CN111675653A - Preparation method and application of impurities of 4-aminoquinoline compound - Google Patents
Preparation method and application of impurities of 4-aminoquinoline compound Download PDFInfo
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- CN111675653A CN111675653A CN202010600557.4A CN202010600557A CN111675653A CN 111675653 A CN111675653 A CN 111675653A CN 202010600557 A CN202010600557 A CN 202010600557A CN 111675653 A CN111675653 A CN 111675653A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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Abstract
A method for preparing impurities of 4-aminoquinoline compounds and application thereof. The invention discloses a preparation method of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer), which is characterized in that 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is separated from a mixture 1 containing 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid by a liquid phase method. Preferably, the mixture 1 is prepared by reacting m-chloroanilino diethyl methylene malonate (LKL-3) in mineral oil and concentrated sulfuric acid, performing post-treatment after the reaction is finished to obtain a mixture 2, and hydrolyzing the mixture 2 under an alkaline condition and performing post-treatment to obtain the mixture 1. The purity of the 5-chloro-4-hydroxy-3-quinoline carboxylic acid is more than 99 percent, preferably more than 99.5 percent, and the 5-chloro-4-hydroxy-3-quinoline carboxylic acid and the subsequent product can be used for impurity reference substances of 4-aminoquinoline compounds and quality control of related raw material medicaments.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method and application of impurities of 4-aminoquinoline compounds, wherein the impurities comprise 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 5-chloro-4-hydroxy-3-quinolinecarboxylic acid, 5-chloro-4-hydroxyquinoline, 4, 5-dichloroquinoline and the like.
Background
The 4, 7-dichloroquinoline is a key intermediate for preparing 4-aminoquinoline compounds such as hydroxychloroquine (Hydroxy Chloroquine), Chloroquine (Chloroquine), Amodiaquine (Amodiaquine), Glafenine (Glafenane) and the like and pharmaceutically acceptable salts thereof, wherein the structural formulas of the hydroxychloroquine (Hydroxy Chloroquine), Chloroquine (Chloroquine), Amodiaquine (Amodiaquine) and Glafenine (Glafenane) are respectively shown as a formula I, a formula II, a formula III and a formula IV. In the prior art, a synthetic route of 4, 7-dichloroquinoline uses chloraniline (LKL-1) and ethoxy diethyl methylene malonate (LKL-2) as reactants to obtain diethyl chloranilino methylene malonate (LKL-3) through substitution, 7-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (LKL-4) is prepared through cyclization, meanwhile, byproducts of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (LKL-4 isomer) are generated, and then the byproducts are converted into 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer), 5-chloro-4-hydroxyquinoline (LKL-6 isomer) and 4, 5-dichloroquinoline (LKL-7 isomer), and then generating corresponding compounds or isomers of pharmaceutically acceptable salts thereof, wherein the isomer structural formulas of hydroxychloroquine isomer, chloroquine isomer, amodiaquine isomer and glafenine are respectively shown as formula A, formula B, formula C and formula D. The impurities are also potential impurities of corresponding compounds, so that the preparation of the impurities with high purity serving as impurity reference substances has important significance on the development and quality control of products.
Patent CN109928925A discloses a sublimation purification method of 4, 7-dichloroquinoline, which adopts a sublimation method to remove 4, 5-dichloroquinoline in a crude product of 4, 7-dichloroquinoline to prepare high-purity 4, 7-dichloroquinoline.
In the prior art, 5-chloro-4-hydroxy-3-quinolinecarboxylic acid, 5-chloro-4-hydroxyquinoline and 4, 5-dichloroquinoline with high purity are not reported, and the LKL-4 isomer in LKL-4 is generally not more than 10% because the LKL-4 is synthesized by LKL-3 with a small proportion of side reaction to generate the LKL-4 isomer. Because the physical and chemical properties of the LKL-4 isomer are very similar to those of LKL-4, and LKL-4 is good in solubility only in DMF or DMSO, is difficult to dissolve in methanol, dichloromethane or ethyl acetate and has a certain solubility in water, recrystallization by using a solvent with a difference in solubility between the LKL-4 isomer and the LKL-4 isomer is difficult to obtain the high-purity LKL-4 isomer, and similarly, a high-purity LKL-5 pure product is difficult to obtain by a solvent recrystallization method. The development of high-purity 5-chloro-4-hydroxy-3-quinoline carboxylic acid and the quality research of subsequent products which can be used as related compounds and pharmaceutically acceptable salts thereof provide guarantee for the safe medication of related raw material medicaments.
Disclosure of Invention
The invention provides a preparation method of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer), which is characterized in that 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is separated from a mixture 1 containing 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid by a liquid phase method.
Preferably, the conditions of the liquid phase process are: the chromatographic column is a C18 column and adopts isocratic elution, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), and the volume ratio of acetonitrile to phosphate aqueous solution is 1: 1-9, preferably 3: 7; the flow rate is 30 ml/min-80 ml/min, preferably 50 ml/min-70 ml/min, and more preferably 65 ml/min; the column temperature is 10-40 ℃, preferably 35 ℃, the sample injection concentration of the sample is 0.1-200 mg/ml, preferably 10-200 mg/ml, more preferably 100-150 mg/ml, the sample injection amount is 0.1-10 ml, preferably 3-10 ml, more preferably 5-8 ml, and the mixture 1 is prepared into the sample by using dimethyl sulfoxide.
Preferably, the purity of the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid in the mixture 1 is 5% -95%;
preferably, the mixture 1 is prepared by hydrolyzing the mixture 2 containing 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester under alkaline conditions and post-treating to obtain a mixture 1; the purity of the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester in the mixture 2 is 5-95%.
Preferably, the preparation method of the mixture 2 is that the m-chloroanilino methylene diethyl malonate (LKL-3) reacts in mineral oil under the condition of concentrated sulfuric acid, and after the reaction is finished, the mixture 2 is obtained through post-treatment;
preferably, the mineral oil is paraffin oil;
the reaction temperature is 80-110 ℃, preferably 100 ℃, the reaction time is 1-3 hours, preferably 2 hours, the post-treatment is cooling to 20-30 ℃ after the reaction is finished, filtering, and washing to obtain a mixture 2; preferably, the washing is sequentially carried out by water, chloroform and ethanol;
wherein the mass volume ratio of the m-chloroanilino methylene malonic acid diethyl ester to the mineral oil is 1: 3-8, preferably 1: 3-5;
wherein the molar ratio of the m-chloroanilino methylene malonic acid diethyl ester to the concentrated sulfuric acid is 1: 2-5, preferably 1: 2.5-3.5, and more preferably 1: 3.
Preferably, the preparation method of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer) provided by the invention is characterized by comprising the following steps:
1) reacting diethyl m-chloroanilino methylene malonate (LKL-3) in mineral oil and concentrated sulfuric acid, and performing post-treatment after the reaction to obtain a mixture 2;
2) hydrolyzing the mixture 2 under an alkaline condition, and carrying out post-treatment to obtain a mixture 1;
3) separating the mixture 1 by a liquid phase method to obtain 5-chloro-4-hydroxy-3-quinoline carboxylic acid;
wherein the mixture 1 contains 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid, and the purity of the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is 5% -95%;
wherein the mixture 2 contains 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, and the purity of the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester is 5% -95%;
wherein the mass-volume ratio of the intermediate chloroanilino diethyl methylene malonate to the mineral oil in the step 1) is 1: 3-8, preferably 1: 3-5; the molar ratio of the m-chloroanilino methylene diethyl malonate to the concentrated sulfuric acid is 1: 2-5, preferably 1: 2.5-3.5, and more preferably 1: 3; preferably, the mineral oil is paraffin oil;
wherein the reaction temperature in the step 1) is 80-110 ℃, preferably 100 ℃, and the reaction time is 1-3 hours, preferably 2 hours;
wherein the post-treatment in the step 1) is cooling to 20-30 ℃ after the reaction is finished, filtering, and washing to obtain a mixture 2; preferably, the washing is sequentially carried out by water, chloroform and ethanol;
after washing in the step 1), continuously performing suction filtration to obtain a mixture 2;
wherein the alkaline condition in the step 2) is an inorganic alkaline aqueous solution, preferably an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution, wherein the mass fraction of the inorganic alkaline aqueous solution is 5-40%, preferably 10-30%, and more preferably 25%;
wherein the reaction temperature in the step 2) is 20-40 ℃, preferably 20-30 ℃, and the reaction time is 1-3 hours, preferably 2 hours;
wherein the post-treatment in the step 2) comprises filtering, washing and drying after the reaction is finished, wherein the washing is preferably ethanol washing;
wherein the conditions of the liquid phase process described in step 3) are: the chromatographic column is a C18 column and adopts isocratic elution, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), and the volume ratio of acetonitrile to phosphate aqueous solution is 1: 1-9, preferably 3: 7; the flow rate is 30 ml/min-80 ml/min, preferably 50 ml/min-70 ml/min, and more preferably 65 ml/min; the column temperature is 10-40 ℃, preferably 35 ℃, the sample injection concentration of the sample is 0.1-200 mg/ml, preferably 10-200 mg/ml, more preferably 100-150 mg/ml, the sample injection amount is 0.1-10 ml, preferably 3-10 ml, more preferably 5-8 ml, and the mixture 1 is prepared into the sample by using dimethyl sulfoxide.
The LKL-6 isomer and the LKL-7 isomer are prepared by using the LKL-5 isomer prepared by the method and referring to the conditions of patent CN103626699A example 1, wherein the purity of the LKL-6 isomer and the purity of the LKL-7 isomer are respectively 99.2% and 99.3%; by referring to the conditions of the patent CN110283121A example, hydroxychloroquine isomers and chloroquine isomers are prepared, and the purity is 99.5 percent and 99.6 percent respectively; with reference to the conditions of patent CN105503718A example 1, amodiaquine isomer with the purity of 99.1% is prepared; reference to "Yang Xiao et al. Synthesis of glatiramer [ J ]. proceedings of Chinese university of pharmacy 1987(01): 48-50." preparation of glatiramer isomer by phthalic anhydride method, purity 99.2%.
The purity of the LKL-5 isomer prepared by the invention is more than 99%, preferably more than 99.5%, and the LKL-5 isomer prepared by the invention can be used for preparing isomers of 5-chloro-4-hydroxyquinoline (LKL-6 isomer), 4, 5-dichloroquinoline (LKL-7 isomer), hydroxychloroquine isomer, chloroquine isomer, amodiaquine isomer, glafenine and pharmaceutically acceptable salts thereof; the substance can be used for impurity reference substances of 4-aminoquinoline compounds, preferably for impurity reference substances of hydroxychloroquine, chloroquine, amodiaquine, glafenine and pharmaceutically acceptable salts thereof.
The invention provides high-purity 5-chloro-4-hydroxy-3-quinoline carboxylic acid, the purity of which is more than 99 percent, preferably more than 99.5 percent and can be used for synthesizing subsequent products, and the 5-chloro-4-hydroxy-3-quinoline carboxylic acid and the synthesized subsequent products can be used for impurity reference substances of 4-aminoquinoline compounds and quality control of related raw material medicines.
Drawings
FIG. 1 HPLC purity profile of LKL-5 isomer in example 2;
FIG. 2 NMR spectrum of LKL-5 isomer in example 2 (DMSO-d 6).
Detailed Description
Mixture 2 (containing ethyl 5-chloro-4-hydroxy-3-quinolinecarboxylate and ethyl 7-chloro-4-hydroxy-3-quinolinecarboxylate) can be prepared by the method disclosed in prior art CN1847226A, and mixture 1 (containing 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid) is obtained by hydrolysis, wherein the purity of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid in mixture 1 is 8% -10%.
Example 1
Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)
3g of the mixture 1 (8.5% purity of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid) was dissolved in dimethyl sulfoxide to prepare a solution having a concentration of 150mg/ml, and the solution was separated by liquid preparative chromatography under the following conditions:
the chromatographic column is a C18 column, and isocratic elution is adopted, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), the volume ratio of acetonitrile to phosphate aqueous solution is 1:4, the flow rate is 30ml/min, the column temperature is 30 ℃, and the sample injection amount is 3 ml. Eluting and collecting the 5-chloro-4-hydroxy-3-quinoline carboxylic acid with the purity of 99.21 percent.
Example 2
Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)
Mixing and stirring 3g (0.01 mol) of LKL-3 and 10ml of paraffin oil, adding 2.94g (0.03 mol) of concentrated sulfuric acid at 20-30 ℃ at one time, continuously stirring, heating to 100 ℃ and reacting for 2 hours. Cooling to 20-30 ℃, performing vacuum filtration to obtain a brown yellow solid, washing the filter cake with 10ml of water, 10ml of chloroform and 10ml of ethanol in sequence, and performing vacuum filtration for 10min to obtain a white-like solid mixture 2 (the purity of LKL-4 isomer is 70.4%). The LKL-4 isomer was directly mixed with 10ml of 25% aqueous sodium hydroxide solution, stirred at 20 to 30 ℃ for 2 hours, the reaction solution was filtered under reduced pressure and washed with 5ml of ethanol, and dried to obtain an off-white solid mixture 1 (LKL-5 isomer purity 75.3%). Dissolving the mixture 1 by using dimethyl sulfoxide to prepare a solution with the concentration of 120mg/ml, and separating by adopting liquid phase preparative chromatography, wherein the chromatographic conditions are as follows:
the chromatographic column is a C18 column and adopts isocratic elution, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), and the volume ratio of acetonitrile to phosphate aqueous solution is 3: 7; the flow rate is 65 ml/min; the column temperature is 35 ℃, the sample amount is 5ml, and the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is eluted, collected, concentrated and dried, the purity is 99.89%, the yield is 64.5% (calculated by LKL-3), and the mass spectrum and hydrogen spectrum data are as follows:
ESI-MS（m/z）:224.0[M+H]+
1H NMR（400MHz，DMSO-d6）15.3068（s,1H,COOH）,13.5(s,1H,OH),8.8734（s,1H,ArH），7.7715~7.8102（d,1H,ArH），7.7439~7.7649（d,1H,ArH），7.5841~7.6062（dd,1H,ArH）。
example 3
Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)
3g (0.01 mol) of LKL-3 and 18ml of paraffin oil are mixed and stirred, 4.45g (0.045 mol) of concentrated sulfuric acid is added at 20-30 ℃ at one time, and the mixture is continuously stirred and heated to 90 ℃ for reaction for 2.5 h. Cooling to 20-30 ℃, performing vacuum filtration to obtain a brown yellow solid, washing the filter cake with 10ml of water, 10ml of chloroform and 10ml of ethanol in sequence, and performing vacuum filtration for 10min to obtain a white-like solid mixture 2 (the purity of LKL-4 isomer is 72.2%). Directly mixing the LKL-4 isomer with 10ml of 30% potassium hydroxide aqueous solution, stirring at 20-30 ℃ for 2h, filtering the reaction solution under reduced pressure, washing with 5ml of ethanol, and drying to obtain an off-white solid mixture 1 (the purity of the LKL-5 isomer is 76.1%). Dissolving the mixture 1 by using dimethyl sulfoxide to prepare a solution with the concentration of 150mg/ml, and separating by adopting liquid phase preparative chromatography, wherein the chromatographic conditions are as follows:
the chromatographic column is a C18 column and adopts isocratic elution, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), and the volume ratio of acetonitrile to phosphate aqueous solution is 1: 4; the flow rate is 75 ml/min; the column temperature is 25 ℃, the sample amount is 3ml, the 5-chloro-4-hydroxy-3-quinoline carboxylic acid is obtained by elution, collection, concentration and drying, the purity is 99.73 percent, the yield is 62.8 percent (calculated by LKL-3),
example 4
Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)
3g (0.01 mol) of LKL-3 and 15ml of paraffin oil are mixed and stirred, 1.96g (0.02 mol) of concentrated sulfuric acid is added at 20-30 ℃ at one time, and the mixture is continuously stirred and heated to 90 ℃ to react for 2.5 hours. Cooling to 20-30 ℃, performing suction filtration under reduced pressure to obtain a brown yellow solid, washing a filter cake by using 15ml of water, 15ml of chloroform and 15ml of ethanol in sequence, and performing suction filtration for 10min to obtain a white-like solid mixture 2 (the purity of LKL-4 isomer is 74.5%). The above LKL-4 isomer was directly mixed with 20ml of a 15% aqueous solution of potassium hydroxide, stirred at 40 ℃ for 2h, the reaction solution was filtered under reduced pressure and washed with 5ml of ethanol, and dried to give an off-white solid mixture 1 (LKL-5 isomer purity 72.9%). Dissolving the mixture 1 by using dimethyl sulfoxide to prepare a solution with the concentration of 100mg/ml, and separating by adopting liquid phase preparative chromatography, wherein the chromatographic conditions are as follows:
the chromatographic column is a C18 column and adopts isocratic elution, wherein the mobile phase is acetonitrile-phosphate aqueous solution (pH = 4.5), and the volume ratio of acetonitrile to phosphate aqueous solution is 1: 6; the flow rate is 50 ml/min; the column temperature is 30 ℃, the sample amount is 8ml, and the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is obtained by elution, collection, concentration and drying, the purity is 99.51%, and the yield is 59.9% (calculated by LKL-3).
Claims (10)
1. A process for the preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid, characterized in that it is obtained by separation from a mixture 1 comprising 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid by the liquid phase method.
2. The process of claim 1, wherein the liquid phase process conditions are: the chromatographic column is a C18 column, isocratic elution is adopted, wherein the mobile phase is acetonitrile-phosphate aqueous solution with pH =4.5, the volume ratio of acetonitrile to phosphate aqueous solution is 1: 1-9, and the flow rate is 30 ml/min-80 ml/min; the column temperature is 10-40 ℃; the sample injection concentration of the test sample is 0.1-200 mg/ml; the sample injection amount is 0.1-10 ml; wherein the mixture 1 is prepared into a test sample by adopting dimethyl sulfoxide.
3. The process of claim 1, wherein the mixture 1 comprises 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and 7-chloro-4-hydroxy-3-quinolinecarboxylic acid, and the purity of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is 5% to 95%.
4. The process according to claim 1, wherein the mixture 1 is prepared by hydrolysis under basic conditions using a mixture 2 comprising ethyl 5-chloro-4-hydroxy-3-quinolinecarboxylate and ethyl 7-chloro-4-hydroxy-3-quinolinecarboxylate, followed by work-up to obtain a mixture 1.
5. The method according to claim 4, wherein the mixture 2 is prepared by reacting diethyl m-chloroanilino methylenemalonate (LKL-3) in mineral oil under concentrated sulfuric acid, and performing post-treatment after the reaction to obtain the mixture 2.
6. Use of 5-chloro-4-hydroxyquinoline prepared by the method of any one of claims 1 to 5 as a control for impurities.
7. Use according to claim 6, characterized by an impurity control for 4-aminoquinolines.
8. A process for the preparation of any one of the compounds selected from the group consisting of 5-chloro-4-hydroxyquinoline, 4, 5-dichloroquinoline, hydroxychloroquine isomers, chloroquine isomers, amodiaquine isomers, glafenine isomers and pharmaceutically acceptable salts thereof, characterized in that 5-chloro-4-hydroxy 3-quinolinecarboxylic acid prepared by the process of any one of claims 1 to 5 is used as starting reactant.
9. Use of any compound selected from the group consisting of 5-chloro-4-hydroxyquinoline, 4, 5-dichloroquinoline, hydroxychloroquine isomers, chloroquine isomers, amodiaquine isomers, isomers of glafenine and pharmaceutically acceptable salts thereof, prepared by the process of claim 8, as an impurity control.
10. A preparation method of 5-chloro-4-hydroxy-3-quinoline carboxylic acid is characterized in that the method comprises the step of reacting diethyl m-chloroanilino methylene malonate (LKL-3) in mineral oil under the condition of concentrated sulfuric acid.
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Cited By (2)
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| CN114456110A (en) * | 2022-03-02 | 2022-05-10 | 重庆南松凯博生物制药有限公司 | Synthesis method of 7-chloro-4-hydroxyquinoline-3-carboxylic acid |
| CN114994201A (en) * | 2022-05-25 | 2022-09-02 | 江苏恒生检测有限公司 | Method for detecting impurities in quinclorac |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847226A (en) * | 2005-04-05 | 2006-10-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Quinolyl amide derivative and its prepn process and use |
| WO2013138200A1 (en) * | 2012-03-13 | 2013-09-19 | Howard University | Green chemistry synthesis of the malaria drug amodiaquine and analogs thereof |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847226A (en) * | 2005-04-05 | 2006-10-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Quinolyl amide derivative and its prepn process and use |
| WO2013138200A1 (en) * | 2012-03-13 | 2013-09-19 | Howard University | Green chemistry synthesis of the malaria drug amodiaquine and analogs thereof |
Non-Patent Citations (8)
| Title |
|---|
| I. NAGIEL-OSTASZEWSKI 等: "Separation of hydroxyquinolines by high-performance liquid chromatography", 《XENOBIOTICA》 * |
| NITIN G. RATHOD 等: "IDENTIFICATION OF IMPURITIES RELATED TO AMODIAQUINE HYDROCHLORIDE BY USING SOME ANALYTICAL TECHNIUQES", 《WORLD JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
| VAIJANATH G. DONGRE 等: "Investigation of amodiaquine bulk drug impurities by liquid chromatography/ion trap mass spectrometry", 《RAPID COMMUN. MASS SPECTROM.》 * |
| ZHANG ZHOUPENG 等: "High performance liquid chromatographic separation and pH-dependent electrochemical properties of pyrroloquinoline quinone and three closely related isomeric analogs", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| 冯大为 等: "氯哇异构体的分离和鉴别", 《中国医药工业杂志》 * |
| 国家药典委员会: "《中华人民共和国药典 临床用药须知》", 30 April 2011, 中国医药科技出版社 * |
| 国家药典委员会: "《中华人民共和国药典 二部 注释》", 31 October 2019, 中国医药科技出版社 * |
| 方文仅 等: "磷酸氯喹中有关杂质的分析", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456110A (en) * | 2022-03-02 | 2022-05-10 | 重庆南松凯博生物制药有限公司 | Synthesis method of 7-chloro-4-hydroxyquinoline-3-carboxylic acid |
| CN114994201A (en) * | 2022-05-25 | 2022-09-02 | 江苏恒生检测有限公司 | Method for detecting impurities in quinclorac |
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