetrahydrofuran and water; more preferably two or three mixtures, preferably isopropanol/acetone; a/refers to a mixture of two or more components, such as isopropanol/acetone refers to a mixture of isopropanol and acetone.
The amount of the crystallization solvent used in the step (1-2) is preferably such that the ratio of the crystallization solvent: calculating the mass ratio of the solid obtained in the step (1) to (1: 2) - (1: 15); more preferably, the ratio of the crystallization solvent: calculating the mass ratio of the solid obtained in the step (1) to (1: 10); most preferably, the crystallization solvent: and (3) calculating the mass ratio of the solid obtained in the step (1) to (1: 6.3) - (1: 8.5).
The heating and dissolving temperature in the step (1-2) is preferably 40-90 ℃; more preferably 60 to 80 ℃.
The temperature reduction in the step (1-2) is carried out to 0-20 ℃, and more preferably to 0-4 ℃.
The standing time in the step (1-2) is preferably 4-8 hours; more preferably 6 h.
The solid-liquid separation mode in the step (1-2) is preferably filtration and pumping.
The preparation method of the chiral chloroquine also comprises the refining step (4): heating and dissolving the chiral chloroquine with the other configuration, which is prepared in the step (3), a resolving agent and a resolving solvent, keeping the temperature, cooling, standing until crystals are separated out, and performing solid-liquid separation to obtain a solid and a liquid; adding the obtained solid into an alkaline solution and an organic solvent for reaction, then adding water and an extraction solvent, stirring, separating out crystals, namely a resolving agent salt, filtering, carrying out phase separation on the obtained filtrate, washing the obtained organic phase material with water, and then removing the water and the organic solvent to obtain refined chiral chloroquine with another configuration; wherein the resolving agent used in the step is different from the resolving agent used in the step (1), and if the step (1) uses (R) - (-) -binaphthol phosphate, the step uses (S) - (+) -binaphthol phosphate; if step (1) uses (S) - (+) -binaphthol phosphate, then this step uses (R) - (-) -binaphthol phosphate.
The dosage of the resolving agent in the step (4) is preferably as follows: chiral chloroquine of another configuration in a molar ratio of 1: 0.2-1.3; more preferably, the ratio of the resolving agent: chiral chloroquine of another configuration in a molar ratio of 1: 0.9-1.18 percent; most preferably, the ratio of the resolving agent: chiral chloroquine of another configuration in a molar ratio of 1: 0.95-1.
The dosage of the resolving solvent in the step (4) is preferably that according to another configuration, the chiral chloroquine: resolving solvent mass ratio of 1: 1-25 parts by weight; more preferably chiral chloroquine in another configuration: resolving solvent mass ratio of 1: 8-18 parts by weight; most preferred is chiral chloroquine in another configuration: resolving solvent mass ratio of 1: 13-18 parts by weight.
The resolution solvent in the step (4) is at least one of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, acetone, diethyl ether, isopropyl ether and tetrahydrofuran; preferably, a mixture of two or more of these is formed, such as isopropanol and acetone, or a mixture of isopropanol, water and acetone.
Step (1) is preferably: mixing a resolving agent and a resolving agent solvent, adding chloroquine racemate, mixing, heating for dissolving, preserving heat, cooling, standing until crystals are separated out, and carrying out solid-liquid separation to obtain a solid and a liquid.
The heating temperature in the step (1) and the step (4) is preferably 50-90 ℃; more preferably 60 to 80 ℃.
The chloroquine racemate is N ', N' -diethyl-N4- (7-chloro-4-quinolyl) -1, 4-pentanediamine.
The resolving agent solvent in the step (1) is at least one of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, acetone, diethyl ether, isopropyl ether and tetrahydrofuran; preferably a mixture of two or more of the above, such as isopropanol and acetone to a mixture, or a mixture of isopropanol, methanol and acetone; more preferably, isopropanol and acetone are mixed according to the mass ratio of 2.7-3.75: 1 part by weight of the resulting mixture.
The dosage of the resolving agent in the step (1) is preferably as follows: chloroquine racemate in a molar ratio of 1: 0.2-1.3; more preferably, the ratio of the resolving agent: chloroquine racemate in a molar ratio of 1: 0.9-1.18 percent; most preferably, the ratio of the resolving agent: chloroquine racemate in a molar ratio of 1: 0.92-1.
The dosage of the resolving agent solvent in the step (1) is preferably as follows: the mass ratio of the resolving agent to the solvent is 1: 1-25 parts by weight; more preferably as chloroquine racemate: the mass ratio of the resolving agent to the solvent is 1: 8-18 parts by weight; most preferably as chloroquine racemate: the mass ratio of the resolving agent to the solvent is 1: 13-15.5.
The heat preservation time in the step (1) and the step (4) is preferably 0.5-1.5 h; more preferably 1 h.
The cooling temperature in the step (1) and the step (4) is preferably-10 ℃ to 10 ℃; more preferably from-10 ℃ to 4 ℃.
The standing time in the step (1) and the step (4) is preferably 12-24 h.
The solid-liquid separation in the step (1) and the step (4) is preferably performed by filtration and suction drying.
The alkaline solution in the step (2) is an alkali metal hydroxide solution, an alkaline earth metal hydroxide solution, a strong base weak acid salt solution or an ammonia-containing solution.
The strong base weak acid carbonate is preferably an alkali metal carbonate or an alkaline earth metal carbonate.
The ammonia-containing solution comprises ammonia water and an ammonia-containing alcohol solution.
The alcohol is preferably methanol or ethanol.
The alkaline solution is preferably a sodium hydroxide solution, a potassium hydroxide solution, a sodium carbonate solution, potassium carbonate or an ammonia solution.
The concentration of the alkaline solution in the step (2) is preferably 5-30% by mass; more preferably 20 to 30%.
The dosage of the alkaline solution in the step (2) is as follows according to the solid obtained in the step (1): the molar ratio of the base in the alkaline solution is 1: 1-10 parts by weight; more preferably the solid obtained according to step (1): the molar ratio of the base in the alkaline solution is 1: 4-9.
The organic solvent in the step (2) is at least one of alcohol with a carbon chain length of C1-C4, acetonitrile and tetrahydrofuran.
The alcohol with the carbon chain length of C1-C4 is preferably at least one of methanol, ethanol, propanol and butanol.
The reaction conditions in step (2) are preferably a stirred reaction for 1 hour.
The reaction product in the step (2) is (R) - (-) -chloroquine or (S) - (+) -chloroquine, wherein when the resolving agent added in the step (1) is (R) - (-) -binaphthol phosphate, the chiral chloroquine obtained in the step (2) is (R) - (-) -chloroquine, and when the resolving agent added in the step (1) is (S) - (+) -binaphthol phosphate, the chiral chloroquine obtained in the step (2) is (S) - (+) -chloroquine.
The extraction solvent in the step (2), the step (3) and the step (4) is preferably at least one of dichloromethane, chloroform, dichloroethane, toluene, diethyl ether, isopropyl ether, ethyl acetate and butyl acetate, and is preferably dichloromethane and chloroform.
The amounts of the extraction solvent and the water used in step (2) and step (4) are preferably as follows: water: the mass ratio of the extraction solvent to the extraction solvent is 1 to (3-25); more preferably, the molar ratio as solid: water: the mass ratio of the extraction solvent is 1 to (6-24).
The solid-liquid separation in step (2) and step (4) is preferably filtration.
The number of times of water washing in step (2), step (3) and step (4) is preferably 3.
The organic phase material in the step (2), the step (3) and the step (4) comprises an organic phase first component, or the organic phase first component and the organic phase second component are formed into a mixture; organic phase the first component is the organic phase obtained in the liquid phase separation step; and the organic phase second component is an organic phase obtained by adding an extractant into the aqueous phase obtained in the obtained liquid phase separation step and then performing back extraction.
The specific steps of removing water and organic solvent described in step (2), step (3) and step (4) are preferably as follows: adding anhydrous sodium sulfate and/or activated carbon into the organic phase material, stirring and drying for 1 h; filtering, distilling under normal pressure to recover solvent, evaporating under reduced pressure, and evaporating until no bubbling occurs.
The reduced pressure evaporation to dryness conditions are preferably as follows: 90 ℃ and 10 kPa.
The resolving agent salt in the step (2) can be prepared by the following steps: and (3) mixing the resolving agent salt with a hydrochloric acid aqueous solution, filtering, washing and drying to obtain the corresponding chiral binaphthol phosphate, wherein the recovered substance can be used as the resolving agent for reuse.
The concentration of the hydrochloric acid aqueous solution is 1-6N; preferably 3N.
The dosage of the hydrochloric acid aqueous solution is preferably 20-30 mL of 3N hydrochloric acid aqueous solution per 4-5 g of resolving agent salt.
The alkaline solution in the step (3) is an alkali metal hydroxide solution, an alkaline earth metal hydroxide solution, a strong base weak acid salt solution or an ammonia-containing solution.
The strong base weak acid carbonate is preferably an alkali metal carbonate or an alkaline earth metal carbonate.
The ammonia-containing solution comprises ammonia water and an ammonia-containing alcohol solution.
The alcohol is preferably methanol or ethanol.
The concentration of the alkaline solution in the step (3) is preferably 5-30% by mass; more preferably 20 to 30%.
The amount of the alkaline solution used in the step (3) is preferably selected from the group consisting of: the molar ratio of chloroquine racemate is 0.5-5: 1; more preferably, the ratio of base in the alkaline solution: the molar ratio of chloroquine racemate to chloroquine racemate is 2.0-2.2: 1.
When the resolving agent in the step (1) is (R) - (-) -binaphthol phosphate, the chiral chloroquine with the other configuration in the step (3) is (S) - (+) -chloroquine; when the resolving agent in the step (1) is (S) - (+) -binaphthol phosphate, the chiral chloroquine with the other configuration in the step (3) is (R) - (-) -chloroquine.
The method for recovering the solvent in the reaction solution C in the step (3) is preferably atmospheric distillation or vacuum distillation.
The amount of the extraction solvent and the water used in step (3) is preferably the amount of the solvent-removed product of step (3): water: the mass ratio of the extraction solvent is 1 to (3-25).
The preparation method of the chiral chloroquine is applied to the preparation of the chiral chloroquine or the chiral chloroquine phosphate.
A preparation method of chiral chloroquine phosphate comprises the following steps: and (3) mixing the chiral chloroquine obtained in the step (2) or the chiral chloroquine obtained in the step (3) with a solvent, heating to dissolve, adding a phosphoric acid solution, keeping the temperature, stirring, cooling, filtering and drying to obtain the corresponding chiral chloroquine phosphate.
The solvent is at least one of alcohol with a carbon chain length of C1-C4, acetone and tetrahydrofuran.
The alcohol with the carbon chain length of C1-C4 is preferably at least one of methanol, ethanol, propanol and butanol.
The dosage of the solvent is preferably as follows: solvent 1: (5-25) proportioning; more preferably chiral chloroquine: solvent 1: (15-23).
The concentration of the phosphoric acid is 20-85% by mass percent; preferably 50-85% by mass.
The dosage of the phosphoric acid is preferably as follows: phosphoric acid in a molar ratio of 1: (1.5-2.5) proportioning; more preferably chiral chloroquine: phosphoric acid in a molar ratio of 1: (2-2.1).
The heating temperature is preferably 60-90 ℃; more preferably 70 to 80 ℃.
The temperature for reducing the temperature is preferably 0-20 ℃; more preferably 10 to 20 ℃.
The drying temperature is preferably 60-90 ℃; more preferably 70 to 80 ℃.
Application of preparation method of chiral chloroquine phosphate in preparation of chiral chloroquine phosphate
Compared with the prior art, the invention has the following advantages and effects:
(1) the method provided by the invention adopts a specific resolution solvent, chloroquine reacts with one enantiomer of binaphthol phosphate to generate corresponding binaphthol phosphate salt of chloroquine, the product is a diastereomer, so that the difference of the solubility of the diastereomer in the specific solvent can be utilized to crystallize and separate out the chloroquine binaphthol phosphate salt with lower solubility at a certain temperature, then an alkaline solution is added to react with the diastereomer to obtain one enantiomer of chloroquine, and the corresponding chiral chloroquine phosphate is obtained by reacting with phosphoric acid. The method of the invention has simple and convenient resolution operation, does not need complicated purification processes such as column separation and the like, and is easy to produce.
(2) The solvent splitting system can obtain crystals with good crystal forms, the crystals are easy to filter and separate, the crystals can be separated out only once in the step (1), and the purity of the finished product can reach 80 percent; if the step (1-2) is added, the whole invention only needs to carry out recrystallization operation once, the operation is simpler, and the product with higher purity (the ee value can be more than 99 percent) can be obtained, and the ee percent of the product obtained by the prior art is higher than 92 percent.
(3) The resolving agent in the invention can be repeatedly used, has low production cost, higher yield and high optical purity of the product, and has good industrial application prospect.
Drawings
FIG. 1 is a photographic image of the products of different steps prepared in example 1; wherein A is the crystal obtained in the step (1), B is the filter cake obtained in the step (1), and C is the filter cake obtained in the step (2).
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
EXAMPLE 1 preparation of chiral chloroquine phosphate
(1) Preparation of R- (-) -chloroquine binaphthol phosphate
Taking 4.6g chloroquine racemate (CAS No.54-05-7), adding 5.4g of (R) - (-) -binaphthol phosphate, adding 50g of isopropanol and 16g of acetone, heating and dissolving at 60 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 12h, precipitating crystals (shown in a figure 1A), filtering, draining, storing filtrate as S-rich mother liquor, wherein a filter cake is light yellow solid (shown in a figure 1B), and drying at 60 ℃ to obtain 6.2g of solid, wherein the solid is R- (-) -chloroquine binaphthol phosphate.
(2) Recrystallization
Adding 30g of isopropanol and 9g of acetone into 6.2g of the solid obtained in the step (1), heating and dissolving at 60 ℃, slowly stirring to room temperature, cooling to 0-4 ℃, standing for 6h, separating out large-particle crystals, filtering, draining to obtain a glossy loose solid (shown in figure 1C), and drying at 60 ℃ to obtain 4.7g of solid.
(3) Preparation of R- (-) -chloroquine and recovery of (R) - (-) -binaphthol phosphate
4.7g (7mmol) of the solid obtained in the step (2) is added with 10g of methanol and 7g of sodium hydroxide solution with the concentration of 20 percent by mass, the mixture is stirred for 1h, then 50ml of dichloromethane and 50ml of water are added, the mixture is stirred, a large amount of solid with good crystal form is separated out, the mixture is filtered, the wet weight is 5.31g of white crystalline solid which is the released (R) - (-) -binaphthol phosphate sodium salt, the filtrate is subjected to phase separation, the water phase is back extracted by 40ml of dichloromethane, the organic phase is washed by 40ml of x 3 water, the organic phases are combined, anhydrous sodium sulfate is added, the mixture is stirred and dried for 1h, the filtrate is filtered, the solvent is recovered by normal pressure distillation, the filtrate is evaporated to dryness under 10kPa under reduced pressure at 90 ℃ until no bubbling is realized, 2.1g of light yellow oily matter is obtained, the solid is cooled and is R- (-) -chloroquine, the enantioselectivity of the product is analyzed by chiral HPLC, ee value is 99%; [ alpha ] to]24 D＝-107.1°(c＝1,EtOH)。
(4) Preparation of R- (-) -chloroquine phosphate
Taking 1.6g of R- (-) -chloroquine prepared in the step (3), adding 25g of ethanol, heating and stirring at 70 ℃ for dissolving, adding 1.2g of phosphoric acid with the concentration of 85% by mass, immediately separating out a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 20 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 2.3g of white solid which is R- (-) -chloroquine phosphate, wherein the product enantioselectivity is analyzed by chiral HPLC, and the ee value is 99%; [ alpha ] to]24D＝-86.8°(c＝1,H2O)。
(5) Preparation of S- (+) -chloroquine
Adding 6g of sodium hydroxide solution with the concentration of 20% in mass into the S-enriched mother liquor obtained in the step (1), distilling and recovering the solvent at normal pressure, adding 40ml of dichloromethane and 40ml of water into the residue of distillation, stirring, carrying out phase separation, carrying out back extraction on the water phase by using 40ml of dichloromethane, washing the organic phase by using 40ml of 3 water, combining the organic phases, adding anhydrous sodium sulfate and active carbon, stirring and drying for 1h, filtering, distilling and recovering the solvent at normal pressure, evaporating to dryness at 90 ℃ and 10kPa under reduced pressure until bubbling does not occur, obtaining 2.15g of light yellow oily matter which is a crude product of S- (+) -chloroquine, and analyzing the enantioselectivity of the product by chiral HPLC, wherein the ee value is 49%; [ alpha ] to]24 D＝+52.5°(c＝1,EtOH)。
(6) S- (+) -chloroquine refining and (S) - (+) -binaphthol phosphate recovery
Adding 2.3g of (S) - (+) -binaphthol phosphate into the S- (+) -chloroquine crude product obtained in the step (5), adding 20g of isopropanol and 7g of acetone, heating and dissolving at 60 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 12h, separating out crystals, filtering, draining to obtain a loose solid with luster, adding 7g of methanol and 5g of sodium hydroxide solution with the concentration of 20% by mass, stirring for 1h, adding 30ml of chloroform and 30ml of water, stirring, separating out a large amount of solid with good crystal forms, filtering to obtain a white crystalline solid with the wet weight of 2.31g, separating the solid to obtain released (S) - (+) -binaphthol phosphate sodium salt, carrying out phase separation on the filtrate, carrying out back extraction on the aqueous phase by using 30ml of chloroform, washing the organic phase by using 30ml of 3 water, merging the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness at 90 ℃ under 10kPa under reduced pressure until no bubbling occurs to obtain 1.5g of light yellow oily matter, cooling to obtain a yellow solid, wherein the solid is S- (+) -chloroquine, and the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 98%; [ alpha ] to]24 D＝+104.9°(c＝1,EtOH)。
(7) Preparation of S- (+) -chloroquine phosphate
Taking 1g of S- (+) -chloroquine prepared in the step (6), adding 20g of ethanol, heating and stirring at 70 ℃ for dissolving, adding 0.72g of phosphoric acid with the concentration of 85% by mass, immediately separating out a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 20 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 1.4g of the white solid which is S- (+) -chloroquine phosphate, wherein the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 98%; [ alpha ] to]24 D＝+85.1°(c＝1,H2O)。
EXAMPLE 2 preparation of chiral chloroquine phosphate
(1) Preparation of R- (-) -chloroquine binaphthol phosphate
Taking 7.2g chloroquine racemate, adding 8.4g of (R) - (-) -binaphthol phosphate, adding 75g of isopropanol and 20g of acetone, heating to dissolve at 80 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 24h, separating out crystals, filtering, draining, storing filtrate as S-enriched mother liquor, obtaining a filter cake which is light yellow solid, and drying at 60 ℃ to obtain 7.5g of the solid which is R- (-) -chloroquine binaphthol phosphate.
(2) Preparation of R- (-) -chloroquine and recovery of (R) - (-) -binaphthol phosphate
Adding 15g of methanol and 10g of sodium hydroxide solution with the concentration of 20 percent by mass into 7.5g (11mmol) of the solid obtained in the step (1), stirring for 1h, adding 50ml of dichloromethane and 50ml of water, stirring, separating out a large amount of solid with good crystal form, filtering to obtain a wet weight of 8.5g of white crystalline solid which is released (R) - (-) -binaphthol phosphate sodium salt, carrying out phase separation on the filtrate, carrying out back extraction on the water phase by using 50ml of dichloromethane, washing the organic phase by using 50ml of x 3 water, combining the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness under reduced pressure at 90 ℃ and 10kPa until no bubbling exists, obtaining 2.7g of light yellow oily matter which is R- (-) -chloroquine, and analyzing the enantioselectivity by chiral HPLC, wherein the ee value is 81%; [ alpha ] to]24 D＝-87.4°(c＝1,EtOH)。
(3) Preparation of R- (-) -chloroquine phosphate
Taking 2.0g of R- (-) -chloroquine prepared in the step (2), adding 40g of ethanol, heating and stirring at 70 ℃ for dissolving, adding 1.5g of phosphoric acid with the concentration of 85% by mass, immediately separating out a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 20 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 2.8g of white solid which is R- (-) -chloroquine phosphate, wherein the product enantioselectivity is analyzed by chiral HPLC, and the ee value is 80%; [ alpha ] to]24 D＝-69.6°(c＝1,H2O)。
(4) Preparation of S- (+) -chloroquine
Adding 9g of sodium hydroxide solution with the concentration of 20% in mass into the S-enriched mother liquor obtained in the step (1), distilling and recovering the solvent at normal pressure, adding 40ml of dichloromethane and 40ml of water into the residue of distillation, stirring, carrying out phase separation, carrying out back extraction on the water phase by using 40ml of dichloromethane, washing the organic phase by using 40ml of 3 water, combining the organic phases, adding anhydrous sodium sulfate and active carbon, stirring and drying for 1h, filtering, distilling and recovering the solvent at the normal pressure of the filtrate, carrying out reduced pressure distillation at 90 ℃ under 10kPa, and steaming until bubbling does not occur to obtain 3.2g of light yellow oily matter, wherein the product is a crude product of S- (+) -chloroquine, and the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 52%; [ alpha ] to]24 D＝+52.5°(c＝1,EtOH)。
(5) Preparation of S- (+) -chloroquine phosphate
Taking 2g of S- (+) -chloroquine prepared in the step (4), adding 45g of ethanol, heating and stirring at 70 ℃ for dissolving, adding 1.55g of phosphoric acid with the concentration of 85% by mass, immediately separating out a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 10 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 2.7g of white solid which is S- (+) -chloroquine phosphate, wherein the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 50%; [ alpha ] to]24 D＝+43.3°(c＝1,H2O)。
EXAMPLE 3 preparation of chiral chloroquine phosphate
(1) Preparation of S- (+) -chloroquine binaphthol phosphate
Taking 8.3g chloroquine racemate, adding 9.7g of (S) - (+) -binaphthol phosphate, adding 90g of isopropanol and 30g of acetone, heating and dissolving at 70 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 18h, separating out crystals, filtering, draining, storing filtrate as R-rich mother liquor, obtaining a light yellow solid filter cake, and drying at 60 ℃ to obtain 11.8g of S- (+) -chloroquine binaphthol phosphate.
(2) Recrystallization
Adding 11.8g (17.7mmol) of the solid obtained in the step (1) into 75g of isopropanol and 25g of acetone, heating to dissolve at 70 ℃, slowly stirring to room temperature, cooling to 0-4 ℃, standing for 6 hours, separating out large-particle crystals, filtering, draining to obtain a loose solid with luster, and drying at 60 ℃ to obtain 8.6g of the solid.
(3) Preparation of S- (+) -chloroquine and recovery of (S) - (+) -binaphthol phosphate
Adding 8.6g (12.9mmol) of solid obtained in the step (2) into 15g of methanol and 10g of sodium hydroxide solution with the concentration of 30 percent by mass, stirring for 1h, adding 80ml of dichloromethane and 80ml of water, stirring, separating out a large amount of solid with good crystal form, filtering to obtain wet 10.2g of white crystalline solid which is released (S) - (+) -binaphthol phosphate sodium salt, separating the filtrate, back-extracting the aqueous phase with 60ml of dichloromethane, washing the organic phase with 60ml of 3 water, combining the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness at 90 ℃ under 10kPa under reduced pressure until no bubbling is achieved, obtaining 3.9g of light yellow oily matter, cooling to obtain a yellow solid, and drying the yellow oily matterThe solid is S- (+) -chloroquine, the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 99.6 percent; [ alpha ] to]24 D＝+107.8°(c＝1,EtOH)。
(4) Preparation of S- (+) -chloroquine phosphate
Taking 3.2g of S- (+) -chloroquine prepared in the step (3), adding 60g of ethanol, heating and stirring at 70 ℃ for dissolving, adding 4.2g of phosphoric acid with the concentration of 50% by mass, immediately separating out a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 10 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 4.7g of white solid which is S- (+) -chloroquine phosphate, wherein the product enantioselectivity is analyzed by chiral HPLC, and the ee value is 99.5%; [ alpha ] to]24 D＝+86.7°(c＝1,H2O)。
(5) Preparation of R- (-) -chloroquine
Adding 7.2g of sodium hydroxide solution with the concentration of 30% by mass into the R-enriched mother liquor obtained in the step (1), distilling and recovering the solvent at normal pressure, adding 80ml of dichloromethane and 80ml of water into a distillation residue, stirring, carrying out phase separation, carrying out back extraction on an aqueous phase by using 60ml of dichloromethane, washing an organic phase by using 60ml of 3 water, combining organic phases, adding anhydrous sodium sulfate and active carbon, stirring and drying for 1h, filtering, distilling and recovering the solvent from the filtrate at normal pressure, carrying out reduced pressure distillation at 90 ℃ under 10kPa, evaporating until bubbling does not occur to obtain 3.8g of light yellow oily matter, wherein the product is a crude product of R- (-) -chloroquine, and the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 53%; [ alpha ] to]24 D＝-58.1°(c＝1,EtOH)。
(6) R-chloroquine refining and (R) - (-) -binaphthol phosphate recovery
Adding 4.1g of (R) - (-) -binaphthol phosphate into the crude product of R- (-) -chloroquine obtained in the step (5), adding 40g of isopropanol, heating and dissolving 10g of acetone and 2g of water at 60 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 12h, precipitating large-particle crystals, filtering, draining to obtain loose solids with luster, adding 10g of methanol and 5g of sodium hydroxide solution with the concentration of 30 percent by mass into the solid, stirring for 1h, adding 60ml of dichloromethane and 80ml of water, stirring, precipitating a large amount of solids with good crystal forms, filtering to obtain wet white crystalline solids which are released (R) - (-) -binaphthol phosphate sodium salt, separating the phases of the filtrate, back-extracting the water phase with 70ml of dichloromethane, and obtaining an organic phase.Washing with 50ml of 3 water, combining organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling and recovering the solvent under normal pressure, evaporating to dryness at 90 ℃ under 10kPa under reduced pressure until no bubbling occurs to obtain 2.7g of light yellow oily matter, cooling to obtain a yellow solid, wherein the solid is R- (-) -chloroquine, and the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 99%; [ alpha ] to]24 D＝-107.0°(c＝1,EtOH)。
(7) Preparation of R- (-) -chloroquine phosphate
Taking 1.6g of R- (-) -chloroquine prepared in the step (6), adding 10g of methanol and 20g of isopropanol, heating and stirring at 70 ℃ for dissolving, adding 1.2g of phosphoric acid with the concentration of 85% by mass, immediately precipitating a white solid, keeping the temperature and stirring for 1h, stirring and cooling to 10 ℃, filtering, draining, and drying in vacuum at 80 ℃ to obtain 2.2g of the white solid which is R- (-) -chloroquine phosphate, wherein the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 99%; [ alpha ] to]24 D＝-86.0°(c＝1,H2O)。
Example 4 recovery of resolving agent to prepare chiral chloroquine
(1) Recovery of (R) - (-) -binaphthol phosphate acidification
The (R) - (-) -binaphthol phosphate sodium salt recovered in the step (6) of example 3 was added to 20ml of a 3N hydrochloric acid solution, stirred for 3 hours, filtered, washed with 10ml of 2 water, and dried under vacuum at 60 ℃ to obtain 3.2g of a white solid, which was (R) - (-) -binaphthol phosphate.
(2) Preparation of R- (-) -chloroquine binaphthol phosphate
And (2) taking 1.6g of chloroquine racemate, adding 1.5g of (R) - (-) -binaphthol phosphate obtained in the step (1), adding 16g of isopropanol and 6g of acetone, heating at 80 ℃ for dissolving, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to 0-4 ℃, standing for 24h, separating out crystals, filtering, draining, wherein a filter cake is a light yellow solid, and drying at 60 ℃ to obtain 1.7g of the solid which is R- (-) -chloroquine binaphthol phosphate.
(3) Preparation of R- (-) -chloroquine and recovery of (R) - (-) -binaphthol phosphate
Adding 1.7g (2.5mmol) of the solid obtained in the step (2) into 5g of methanol and 4g of sodium hydroxide solution with the concentration of 20 percent by mass, stirring for 1h, adding 40ml of dichloromethane and 40ml of water, stirring, and separating out a large amount of solid with good crystal formAfter the reaction is finished, filtering to obtain 1.6g of wet white crystalline solid which is released (R) - (-) -binaphthol phosphate sodium salt, separating phases of the filtrate, back extracting the water phase by using 30ml of dichloromethane, washing the organic phase by using 30ml of 3 water, combining the organic phases, adding anhydrous sodium sulfate, stirring and drying for 1h, filtering, distilling the filtrate at normal pressure to recover the solvent, evaporating to dryness at 90 ℃ under 10kPa under reduced pressure until no bubbling occurs to obtain 0.6g of light yellow oily substance which is R- (-) -chloroquine, analyzing the enantioselectivity of the product by chiral HPLC, and obtaining an ee value which is 79%; [ alpha ] to]24 D＝-85.1°(c＝1,EtOH)。
EXAMPLE 5 preparation of chiral chloroquine
(1) Preparation of R- (-) -chloroquine binaphthol phosphate
Taking 2.0g chloroquine racemate, adding 2.1g of (R) - (-) -binaphthol phosphate, adding 25g of isopropanol, 1g of methanol and 5g of acetone, heating to 70 ℃ for dissolving, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to-10 ℃, standing for 24h, separating out crystals, filtering, draining to obtain a light yellow solid filter cake, and drying at 60 ℃ to obtain 1.9g of the solid R- (-) -chloroquine binaphthol phosphate.
(2) Preparation of R-chloroquine and recovery of (R) - (-) -binaphthol phosphate
Adding 1.9g (2.8mmol) of the solid obtained in the step (1) into 7g of methanol and 5g of 20% sodium hydroxide solution, stirring for 1h, adding 40ml of dichloromethane and 40ml of water, stirring to separate out a large amount of solid with good crystal form, and filtering to obtain 2.3g of white crystalline solid with wet weight, wherein the solid is released (R) - (-) -binaphthol phosphate sodium salt; the phases of the filtrate are separated, the water phase is back extracted by 40ml of dichloromethane, the organic phase is washed by 30ml of 3 water, the organic phases are combined, anhydrous sodium sulfate is added, the mixture is stirred and dried for 1h, the mixture is filtered, the solvent is recovered by distillation under normal pressure, the mixture is evaporated to dryness under reduced pressure of 10kPa at 90 ℃ until no bubbling occurs, 0.65g of light yellow oily matter is obtained, the product is R- (-) -chloroquine, the enantioselectivity of the product is analyzed by chiral HPLC, and the ee value is 75%; [ alpha ] to]24 D＝-80.7°(c＝1,EtOH)。
Comparative example 1 preparation of chiral chloroquine
(1) Preparation of R-chloroquine binaphthol phosphate
Taking 1.6g chloroquine racemate, adding 1.7g of (R) - (-) -binaphthol phosphate, adding 15g of methanol, heating and dissolving at 70 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to-20 ℃, standing for 24h, and not separating out crystals.
Comparative example 2 preparation of chiral chloroquine
(1) Preparation of R-chloroquine binaphthol phosphate
Taking 1.6g chloroquine racemate, adding 1.7g (R) - (-) -binaphthol phosphate, adding 20g acetone, heating and dissolving at 70 ℃, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to-20 ℃, standing for 24h, and not precipitating crystals.
Comparative example 3 preparation of chiral chloroquine
(1) Preparation of R-chloroquine binaphthol phosphate
Taking 1.6g chloroquine racemate, adding 1.7g of (R) - (-) -binaphthol phosphate, adding 25g of isopropanol and 2g of water, heating at 70 ℃ to dissolve, keeping the temperature for 1h, stirring and cooling to room temperature, cooling to-20 ℃, standing for 24h, precipitating pasty sticky solid which is difficult to filter.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of chiral chloroquine is characterized by comprising the following steps:
(1) mixing chloroquine racemate, a resolving agent and a resolving agent solvent, heating for dissolving, preserving heat, cooling, standing until crystals are separated out, and carrying out solid-liquid separation to obtain a solid and a liquid; the resolving agent is (R) -binaphthol phosphate or (S) -binaphthol phosphate;
(2) adding the solid obtained in the step (1) into an alkaline solution and an organic solvent for reaction to obtain a reaction solution A containing a corresponding reaction product; adding water and an extraction solvent into the reaction solution A, and uniformly mixing to obtain a reaction solution B, wherein the reaction solution B contains a resolving agent salt and corresponding chiral chloroquine; performing solid-liquid separation, drying the obtained solid, recovering corresponding resolving agent salt, performing phase separation on the obtained liquid, washing the obtained organic phase material with water, and removing water and an organic solvent to obtain corresponding chiral chloroquine;
(3) adding the liquid obtained in the step (1) into an alkaline solution for reaction to obtain a reaction liquid C containing chiral chloroquine with another configuration; and (3) recovering the solvent in the reaction liquid C, adding water and the extraction solvent into the product after the solvent is removed, uniformly mixing, carrying out phase separation, washing the obtained organic phase material with water, and then removing the water and the organic solvent to obtain the chiral chloroquine with the other configuration.
2. The method for preparing chiral chloroquine according to claim 1, wherein: the method also comprises (1-2) a recrystallization step, and the specific steps between the step (1) and the step (2) are as follows: and (2) mixing the solid obtained in the step (1) with a crystallization solvent, heating to dissolve, cooling, standing until crystals are separated out, and performing solid-liquid separation to obtain the solid, namely the further purified chiral chloroquine.
3. The method for preparing chiral chloroquine according to claim 2, wherein:
the crystallization solvent in the step (1-2) is a mixture formed by at least two of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, acetone, diethyl ether, isopropyl ether, tetrahydrofuran and water;
the dosage of the crystallization solvent in the step (1-2) is as follows: calculating the mass ratio of the solid obtained in the step (1) to (1: 2) - (1: 15);
the heating and dissolving temperature in the step (1-2) is 40-90 ℃;
and (3) reducing the temperature to 0-20 ℃ in the step (1-2).
4. The method for producing chiral chloroquine according to claim 1 or 2, wherein: further comprises (4) a refining step: heating and dissolving chiral chloroquine with another configuration, a resolving agent and a resolving solvent which are prepared in the step (3) of the claim 1 or 2, preserving heat, cooling, standing until crystals are separated out, and performing solid-liquid separation to obtain a solid and a liquid; adding the obtained solid into an alkaline solution and an organic solvent for reaction, then adding water and an extraction solvent, stirring, separating out crystals, namely a resolving agent salt, filtering, carrying out phase separation on the obtained filtrate, washing the obtained organic phase material with water, and then removing the water and the organic solvent to obtain refined chiral chloroquine with another configuration; wherein the resolving agent used in the step is different from the resolving agent used in the step (1).
5. The method for preparing chiral chloroquine according to claim 1, wherein:
the resolving agent solvent in the step (1) is at least one of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, acetone, diethyl ether, isopropyl ether and tetrahydrofuran;
the alkaline solution in the step (2) is an alkali metal hydroxide solution, an alkaline earth metal hydroxide solution, a strong base weak acid salt solution or an ammonia-containing solution;
the organic solvent in the step (2) is at least one of alcohol with a carbon chain length of C1-C4, acetonitrile and tetrahydrofuran;
the extraction solvent in the step (2) is at least one of dichloromethane, chloroform, dichloroethane, toluene, diethyl ether, isopropyl ether, ethyl acetate and butyl acetate;
the organic phase material in the step (2) comprises an organic phase first component, or the organic phase first component and the organic phase second component are formed into a mixture; organic phase the first component is the organic phase obtained in the liquid phase separation step; the organic phase second component is an organic phase obtained by adding an extractant into the aqueous phase obtained in the liquid phase separation step and then performing back extraction;
the alkaline solution in the step (3) is an alkali metal hydroxide solution, an alkaline earth metal hydroxide solution, a strong base weak acid salt solution or an ammonia-containing solution;
the extraction solvent in the step (3) is at least one of dichloromethane, chloroform, dichloroethane, toluene, diethyl ether, isopropyl ether, ethyl acetate and butyl acetate.
6. The method for preparing chiral chloroquine according to claim 1, wherein:
the dosage of the resolving agent in the step (1) is as follows: chloroquine racemate in a molar ratio of 1: calculating the mixture ratio of 0.2-1.2;
the dosage of the resolving agent solvent in the step (1) is as follows: the mass ratio of the resolving agent to the solvent is 1: 1-25 proportion calculation;
the dosage of the alkaline solution in the step (2) is as follows according to the solid obtained in the step (1): the molar ratio of the base in the alkaline solution is 1: 1-10 proportion calculation;
the amount of the extraction solvent and the water used in the step (2) is the solid in the step (2): water: the mass ratio of the extraction solvent to the extraction solvent is 1 to (3-25);
the concentration of the alkaline solution in the step (3) is preferably 5-30% by mass;
the dosage of the alkaline solution in the step (3) is as follows according to the alkali in the alkaline solution: calculating the molar ratio of chloroquine racemate to 0.5-5: 1;
the dosage of the extraction solvent and the water in the step (3) is the product after the solvent is removed in the step (3): water: the mass ratio of the extraction solvent is 1 to (3-25).
7. The method for preparing chiral chloroquine according to claim 1, wherein:
the heat preservation time in the step (1) is 0.5-1.5 h;
the cooling temperature in the step (1) is-10 ℃ to 10 ℃;
the standing time in the step (1) is 12-24 hours;
the reaction condition in the step (2) is stirring reaction for 1 h;
the specific steps of removing water and organic solvent described in step (2) are as follows: adding anhydrous sodium sulfate and/or activated carbon into the organic phase material, stirring and drying for 1 h; filtering, distilling under normal pressure to recover solvent, evaporating under reduced pressure, and evaporating until no bubbling occurs;
the resolving agent salt in the step (2) is prepared by the following steps: mixing resolving agent salt and hydrochloric acid aqueous solution, filtering, washing and drying to obtain corresponding chiral binaphthol phosphate;
the method for recovering the solvent in the reaction liquid C in the step (3) is atmospheric distillation or reduced pressure distillation;
the specific steps of removing water and organic solvent described in step (3) are as follows: adding anhydrous sodium sulfate and/or activated carbon into the organic phase material, stirring and drying for 1 h; filtering, distilling under normal pressure to recover solvent, evaporating under reduced pressure, and evaporating until no bubbling occurs.
8. The use of a process for the preparation of chiral chloroquine according to any one of claims 1 to 7 in the preparation of chiral chloroquine or chiral chloroquine phosphates.
9. A preparation method of chiral chloroquine phosphate is characterized by comprising the following steps: mixing the chiral chloroquine obtained in the step (2) or the chiral chloroquine obtained in the step (3) in the preparation method of chiral chloroquine in any claim with a solvent, heating for dissolving, adding a phosphoric acid solution, keeping the temperature and stirring, cooling, filtering and drying to obtain the corresponding chiral chloroquine phosphate.
10. The method for preparing chiral chloroquine phosphate according to claim 9, wherein:
the solvent is at least one of alcohol with a carbon chain length of C1-C4, acetone and tetrahydrofuran;
the dosage of the solvent is as follows: solvent 1: (5-25) calculating the mixture ratio;
the dosage of the phosphoric acid is as follows: phosphoric acid in a molar ratio of 1: (1.5-2.5) proportioning;
the heating temperature is 60-90 ℃;
the temperature for reducing the temperature is 0-20 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010150710.8A CN113354581B (en) | 2020-03-06 | 2020-03-06 | Preparation method and application of chiral chloroquine and phosphate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010150710.8A CN113354581B (en) | 2020-03-06 | 2020-03-06 | Preparation method and application of chiral chloroquine and phosphate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113354581A true CN113354581A (en) | 2021-09-07 |
| CN113354581B CN113354581B (en) | 2023-06-20 |
Family
ID=77524022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010150710.8A Active CN113354581B (en) | 2020-03-06 | 2020-03-06 | Preparation method and application of chiral chloroquine and phosphate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113354581B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591251A (en) * | 2022-02-14 | 2022-06-07 | 华南理工大学 | Chiral aminoquinazoline compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004660A2 (en) * | 2002-07-09 | 2004-01-15 | Alpha Research Group, L.L.C. | Compositions and methods for the treatment of parkinson’s disease and tardive dyskinesias |
| CN105693605A (en) * | 2016-03-09 | 2016-06-22 | 西安科技大学 | Asymmetric synthesis method of optically pure (R)/(S)-chloroquine |
| CN107922404A (en) * | 2015-06-30 | 2018-04-17 | 艾格集团国际公司 | Chloroquine and clemizole compound are used for the purposes for treating inflammation and cancer |
-
2020
- 2020-03-06 CN CN202010150710.8A patent/CN113354581B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004660A2 (en) * | 2002-07-09 | 2004-01-15 | Alpha Research Group, L.L.C. | Compositions and methods for the treatment of parkinson’s disease and tardive dyskinesias |
| CN107922404A (en) * | 2015-06-30 | 2018-04-17 | 艾格集团国际公司 | Chloroquine and clemizole compound are used for the purposes for treating inflammation and cancer |
| CN105693605A (en) * | 2016-03-09 | 2016-06-22 | 西安科技大学 | Asymmetric synthesis method of optically pure (R)/(S)-chloroquine |
Non-Patent Citations (3)
| Title |
|---|
| ALEXANDER R. SURREY AND HENRY F. HAMMER: "Some 7-substituted 4-aminoquinoline derivatives", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| J. CYMERMAN CRAIG AND ASLAM M. ANSARI: "Resolution of 7-chloro-4-(4’-diethylamino-1’-methylbutyl)aminoquinoline (chloroquine) into its enantiomers", 《CHIRALITY》 * |
| NATHAN L. DRAKE ET AL.: "Synthetic antimalarials. The preparation and properties of 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline (SN7618)", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591251A (en) * | 2022-02-14 | 2022-06-07 | 华南理工大学 | Chiral aminoquinazoline compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113354581B (en) | 2023-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113354581B (en) | Preparation method and application of chiral chloroquine and phosphate thereof | |
| CN103288801A (en) | Preparation method for high-purity esomeprazole sodium | |
| CN111233689A (en) | 13Purification method and preparation method of C-methaoxetine | |
| CN113350343A (en) | Application of dextro-chiral chloroquine phosphate in preparing medicine for treating coronavirus | |
| CN102558170B (en) | Method for preparing optically pure cis apovincaminic acid ester | |
| EP0036265B1 (en) | Method of optical resolution of (+/-)-2-amino-1-butanol and/or (+/-) -mandelic acid | |
| WO2007080470A2 (en) | A method for the purification of levetiracetam | |
| CN111056939B (en) | Preparation method of (1R,3S) -3-aminocyclopentanol and intermediate thereof | |
| CN114163411A (en) | Preparation method of enantiomer pure dihydromyricetin | |
| US5510520A (en) | Optical resolution method | |
| US4111980A (en) | Process for preparing optically active phenyl glycine | |
| JP2007332050A (en) | Manufacturing method of optically active n-tert-butylcarbamoyl-l-tert-leucine | |
| CN110590602A (en) | Resolution refining method of racemic citalopram diol | |
| JP2830364B2 (en) | Method for producing optically active 1-benzyl-3-hydroxypyrrolidine | |
| JP4104319B2 (en) | Process for producing optically active 2-hydroxy-3-nitropropionic acid | |
| JP2884703B2 (en) | Method for producing optically active 2-methylpiperazine | |
| JPH037272A (en) | Production of optically active tetrahydro-2-furoic acid | |
| US2766286A (en) | Process for the resolution of racemic threo-1-phenyl-2-amino-1. 3-propanediol | |
| CN115043835B (en) | Method for refining and purifying valcigua | |
| JPH05279325A (en) | Production of optically active 3-hydroxypyrolidine | |
| WO1993013087A1 (en) | A PROCESS FOR THE RESOLUTION OF (+-)-α-[2-[ACETYL(1-METHYLETHYL)AMINO]ETHYL]-α-(2-CHLOROPHENYL)-1-PIPERIDINEBUTANAMIDE | |
| CN106496191B (en) | A kind of preparation method of S-pantoprazole sodium | |
| CN109384814B (en) | Purification method of novel tenofovir prodrug | |
| JP2576598B2 (en) | Process for producing optically active 1-methyl-3-phenylpropylamine | |
| JP3959798B2 (en) | Method for optical resolution of 1- (3-methoxyphenyl) ethylamine |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |