阅读说明：本技术 一种高纯度高收率的硫酸羟氯喹产业化制备方法 (Industrial preparation method of hydroxychloroquine sulfate with high purity and high yield ) 是由 覃志俊 董雪林 蔡强 胡双龙 李光辉 吴挺强 吉秀球 焦慎超 于 2020-05-29 设计创作，主要内容包括：本发明公开了一种高纯度高收率的硫酸羟氯喹产业化制备方法,所述方法反应条件温和,采用醇类有机溶剂,在80~100℃条件下进行反应,反应温度不大于100℃,无需氮气保护,适合工业化生产,该方法制备得到的羟氯喹收率≥85%,纯度≥99.70%,最大单杂小于0.10%；所制备的羟氯喹可进一步成盐,所制备得到的盐纯度≥99.8%,最大单杂小于0.1%。(The invention discloses a high-purity high-yield hydroxychloroquine sulfate industrial preparation method, which is mild in reaction conditions, adopts an alcohol organic solvent to carry out reaction at the temperature of 80-100 ℃, has the reaction temperature of not more than 100 ℃, does not need nitrogen protection, and is suitable for industrial production, wherein the yield of hydroxychloroquine prepared by the method is not less than 85%, the purity is not less than 99.70%, and the maximum single impurity is less than 0.10%; the prepared hydroxychloroquine can be further salified, the purity of the prepared salt is more than or equal to 99.8 percent, and the maximum single impurity is less than 0.1 percent.)

1. A preparation method of hydroxychloroquine is characterized by comprising the steps of reacting 4, 7-dichloroquinoline and 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine in an alcohol organic solvent at the temperature of 80-100 ℃, and carrying out post-treatment and refining after the reaction is finished to obtain the hydroxychloroquine.

2. The method of claim 1, wherein the 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine, the 4, 7-dichloroquinoline and the alcohol organic solvent are added into a reaction kettle, heated to 80 ℃ to 100 ℃ for reaction, after the reaction is finished, alkaline aqueous solution is added for alkalization, halogenated alkane is added for extraction, the mixture is concentrated to be dry to obtain oily matter, the oily matter is refined by adopting the ester organic solvent, and the hydroxychloroquine is obtained by drying.

3. The method according to claim 2, wherein the molar ratio of 4, 7-dichloroquinoline to 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine is 1: 1.1-1.5.

4. The method according to claim 2, wherein the alcohol organic solvent is selected from one or more of ethylene glycol, methanol, ethanol and isopropanol.

5. The method according to claim 2, wherein the weight ratio of the alcoholic organic solvent to the 4, 7-dichloroquinoline is 1: 2-5.

6. The process according to any one of claims 1 to 5, wherein the reaction temperature is 90 to 100 ℃.

7. The method according to any one of claims 1 to 5, wherein the purification is carried out using an ester-based organic solvent.

8. The method according to claim 7, wherein the ester organic solvent is one or more selected from ethyl acetate, isopropyl formate and butyl acetate.

9. A preparation method of hydroxychloroquine sulfate, which is characterized in that hydroxychloroquine prepared by the method of any one of claims 1 to 5 or 8 is salified with sulfuric acid in an alcohol organic solvent to prepare the hydroxychloroquine sulfate.

10. The method of claim 9, wherein the mass fraction of sulfuric acid is 75% to 90%.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of hydroxychloroquine and a salt thereof, wherein the chemical name of the hydroxychloroquine is 2- [ [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino ] -ethanol.

Background

Hydroxychloroquine sulfate (Hydroxychloroquine sulfate), chemically named 2- [ [4- [ (7-chloro-4-quinolyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure as shown in formula I, hydroxychloroquine as its free baseClinically used for rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus and systemic lupus erythematosus, and skin lesions caused or exacerbated by sunlight, treatment for novel coronavirus pneumonia (coronavirus disease2019, covi-19) is currently being developed.

Patent documents CN102050781B, CN103724261B, CN104230803B, CN108658858A, CN107266323B, CN108689929A, CN109456266A, CN109280029A, CN110283121A, US2546658, CA2561987a1, WO2005062723a2, US5314894, WO2010027150 and the like disclose methods for producing hydroxychloroquine. The reported hydroxychloroquine sulfate is prepared by condensation reaction of 4, 7-dichloroquinoline (formula II) and 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine (formula III) which are used as reactants and further salifying. The condensation reaction has the main problems that the reaction temperature is high, the reaction is mostly carried out at more than 120 ℃, the temperature is too low, the reaction is incomplete, the reaction is carried out at more than 120 ℃, particularly at more than 125 ℃, the deethylation product and nitrogen oxide impurities are obviously increased along with the extension of the reaction time, and the incomplete conversion exists when the reaction time is short.

Patent CN104230803B discloses a method for preparing hydroxychloroquine by heating in stages with sodium alkoxide as catalyst and esters as reaction solvent. The scheme adopts staged heating, namely heating to 110 ℃, then heating to 120-122 ℃, and then reacting at the temperature. When the temperature is lower than 120 ℃, the reaction is incomplete, more than 15% of 4, 7-dichloroquinoline can not be converted, when the temperature is higher than 125 ℃, the content of the deethylation impurities and the nitrogen oxides is obviously increased, and the reaction effect is worse in industrial production. According to the scheme, as the solvent is completely evaporated during high-temperature reaction, the solvent is solvent-free reaction, great risk exists in industrial production, and under the condition of no solvent, as the heat transfer coefficient of the material is low, the edge temperature and the central temperature difference of the reaction kettle are large, the nonuniform material reaction is easily caused, or the incomplete reaction of local materials occurs, or the amount of local impurities is obviously increased, the industrial production is not facilitated, and the stability of quality among batches is difficult to ensure.

In the prior art for preparing hydroxychloroquine, the prepared hydroxychloroquine has low yield or low purity, and the method for preparing the hydroxychloroquine with high purity or high yield or the reaction conditions are harsh, or the operation is complicated, the repeatability is low, and the method is not suitable for industrial production.

Aiming at the problems in the prior art of condensation reaction, the inventor carries out extensive research and develops a condensation reaction process suitable for industrial production, and the process has strong reaction conditions and operation controllability, mild reaction conditions, no more than 100 ℃ of reaction temperature and high product yield and quality reproducibility; the yield of hydroxychloroquine prepared by the process is more than or equal to 85 percent, and the purity is more than or equal to 99.70 percent; furthermore, the hydroxychloroquine can be prepared into salt, preferably, the yield of the hydroxychloroquine sulfate is more than or equal to 90%, and the purity is more than or equal to 99.80%.

Disclosure of Invention

Aiming at the problems in the preparation method of hydroxychloroquine in the prior art, the inventor conducts extensive research, the reaction temperature is too high, the reaction time is long, the impurity amount is greatly increased, the reaction temperature is low, the conversion rate of 4, 7-dichloroquinoline is low, the final product is not easy to refine or has low yield, or the operation is complicated, the conditions are not easy to control, the repeatability is low, and the method is not suitable for industrial production. The inventor unexpectedly finds that the hydroxychloroquine can be prepared with high yield and high purity by adopting an alcohol organic solvent at the temperature of 80-100 ℃, and the adopted method has strong operability and is suitable for industrial production. The reaction formula for preparing the hydroxychloroquine is as follows:

the invention provides a preparation method of hydroxychloroquine, which is characterized by comprising the steps of reacting 4, 7-dichloroquinoline and 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine in an alcohol organic solvent at 80-100 ℃, and obtaining hydroxychloroquine through aftertreatment and refining after the reaction is finished;

wherein the molar ratio of the 4, 7-dichloroquinoline to the 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine is 1: 1.1-1.5, preferably 1: 1.1-1.2;

wherein the alcohol organic solvent is selected from one or more of ethylene glycol, methanol, ethanol and isopropanol, and preferably ethylene glycol;

wherein the weight ratio of the alcohol organic solvent to the 4, 7-dichloroquinoline is 1: 2-5, preferably 1: 3-4;

the post-treatment comprises the steps of alkalifying the reaction liquid by using an alkaline aqueous solution, extracting by using halogenated hydrocarbon after alkalifying, wherein the halogenated hydrocarbon is one or more of dichloromethane, trichloromethane and dichloroethane, the weight ratio of the 4, 7-dichloroquinoline to the halogenated alkane is 1: 2-5, preferably 1: 3-4, and concentrating to be dry after extracting;

wherein the refining is carried out by adopting an ester organic solvent, the ester organic solvent is selected from one or more of ethyl acetate, isopropyl formate and butyl acetate, and ethyl acetate is preferred.

Preferably, the method comprises the steps of adding 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine, 4, 7-dichloroquinoline and an alcohol organic solvent into a reaction kettle, heating to 80-100 ℃ for reaction, adding an alkaline aqueous solution for alkalization after the reaction is finished, adding halogenated alkane for extraction, concentrating to dryness to obtain an oily substance, refining the oily substance by adopting an ester organic solvent, and drying to obtain hydroxychloroquine;

wherein the molar ratio of 4, 7-dichloroquinoline to 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine, the alcoholic organic solvent, the weight ratio of the alcoholic organic solvent to 4, 7-dichloroquinoline, the halogenated hydrocarbon, the weight ratio of 4, 7-dichloroquinoline to the halogenated alkane, and the purification are as described above.

The invention also provides a preparation method of hydroxychloroquine sulfate, which comprises the step of salifying hydroxychloroquine prepared by the method with sulfuric acid in an alcohol organic solvent to prepare the hydroxychloroquine sulfate, wherein the mass fraction of the sulfuric acid is 70-90%, and preferably 90%.

The hydroxychloroquine side chain is a compound shown in a formula III, namely 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine.

The preparation method of hydroxychloroquine provided by the invention has the advantages that the reaction temperature is not more than 100 ℃, nitrogen protection is not needed, the problems of low reaction temperature, low conversion rate, high reaction temperature and obvious increase of nitrogen oxides, deethylation impurities and the like in the prior art are well solved, the yield of hydroxychloroquine obtained by the preparation method is more than or equal to 85%, the purity is more than or equal to 99.70%, the maximum single impurity is less than 0.1%, the reaction condition is easy to control, and the preparation method is suitable for industrial production. The hydroxychloroquine prepared by the method can be further prepared into pharmaceutically usable salts of hydroxychloroquine, preferably phosphate, sulfate and hydrochloride, more preferably sulfate, wherein the purity of the pharmaceutically usable salts of hydroxychloroquine is more than or equal to 99.8 percent, and the maximum single impurity is less than 0.1 percent.

Drawings

FIG. 1 example 3 Hydroxychloroquine purity HPLC chromatogram

FIG. 2 example 6 Hydroxychloroquine sulfate purity HPLC chromatogram

Detailed Description

The method for detecting the purity of the hydroxychloroquine and the salt thereof comprises the following steps:

chromatographic conditions

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: