阅读说明：本技术 硫酸羟氯喹的制备方法 (Preparation method of hydroxychloroquine sulfate ) 是由 苗得足 高峰 陈雪亮 孙兆柱 李卫 聂爱华 于 2020-05-19 设计创作，主要内容包括：本发明涉及一种硫酸羟氯喹的制备方法,属于药物合成技术领域。本发明所述的硫酸羟氯喹的制备方法,以7-氯-4-氟喹啉与5-(N-乙基-N-2-羟乙基胺)-2-戊胺进行反应制得羟氯喹,然后由羟氯喹与硫酸成盐制得所述的硫酸羟氯喹。所述的7-氯-4-氟喹啉由4,7-二氯喹啉经卤交换反应制得。本发明所述的硫酸羟氯喹的制备方法,其反应温度较低、反应时间较短、副产物较少,工艺简单且重现性好,利于工业化生产。(The invention relates to a preparation method of hydroxychloroquine sulfate, belonging to the technical field of drug synthesis. The preparation method of hydroxychloroquine sulfate comprises the steps of reacting 7-chloro-4-fluoroquinoline with 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to prepare hydroxychloroquine, and salifying hydroxychloroquine and sulfuric acid to prepare the hydroxychloroquine sulfate. The 7-chloro-4-fluoroquinoline is prepared by carrying out halogen exchange reaction on 4, 7-dichloroquinoline. The preparation method of hydroxychloroquine sulfate has the advantages of low reaction temperature, short reaction time, fewer byproducts, simple process, good reproducibility and contribution to industrial production.)

1. The preparation method of hydroxychloroquine sulfate is characterized by comprising the steps of salifying hydroxychloroquine and sulfuric acid, and is characterized in that: the hydroxychloroquine is prepared by the reaction of 7-chloro-4-fluoroquinoline and 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine.

2. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: the 7-chloro-4-fluoroquinoline is prepared by carrying out halogen exchange reaction on 4, 7-dichloroquinoline.

3. The method for producing hydroxychloroquine sulfate according to claim 2, wherein:

the method comprises the steps of taking 4, 7-dichloroquinoline as a starting material to carry out halogen exchange reaction to prepare 7-chloro-4-fluoroquinoline, separating and purifying to obtain 7-chloro-4-fluoroquinoline, reacting with 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to prepare hydroxychloroquine, and salifying the prepared hydroxychloroquine and sulfuric acid to obtain hydroxychloroquine sulfate;

or the method comprises the steps of taking 4, 7-dichloroquinoline as a starting material to carry out halogen exchange reaction to prepare 7-chloro-4-fluoroquinoline, adding 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to react with the 7-chloro-4-fluoroquinoline in the reaction solution to prepare hydroxychloroquine, and salifying the hydroxychloroquine and sulfuric acid to obtain hydroxychloroquine sulfate.

4. The method for producing hydroxychloroquine sulfate according to claim 3, wherein: a method for separating and purifying 7-chloro-4-fluoroquinoline comprises the steps of performing suction filtration on reaction liquid after 4, 7-dichloroquinoline halogen exchange reaction is finished, performing reduced pressure concentration, pulping, performing suction filtration, and drying to obtain the 7-chloro-4-fluoroquinoline.

5. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: the 7-chloro-4-fluoroquinoline is prepared by carrying out halogen exchange reaction on 4, 7-dichloroquinoline and fluorine salt in the presence of a catalyst;

wherein:

the fluorine salt is one or more of potassium fluoride, sodium fluoride or cesium fluoride;

the catalyst is one or more of cetyl trimethyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride or PEG 200-1000;

in the halogen exchange reaction, the mol ratio of the 4, 7-dichloroquinoline to the villaumite to the catalyst is 1:1-3: 0.01-0.1;

in the halogen exchange reaction, the used solvent is one or more of DMF, DMSO or acetonitrile;

the temperature of the halogen exchange reaction is 60-115 ℃.

6. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: the reaction temperature for preparing the hydroxychloroquine by the 7-chloro-4-fluoroquinoline and the 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 60-115 ℃.

7. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: the molar ratio of 7-chloro-4-fluoroquinoline to 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 1: 1.0-1.5.

8. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: after the reaction of 7-chloro-4-fluoroquinoline and 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine is finished, cooling to be not higher than 30 ℃, adding a poor solvent of hydroxychloroquine, adjusting the pH to be not lower than 9, and crystallizing to obtain a hydroxychloroquine crude product; the poor solvent is water.

9. The method for producing hydroxychloroquine sulfate according to claim 8, wherein: the purification process of the crude hydroxychloroquine product is as follows:

the purification comprises the steps of adding n-heptane into the crude hydroxychloroquine, heating to reflux, pulping, cooling to 0-10 ℃, preserving heat, crystallizing, filtering and drying to obtain the purified hydroxychloroquine.

10. The method for producing hydroxychloroquine sulfate according to claim 1, wherein: the salification of hydroxychloroquine with sulfuric acid is as follows:

adding hydroxychloroquine into water, dropwise adding sulfuric acid to dissolve, heating to 30-40 deg.C to dissolve, decolorizing, vacuum filtering, dropwise adding ethanol into the filtrate, cooling to 0-10 deg.C, vacuum filtering, and drying the filter cake to obtain hydroxychloroquine sulfate.

Technical Field

The invention relates to a preparation method of hydroxychloroquine sulfate, belonging to the technical field of drug synthesis.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Hydroxychloroquine sulfate (CAS number 747-36-4, structure shown as the following formula) is an antimalarial drug, and also has anti-inflammatory, immunoregulation and anticoagulation effects, and at present, hydroxychloroquine is mainly used for treating rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus and systemic lupus erythematosus in clinic.

The inventor finds that the current synthetic routes aiming at the hydroxychloroquine sulfate mainly comprise the following several routes

Chinese patent CN102050781B discloses that 4, 7-dichloroquinoline and hydroxychloroquine side chain are condensed in an organic solvent by heating and heating to evaporate the solvent to obtain a crude hydroxychloroquine product, and then the crude hydroxychloroquine product is subjected to a salt-forming reaction with sulfuric acid to prepare hydroxychloroquine sulfate, wherein the reaction route is as follows:

however, the preparation method requires that the temperature is raised to 120-150 ℃ within 7-12 hours, and the reaction is carried out at the temperature for 13-18 hours, a higher reaction temperature is required, the temperature raising process and the reaction time are both too long, the energy consumption is high, the yield in unit time is reduced, the industrial production is not facilitated, and the long-time reaction not only increases the production cost, but also increases the content and the quantity of impurities.

Chinese patent CN104230803B discloses hydroxychloroquine sulfate prepared by performing condensation reaction of 4, 7-dichloroquinoline and hydroxychloroquine side chain in an acetate solvent under the action of a sodium alkoxide catalyst, then alkalifying, extracting and crystallizing with the acetate solvent to obtain hydroxychloroquine, and salifying hydroxychloroquine and sulfuric acid in a mixed solvent system containing water and alcohols, wherein the reaction route is as follows:

however, in the method, under a high temperature condition, sodium alkoxide and 4, 7-dichloroquinoline undergo nucleophilic substitution reaction to generate an ether product, which is not easy to remove and can affect the purification of hydroxychloroquine free alkali, and alcoholic hydroxyl on a side chain can form hydroxyl anions in the presence of sodium alkoxide to generate a byproduct with 4, 7-dichloroquinoline, which further causes purification difficulty.

Chinese patent CN108689929A discloses a preparation method of hydroxychloroquine and sulfate thereof. The preparation method of the hydroxychloroquine comprises the following steps: under the protection of inert gas, 4, 7-dichloroquinoline reacts with a hydroxychloroquine side chain compound at 134-144 ℃ until the content of the 4, 7-dichloroquinoline is less than or equal to 10 percent, and a crude product of the hydroxychloroquine is obtained; the hydroxychloroquine content in the hydroxychloroquine crude product is more than 92 percent; recrystallizing the prepared crude hydroxychloroquine product in a mixed solvent of an alcohol solvent and an ester solvent to obtain a refined hydroxychloroquine product; in a solvent, carrying out salt-forming reaction on a sulfuric acid aqueous solution and a hydroxychloroquine refined product to obtain the hydroxychloroquine sulfate. However, this method requires a high reaction temperature and a long reaction time, and the long reaction time not only increases the production cost, but also increases the content and amount of impurities, which is not suitable for industrial production.

Chinese patent CN109456266A discloses a preparation method of hydroxychloroquine sulfate, which takes mother nucleus 4, 7-dichloroquinoline as an initial raw material, performs condensation reaction with hydroxychloroquine side chain 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine in the presence of a catalyst (self-made fluoride salt loaded by alumina) to obtain hydroxychloroquine free alkali, and salifies with sulfuric acid to obtain hydroxychloroquine sulfate; the reaction route is as follows:

however, the method has the disadvantages that the time of the whole preparation process is too long, the energy consumption is high, the yield in unit time is reduced, and the content and the amount of impurities are increased due to long-time reaction, so that the method is not favorable for industrial production.

Disclosure of Invention

The invention aims to provide a preparation method of hydroxychloroquine sulfate, which has the advantages of lower reaction temperature, shorter reaction time, fewer byproducts, simple process, good reproducibility and contribution to industrial production.

The preparation method of hydroxychloroquine sulfate comprises the steps of reacting 7-chloro-4-fluoroquinoline with 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to prepare hydroxychloroquine, and salifying hydroxychloroquine and sulfuric acid to prepare the hydroxychloroquine sulfate.

Preferably, the 7-chloro-4-fluoroquinoline is prepared from 4, 7-dichloroquinoline by a halogen exchange reaction.

Preferably, 7-chloro-4-fluoroquinoline is prepared by halogen exchange reaction of 4, 7-dichloroquinoline with fluorine salt in the presence of a catalyst.

In the preparation process, there are two implementation modes:

one method is to use 4, 7-dichloroquinoline as the starting material to carry out halogen exchange reaction to prepare 7-chloro-4-fluoroquinoline, separate and purify to obtain 7-chloro-4-fluoroquinoline and react with 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to prepare hydroxychloroquine, and salify the prepared hydroxychloroquine and sulfuric acid to obtain hydroxychloroquine sulfate;

a method for preparing hydroxychloroquine sulfate by using 4, 7-dichloroquinoline as a starting material to perform halogen exchange reaction to obtain 7-chloro-4-fluoroquinoline, adding 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentylamine to react with 7-chloro-4-fluoroquinoline in a reaction solution to obtain hydroxychloroquine, and salifying the hydroxychloroquine and sulfuric acid to obtain the hydroxychloroquine sulfate.

In one of the two modes, the prepared 7-chloro-4-fluoroquinoline needs to be separated and purified, and in the other mode, 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is directly added into the reaction liquid without being separated and purified and reacts with the 7-chloro-4-fluoroquinoline in the reaction liquid.

Preferably, the fluorine salt is one or more of potassium fluoride, sodium fluoride, and cesium fluoride, and more preferably potassium fluoride or cesium fluoride, the halogen exchange reaction is more effective.

Preferably, the catalyst is one or more of cetyltrimethylammonium bromide (CTMAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBAC) or PEG200-1000, and further preferably cetyltrimethylammonium bromide or tetrabutylammonium fluoride.

Preferably, in the halogen exchange reaction, the molar ratio of 4, 7-dichloroquinoline, the fluorine salt and the catalyst is 1:1 to 3:0.01 to 0.1, more preferably 1:2: 0.03.

Preferably, the temperature of the halogen exchange reaction is 60 to 115 ℃, more preferably 80 to 110 ℃, and still more preferably 80 to 100 ℃. At the reaction temperature, the selectivity is better, the by-products are less, and particularly, the selectivity is better in the range of 80-100 ℃ and the by-products are less.

Preferably, in the halogen exchange reaction, the solvent used is one or more of DMF, DMSO or acetonitrile. Further, DMF or acetonitrile is preferable, and the solvent has less by-products and less influence on the subsequent reaction, and particularly, when the solvent is acetonitrile, DMF or acetonitrile is preferable.

Preferably, the reaction temperature for preparing hydroxychloroquine from 7-chloro-4-fluoroquinoline and 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is 60 to 115 ℃, more preferably 80 to 110 ℃, and still more preferably 80 to 100 ℃. At the reaction temperatures according to the invention, fewer by-products are produced, in particular fewer by-products in the range from 80 to 100 ℃.

Preferably, the molar ratio of 4, 7-dichloroquinoline to 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is from 1:1.0 to 1.5, preferably 1: 1.25.

preferably, the molar ratio of 7-chloro-4-fluoroquinoline to 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is from 1:1.0 to 1.5, more preferably from 1:1.3 to 1.5.

Preferably, after the reaction of 7-chloro-4-fluoroquinoline and 5- (N-ethyl-N-2-hydroxyethylamine) -2-pentylamine is finished, cooling to a temperature of not higher than 30 ℃, preferably 0-30 ℃, adding a poor solvent of hydroxychloroquine, adjusting the pH to be not lower than 9, and crystallizing to obtain a crude hydroxychloroquine product; the poor solvent is water.

The preparation method also comprises a process of purifying the hydroxychloroquine crude product, which comprises the following steps:

the purification comprises the steps of adding n-heptane into the crude hydroxychloroquine, heating to reflux, pulping, cooling to 0-10 ℃, preserving heat, crystallizing, filtering and drying to obtain the purified hydroxychloroquine.

A method for separating and purifying 7-chloro-4-fluoroquinoline comprises the steps of performing suction filtration on reaction liquid after 4, 7-dichloroquinoline halogen exchange reaction is finished, performing reduced pressure concentration, pulping, performing suction filtration, and drying to obtain the 7-chloro-4-fluoroquinoline.

The method for obtaining hydroxychloroquine sulfate by salifying hydroxychloroquine and sulfuric acid can adopt a conventional method in the field, or, preferably, comprises the following steps: adding hydroxychloroquine into water, dropwise adding sulfuric acid to dissolve, heating to 30-40 deg.C to dissolve, decolorizing, vacuum filtering, dropwise adding ethanol into the filtrate, slowly cooling to 0-10 deg.C, vacuum filtering, and drying the filter cake to obtain hydroxychloroquine sulfate.

Compared with the prior art, the invention has the following beneficial effects:

(1) the preparation method has simple process and good reproducibility;

(2) the preparation method has the advantages that the reaction temperature is low, the highest temperature is not more than 115 ℃, the reaction time is short, and the reaction time for preparing the hydroxychloroquine from the 4, 7-dichloroquinoline is not more than 5 hours;

(3) the preparation method has low energy consumption in the whole preparation process, reduces the production cost, has fewer byproducts (the purity of the hydroxychloroquine is more than 99.7 percent, the yield is more than 80 percent and can reach 85.7 percent to the maximum, the single impurity is not more than 0.09 percent, the purity of the hydroxychloroquine sulfate is more than 99.9 percent, the yield of the hydroxychloroquine sulfate is more than 94.5 percent, and the single impurity is not more than 0.06 percent) and is beneficial to industrial production.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to limit the practice of the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.