CN110606830B - Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine - Google Patents
Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine Download PDFInfo
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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
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Abstract
The invention discloses a method for preparing high-purity quinoline piperazine hydrochloride, which has the advantages of simple process, easy purification of products, purity of more than or equal to 99.5 percent, avoidance of toxic reagents, little environmental pollution, low production cost and suitability for industrial production. The invention also discloses a method for producing quinoline piperazine hydrochloride by applying piperazine, which is used for directly applying mother liquor for the next production of quinoline piperazine hydrochloride without separating piperazine from the mother liquor.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synthetic method of an antimalarial piperaquine phosphate intermediate 7-chloro-4- (1-piperazinyl) quinoline (quinoline piperazine for short) and a method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine.
Background
Today, malaria remains as three catastrophic diseases in the world, alongside aids and tuberculosis, with over 90 countries and regions still at the medium and high prevalence level of malaria. According to the statistics of the World Health Organization (WHO), malaria infected people take 3-5 hundred million people every year in the world, the number of dead people exceeds 100 million, and most of the malaria infected people are children under five years of age. In order to enhance the therapeutic effect and slow down the development of drug resistance, the WHO recommended the use of "artemisinin-based Combination Therapy" (ACT) for the treatment of malaria since 2001. Piperaquine phosphate belongs to a synthetic antimalarial drug and is mainly applied to the treatment of malaria with chloroquine resistance. In recent years, the combined application of the artemisinin and the derivatives thereof is increasingly emphasized. The compound preparation dihydroartemisinin piperaquine tablet composed of dihydroartemisinin and piperaquine phosphate not only overcomes the defect of long treatment course of dihydroartemisinin, but also makes up the defect of slow effect of piperaquine, has obvious synergistic effect, and is an excellent medicine for treating various malaria, especially multiple drug resistance malignant malaria.
Although various methods for synthesizing piperaquine have been disclosed in the literature, the synthetic route for preparing piperaquine phosphate by two condensations and then reacting with phosphoric acid has been studied more, and is specifically shown in scheme 1. 2015 latest edition of Chinese pharmacopoeia stipulates quality standards of piperaquine phosphate, but only 3 known impurities are confirmed in related substances stipulated by the quality standards, wherein a single impurity is stipulated to be not more than 0.5%, and the total impurities are stipulated to be not more than 2%. The international mainstream market generally requires that the related substances of the product are less than 0.1 percent, and the limit of the impurities can be determined only by performing pharmacological and toxicological tests on more than 0.1 percent of the impurities. Therefore, the national pharmacopoeia standard of piperaquine phosphate has a large difference with the advanced international standard, and a more advanced process is needed to prepare a high-purity product, so that the international advanced level is reached. In the route, the formula II, namely the quinoline piperazine, is a key intermediate, and the quality of the quinoline piperazine has great influence on the quality of a final product.
Scheme 1:
the main differences in the methods for preparing quinolyl piperazine disclosed in the prior art are the reaction conditions used (i.e., type of solvent, reaction temperature, whether acid-binding agent is added, post-treatment conditions, etc.) and the choice of the piperazine form of the reactant, either anhydrous or hexahydrate, which are not significantly different. Common to most of these syntheses is the difficulty in purifying the key intermediate quinoline piperazine from by-products or excess piperazine, resulting in low quality of the final piperaquine. In fact, the main by-product identified when reacting 4, 7-dichloroquinoline with piperazine is formula II-a, the bis-quinolinepiperazine, also known as acid-insoluble. This by-product has been reported to have some toxicity (singht, et al, j.med. hem, 1971,14,4, 283).
Furthermore, the synthesis of large amounts of the existing compounds of formula II requires elevated reaction mixture temperatures, and/or toxic solvents, and/or cumbersome extraction procedures, and/or highly diluted reaction conditions, and/or large excesses of piperazine.
The method for preparing quinoline piperazine in the patent US20060270852 comprises the steps of refluxing 4, 7-dichloroquinoline and anhydrous piperazine (the molar ratio is 1: 3) at 84-85 ℃ for 36 hours in the presence of potassium carbonate and isopropanol, and carrying out aftertreatment by carrying out reduced pressure distillation, extraction, concentration, addition of n-hexane and stirring to obtain a target product. The yield was about 95% and the purity was only 96.64%. It can be seen that the process has a long reaction time, complicated workup and low purity.
Patent CN101440063 discloses a method for preparing quinoline piperazine, wherein 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio is 1: 8-1: 13) are refluxed for 36 hours in potassium carbonate, isopropanol/water/propanol and the like, and the target product is obtained by performing after-treatment through reduced pressure concentration, extraction, concentration and the like. The optimal purity is 99.2 percent, and the defect is that the post-treatment is complicated after the reaction time is long.
Patent CN103360309 discloses a method for preparing quinoline piperazine, in which 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio 1: 1-4) are reacted in the presence of butanol, methanol or no solvent, after the reaction is finished, the mixture is added into water, concentrated hydrochloric acid is adjusted to be acidic, filtration and extraction are performed, pH of a water phase is adjusted to be alkaline, and a product is obtained by extracting and concentrating an organic phase, wherein the optimal purity is 99.5%. The patent also discloses a process for recovering piperazine by heating the aqueous phase to evaporate water and recovering piperazine. The defects are that two times of extraction is needed, and the operation is complicated.
Patent CN103596927 discloses a method for preparing quinoline piperazine, in which 4, 7-dichloroquinoline and anhydrous piperazine (molar ratio is about 1: 2.5) are reacted in methanol, after the reaction is finished, the mixture is filtered, decompressed and concentrated, and water is added for filtration to obtain the target product, which is a B crystal form, the yield is 86%, and the purity of HPLC test samples is not reported.
The patent CN102558048 discloses a method for preparing quinoline piperazine, wherein 4, 7-dichloroquinoline and piperazine hexahydrate (the molar ratio is about 1:3.9) are subjected to solvent-free reaction, water is added into lower-layer oily matter after the reflux reaction is finished, and the oily matter is taken out by layers and washed by water until the pH value is 7-8. Adjusting the pH value of the oily substance to 2.5-3.5, and filtering to remove insoluble substances. And adjusting the pH value of the filtrate to 9-10, standing for layering, taking the oily substance, adding purified water, stirring into solid particles, and drying to obtain the target product.
The document (Zhengqing four, synthesis and structural characterization of high-purity piperaquine phosphate, university of Guangxi science and technology, 2016,27(2): 107-.
Generally, a large amount of excess piperazine is used in the reaction, so that the recovery and reuse of piperazine also has an extremely important practical significance, and reports on the recovery and reuse of piperazine are few, as disclosed in the patent CN103360309, a method for recovering piperazine after the piperazine exists in an aqueous phase and is heated by the aqueous phase and water is evaporated is adopted, and the method for recovering piperazine by evaporating water is large in energy consumption, complex in operation process and high in cost due to the high boiling point of water. Therefore, the other invention of the invention adopts a mode of directly applying the piperazine rather than recycling the piperazine, thereby simplifying the operation and reducing the cost.
The method for preparing quinoline piperazine mainly has the defects of low purity of prepared products, low yield, complex operation, long production period, serious environmental pollution, high production cost and the like, so a new preparation method needs to be developed aiming at the defects, and the method has important significance for recycling or applying excessive reaction raw material piperazine.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity quinoline piperazine hydrochloride, which has the advantages of simple process, no extraction and concentration procedures, easy purification of products, purity of more than or equal to 99.5 percent, no toxic reagent, little environmental pollution, low production cost and suitability for industrial production. The invention also aims to provide a method for producing piperaquine phosphate intermediate by using piperazine, which comprises the following steps: the method does not need to separate the piperazine from the mother liquor, and directly applies the mother liquor to the production of the next batch of quinoline piperazine, so that the yield of the intermediate quinoline piperazine hydrochloride can be improved, the environmental pollution is reduced, and the production cost is reduced.
The invention discloses a preparation method of high-purity quinoline piperazine hydrochloride, which comprises the following steps:
(1) adding water and anhydrous piperazine into a reactor, stirring, adjusting the pH value with acid, continuing stirring, adding 4, 7-dichloroquinoline, and continuing stirring for reaction after the addition is finished;
(2) cooling after the reaction is finished, and filtering (collecting mother liquor as a solvent for next use);
wherein the method further comprises the step (3) of drying.
Wherein the molar ratio of the 4, 7-dichloroquinoline to the anhydrous piperazine in the step (1) is 1: 3-1: 8, preferably 1: 4-1: 6.
Wherein the weight ratio of the 4, 7-dichloroquinoline to the water in the step (1) is 1: 1.5-1: 3, preferably 1: 2-1: 2.5.
wherein the acid in the step (1) is hydrochloric acid, preferably concentrated hydrochloric acid.
Wherein the pH value adjusting range in the step (1) is 6.0-8.0, preferably 6.5-7.0.
Wherein the pH value is adjusted in the step (1) and then the mixture is heated to 60-100 ℃.
Wherein the reaction temperature after the 4, 7-dichloroquinoline is added in the step (1) is 80-100 ℃, and preferably 90-100 ℃.
Wherein the temperature of the temperature reduction in the step (2) is 45-65 ℃, preferably 50-60 DEG C
The invention relates to a method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by using piperazine, which comprises the following steps:
(1) adding anhydrous piperazine into all mother liquor of the previous batch, stirring, adjusting the pH value with acid, continuing stirring, adding 4, 7-dichloroquinoline, and continuing stirring for reaction after the addition is finished;
(2) cooling after the reaction is finished, and filtering (collecting mother liquor as a solvent for next use);
wherein the method further comprises the step (3) of drying.
Wherein the mother liquor in the step (1) is generated in the reaction process of anhydrous piperazine and 4, 7-dichloroquinoline, and is a filtrate obtained after cooling and filtering.
Wherein the molar ratio of the 4, 7-dichloroquinoline to the anhydrous piperazine in the step (1) is 1: 1.5-1: 4, preferably 1: 2-1: 3.
Wherein the weight ratio of the 4, 7-dichloroquinoline in the step (1) to the 4, 7-dichloroquinoline in the first preparation is 0.9: 1-1.1: 1, preferably 1:1.
Wherein the acid in the step (1) is hydrochloric acid, preferably concentrated hydrochloric acid.
Wherein the pH value adjusting range in the step (1) is 6.0-8.0, preferably 6.5-7.0.
Wherein the pH value is adjusted in the step (1) and then the mixture is heated to 60-100 ℃.
Wherein the reaction temperature after the 4, 7-dichloroquinoline is added in the step (1) is 80-100 ℃, and preferably 90-100 ℃.
Wherein the temperature of the temperature reduction in the step (2) is 45-65 ℃, preferably 50-60 DEG C
The application times are 4 times at most.
The preparation method adopts fresh solvent for the first time, the indiscriminate preparation is generated in the reaction process of the anhydrous piperazine and the 4, 7-dichloroquinoline, and the filtrate obtained after cooling and filtering is the solvent.
The preparation method of the high-purity quinoline piperazine hydrochloride provided by the invention has the advantages of simple process, easiness in product purification, purity of more than or equal to 99.5%, avoidance of toxic reagents, small environmental pollution and low production cost, and is suitable for industrial production. The method for producing the piperaquine phosphate intermediate by applying the piperazine provided by the invention has the advantages that the piperazine is not required to be separated from the mother liquor, and the mother liquor is directly applied to the production of the quinoline piperazine hydrochloride in the next batch.
Drawings
FIG. 1 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 1.
FIG. 2 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 2.
FIG. 3 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 3.
FIG. 4 is an HPLC plot of the purity of quinolyl piperazine hydrochloride prepared in example 4.
FIG. 5 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 5.
FIG. 6 is an HPLC chromatogram of the purity of quinolyl piperazine hydrochloride prepared in example 6.
Detailed Description
Example 1
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 40g of water and 36g of anhydrous piperazine into a three-necked bottle, stirring, adjusting the pH of a system to 6.0 by using concentrated hydrochloric acid, heating to 65 ℃, and stirring for reacting for 1 hour; continuously heating to 90 ℃, slowly adding 20g of 4, 7-dichloroquinoline, continuously heating to 95 ℃ after the addition is finished, stirring for reaction, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 45 ℃, the mixture is stirred for 1 hour, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 26.1g of the quinolyl piperazine hydrochloride, wherein the yield is 91.0 percent, and the purity is 99.7 percent.
Example 2
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 60g of water and 52g of anhydrous piperazine into a three-necked bottle, stirring, adjusting the pH value of a system to 7.0 by using 30% hydrochloric acid, heating to 80 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, continuing to stir for reaction after the addition is finished, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 25.9g of the quinolyl piperazine hydrochloride, wherein the yield is 90.3 percent, and the purity is 99.6 percent.
Example 3
Preparation of quinoline piperazine hydrochloride (first preparation)
Adding 80kg of water and 150kg of piperazine into a 1000L reaction tank, stirring, adjusting the pH of the system to 7.5 by using concentrated hydrochloric acid, heating to 75 +/-10 ℃, and stirring for reacting for 1 hour; continuously heating to 95 +/-5 ℃, slowly adding 100kg of 4, 7-dichloroquinoline, and after the addition is finished, controlling the temperature to be 95 +/-5 ℃ and stirring for reaction for 4-5 hours; after the reaction is finished, the temperature is reduced to 60 +/-5 ℃, the mixture is stirred for 1 hour, the mixture is centrifuged while the mixture is hot (the mother solution is collected and used as a solvent), and a filter cake is dried to obtain 131kg of the quinolyl piperazine hydrochloride, wherein the yield is 91.3 percent, and the purity is 99.6 percent.
Example 4
Preparation of quinoline piperazine hydrochloride (first use preparation)
Adding 28g of anhydrous piperazine into the total amount of mother liquor in the embodiment 1, adjusting the pH value of a system to 8.0 by using 35% hydrochloric acid, heating to 60 ℃, stirring for 30 minutes, continuously heating to 80 ℃, stirring for 30 minutes, slowly adding 22g of 4, 7-dichloroquinoline, continuously stirring for reaction after the addition is finished, and reacting for 5 hours; after the reaction is finished, the temperature is reduced to 45 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 30g of the quinolyl piperazine hydrochloride, wherein the yield is 95.0 percent, and the purity is 99.7 percent.
Example 5
Preparation of quinoline piperazine hydrochloride (first use preparation)
Adding 13.1g of anhydrous piperazine into the total amount of mother liquor in the embodiment 2, adjusting the pH value of a system to 6.5 by using concentrated hydrochloric acid, heating to 75 ℃, stirring for 30 minutes, continuously heating to 85 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, heating to 95 ℃ after the addition is finished, continuously stirring for reaction, and reacting for 4 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot (mother liquor is collected and used as a solvent), and a filter cake is dried to obtain 26.9g of the quinolyl piperazine hydrochloride, wherein the yield is 93.7 percent, and the purity is 99.6 percent.
Example 6
Preparation of quinolinylpiperazine hydrochloride (fourth application preparation)
The amount of 4, 7-dichloroquinoline at the time of first preparation was 20 g. Adding 13.1g of anhydrous piperazine into the whole mother liquor of the previous batch, adjusting the pH value of the system to 7 by using concentrated hydrochloric acid, heating to 75 ℃, stirring for 30 minutes, continuously heating to 85 ℃, stirring for 30 minutes, slowly adding 20g of 4, 7-dichloroquinoline, heating to 95 ℃ after the addition is finished, continuously stirring for reaction, and reacting for 4 hours; after the reaction is finished, the temperature is reduced to 60 ℃, the mixture is stirred for 30 minutes, the mixture is filtered while the mixture is hot, and a filter cake is dried to obtain 27.0g of quinoline piperazine hydrochloride, wherein the yield is 94.1 percent, and the purity is 99.5 percent.
Comparative example 1
Preparation of quinolinylpiperazines
In a three-necked flask, 59.4g of 4, 7-dichloroquinoline and 103.2g of anhydrous piperazine were added, 50mL of butanol was added, the mixture was stirred, heated to 110 ℃ and reacted for 1 hour, and the progress of the reaction was followed by Thin Layer Chromatography (TLC). After the reaction is completed, transferring the reaction solution into 200mL of water, adjusting the solution to acidity by using concentrated hydrochloric acid, filtering, extracting by using dichloromethane (2X 100 mL), collecting and combining organic layers, concentrating and recovering the solvent; adjusting the water phase of the NaOH aqueous solution to be strong alkaline, separating an oil phase from a water phase, extracting the water phase twice by using dichloromethane (2X 100 mL), combining organic layers, washing by using a small amount of water, dehydrating, and concentrating to obtain 66g of quinoline piperazine with the purity of 99.3%; the yield is 88.8%.
Comparative example 2
Preparation of quinolinylpiperazines
Piperazine 54g was stirred in 150ml of anhydrous methanol to give a clear solution. Then 50g of 4, 7-dichloroquinoline were slowly added to the solution. The solution was refluxed for 8 hours and cooled to room temperature. Filtering, and concentrating under reduced pressure. The resulting oil was washed with water (150ml) to give a solid precipitate. Filtration, washing with water and drying gave 53g of quinolinylpiperazine in 84.7% yield and 95.8% purity.
Comparative example 3
Preparation of quinolinylpiperazines
Adding 112g of piperazine hexahydrate into a reaction bottle, heating until the solid is completely melted, keeping the temperature at 60 ℃, slowly adding 30g of 4, 7-dichloroquinoline while stirring, continuously heating to 100 ℃, and stirring and refluxing for 6 hours. Stopping heating and stirring, cooling to 90 ℃, preserving heat, standing and layering. Taking the lower oily substance, adding 50ml of purified water, heating to 80 ℃, stirring for 10 minutes, standing for layering, taking the lower oily substance, and repeatedly washing with water until the pH value is 7. Adding the oily substance into the reaction flask again, adding concentrated hydrochloric acid with concentration of 35.8% and 100g of purified water with temperature of 80 deg.C under stirring, acidifying to pH 3, stopping stirring, and filtering. Transferring the filtrate to a reaction bottle, cooling to 20 ℃, adding 25% sodium hydroxide solution with stirring, alkalifying to pH 10, and standing for layering. And (3) taking the lower oily substance, adding 50ml of water, stirring until the material becomes solid particles, filtering, washing a filter cake with water until the pH value of the filtrate is 7, and drying to obtain 29.8g of the quinoline piperazine, wherein the yield is 79.4% and the purity is 93.9%.
Comparative example 4
Preparation of quinolinylpiperazines
Adding 15g of water, 15g of methanol, 15g of 4, 7-dichloroquinoline and 30g of anhydrous piperazine into a reaction bottle, stirring and heating to 70 ℃, refluxing for 5 hours, cooling to room temperature after the reaction is finished, stirring for 1 hour, filtering, pouring the filtrate into the reaction bottle, adding 15g of water, adding hydrochloric acid to adjust the pH value to be 8, stirring for 1 hour after the pH value is measured again, and filtering. Adding 60g of water into the filter cake, stirring, adding hydrochloric acid solution to adjust the pH value to 4.5, adding 0.15g of activated carbon after the solid is dissolved, heating to 60 ℃ for decoloring for 30 minutes, filtering, neutralizing the filtrate with 30% sodium hydroxide, adjusting the pH value to 8, cooling to room temperature, stirring for 30 minutes, filtering, washing with water, and drying to obtain 15.2g of quinoline piperazine with the yield of 81% and the purity of 96.8%.
Comparative example 5
Preparation of quinolinylpiperazines
26.1g of piperazine is taken, 400g of purified water is added, stirring is carried out, concentrated hydrochloric acid is added to adjust the pH value to 6.5 after dissolution, 20g of 4, 7-dichloroquinoline is added, heating and stirring are carried out for 4 hours, filtering is carried out, cooling is carried out, sodium hydroxide is added to adjust the pH value to 10, standing is carried out for crystallization at 20 ℃, filtering and drying are carried out to obtain 23g of piperazine, the yield is 91.9%, and the purity is 97.3%.
Claims (6)
1. A method for producing quinoline piperazine hydrochloride serving as a piperaquine phosphate intermediate by using piperazine mechanically comprises the following steps:
(1) preparation of quinoline piperazine hydrochloride and mother liquor
Adding water and anhydrous piperazine into a reactor, stirring, adjusting the pH value to 6.0-8.0 by hydrochloric acid, heating to 60-100 ℃ after adjusting the pH value, continuing stirring, slowly adding 4, 7-dichloroquinoline, keeping the reaction temperature at 90-100 ℃ after adding, and continuing stirring for reaction; cooling after the reaction is finished, wherein the cooling temperature is 45-65 ℃, filtering, and collecting filtrate as mother liquor to be used as a solvent for next application; in the step (1), the molar ratio of 4, 7-dichloroquinoline to anhydrous piperazine is 1: 4-1: 8, and the weight ratio of 4, 7-dichloroquinoline to water is 1: 1.5-1: 3;
(2) application of quinoline piperazine hydrochloride
Adding anhydrous piperazine into all mother liquor of the previous batch, stirring, adjusting the pH value to be 6.0-8.0 by hydrochloric acid, heating to 60-100 ℃ after adjusting the pH value, continuing stirring, slowly adding 4, 7-dichloroquinoline, keeping the reaction temperature to be 90-100 ℃ after adding, and continuing stirring for reaction; cooling after the reaction is finished, wherein the cooling temperature is 45-65 ℃, filtering, and collecting mother liquor as a solvent for next use; the molar ratio of the 4, 7-dichloroquinoline to the anhydrous piperazine in the step (2) is 1: 1.5-1: 4, and the weight ratio of the 4, 7-dichloroquinoline to the 4, 7-dichloroquinoline in the first preparation in the step (2) is 0.9: 1-1.1: 1.
2. The method of claim 1, wherein step (1) and step (2) each comprise a drying step.
3. The method according to claim 1, wherein the molar ratio of 4, 7-dichloroquinoline to anhydrous piperazine in step (1) is 1:4 to 1: 6.
4. The method according to claim 1, wherein the weight ratio of 4, 7-dichloroquinoline to water in step (1) is 1:2 to 1: 2.5.
5. The method according to claim 1, wherein the molar ratio of 4, 7-dichloroquinoline to anhydrous piperazine in the step (2) is 1:2 to 1:3.
6. The method of claim 1, wherein the weight ratio of 4, 7-dichloroquinoline to 4, 7-dichloroquinoline at the time of first preparation in step (2) is 1:1.
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| GB1047935A (en) * | 1963-04-04 | 1966-11-09 | American Cyanamid Co | Substituted piperazines and preparation thereof |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| WO2010081851A1 (en) * | 2009-01-14 | 2010-07-22 | Genoscience Pharma | Piperidin-4-ylpiperazine compounds for the treatment of hcv infection |
| CN103058926A (en) * | 2012-12-14 | 2013-04-24 | 重庆康乐制药有限公司 | Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1047935A (en) * | 1963-04-04 | 1966-11-09 | American Cyanamid Co | Substituted piperazines and preparation thereof |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| WO2010081851A1 (en) * | 2009-01-14 | 2010-07-22 | Genoscience Pharma | Piperidin-4-ylpiperazine compounds for the treatment of hcv infection |
| CN103058926A (en) * | 2012-12-14 | 2013-04-24 | 重庆康乐制药有限公司 | Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline |
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