CN105330601A - Preparation method of piperaquine derivative - Google Patents
Preparation method of piperaquine derivative Download PDFInfo
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- CN105330601A CN105330601A CN201510730934.5A CN201510730934A CN105330601A CN 105330601 A CN105330601 A CN 105330601A CN 201510730934 A CN201510730934 A CN 201510730934A CN 105330601 A CN105330601 A CN 105330601A
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- piperaquine
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a piperaquine derivative III, namely, 1,4-bi(7-chloroquinolin-4-yl)piperazine. The piperaquine derivative III is a piperaquine dimmer impurity and is one of main impurities of crude drugs or preparations of piperaquine and piperaquine salt. The piperaquine derivative III can be used for analyzing and detecting the purity of chemicals piperaquine and piperaquine salt, thereby controlling the quality of piperaquine and piperaquine salt.
Description
Technical field
The invention belongs to medicine and chemical technology field, be specifically related to PIPERAQUINE derivative III, be i.e. the preparation method of Isosorbide-5-Nitrae-two (7-chloroquinoline-4-base) piperazine and purposes.
Background technology
PIPERAQUINE is two quinolinic antimalarial medicines, and in the three large fatal diseases of Africa, malaria ranks first.According to World Bank's statistics, malaria causes financial loss to reach 12,000,000,000 dollars to every year the African country on the south the Sahara, seriously hinders African expanding economy.The malariated crowd in Africa mostly is children, faces death threats because they can not get effectively treatment.In state-owned tens provinces, municipalities and autonomous regions have malaria prevalence, annual number of the infected reaches about 40,000.The World Health Organization points out, existing inexpensive drugs has used for many years, and plasmodium has produced stronger resistance, and in Africa, these medicines of a lot of areas lost efficacy, and efficient medicine is expensive, and most African cannot bear.
Piperaquine phosphate belongs to synthesizing antimalarial, is modal anti-malarial quinolines, is mainly used in the drug-fast malaria treatment produced chloroquine.The combined utilization of itself and Artemisinin and derivative thereof comes into one's own day by day in recent years, the compound preparation dihydroarteannuin piperaquine tablet be made up of dihydroarteannuin and piperaquine phosphate, both the deficiency of the dihydroarteannuin length course for the treatment of had been overcome, compensate for again the shortcoming that PIPERAQUINE onset is slow, having significant synergistic function, is the superior drug of the various malaria for the treatment of especially multiple drug resistance pernicious malaria.
The chemistry of PIPERAQUINE derivative III is called: Isosorbide-5-Nitrae-two (7-chloroquinoline-4-base) piperazine, and structural formula is as follows:
It is one of cylinder metabolism-ure of piperaquine phosphate that CN101293871A reports PIPERAQUINE derivative III, and can be used as antimalarial active medicine, obtains by extracting the urine after taking piperaquine phosphate.
The present inventor is through the mass analysis to piperaquine phosphate preparation technology and intermediate and finished product, and PIPERAQUINE derivative III is one of impurity that in piperaquine phosphate building-up process, side reaction produces.
According to the standard of piperaquine phosphate raw material and preparation in " Chinese Pharmacopoeia " 2015 editions, PIPERAQUINE derivative III is present in piperaquine phosphate and preparation thereof as impurity.Carrying out in drug quality testing process, needing to use highly purified impurity product in contrast, for controlling the quality that may contain the medicine of this impurity.Therefore this impurity compound highly purified must be synthesized.
Synthesis and the purification process of existing PIPERAQUINE derivative III have no report.Therefore, be badly in need of solving the preparation of PIPERAQUINE derivative III and the associated problem of purifying, therefore the present invention produces.
Summary of the invention
The invention provides preparation and the purification process of PIPERAQUINE derivative III.PIPERAQUINE derivative III can be obtained by reacting by 4,7-dichloroquinoline and Piperazine anhydrous, and syntheti c route is as follows:
Preparation and the purification process of PIPERAQUINE derivative III are specially:
A) in alcoholic solvent, add 4,7-dichloroquinoline, Piperazine anhydrous reaction;
B) after reacting completely, steam solvent, add dilute hydrochloric acid, stir cooling, separate solid;
C) sig water making beating is used, separate solid by b) obtaining solid;
D) dilute hydrochloric acid making beating is used, separate solid by c) obtaining solid;
E) repeat c) successively, d) operate 3 times;
F) purified water making beating is used, separate solid by e) obtaining solid;
G) separate solid is carried out drying.
In above-mentioned preparation method, the mol ratio of 4,7-dichloroquinoline and Piperazine anhydrous is 4 ~ 6:1; Alcoholic solvent comprises methyl alcohol, ethanol.
In above-mentioned preparation method, sig water refers to sodium hydroxide or the potassium hydroxide aqueous solution of 5%; Dilute hydrochloric acid refers to the aqueous hydrochloric acid of 5%.
In above-mentioned preparation method, " making beating " refers to and utilizes mechanical effect by material even suspension in solvent, slowly stirs in certain temperature range, by the way of purification of liquid-solid extraction or exchange.
Show through the present inventor's research, by above-mentioned preparation and purification process, product purity >=99.5% (HPLC area normalization method) obtained, HPLC retention time is consistent with the retention time of impurity III under piperaquine phosphate raw material in " Chinese Pharmacopoeia " 2015 editions and preparation item, can be used as the bulk drug of PIPERAQUINE and salt thereof and the contamination levels product of preparation or impurity reference substance completely.
Testing conditions about related substance HPLC under piperaquine phosphate raw material and preparation item in " Chinese Pharmacopoeia " 2015 editions is:
Chromatographic condition:
Chromatographic column: LichrospherC18,4.6mm × 250mm, 5 μm
Moving phase: A:100% acetonitrile; B:0.1% trifluoroacetic acid solution (phosphoric acid regulates pH=2.1 ± 0.05) (A: B=25: 75)
Determined wavelength: 349nm
Flow velocity: 1.0ml/min
Sample size: 20 μ l
Accompanying drawing explanation
Fig. 1 is PIPERAQUINE derivative III HPLC collection of illustrative plates.
Embodiment
With specific embodiment, technical scheme of the present invention is described further below, those skilled in the art can be made better to understand the present invention, but protection scope of the present invention is not limited thereto.
The preparation of embodiment 1 PIPERAQUINE derivative III
Add 100ml ethanol, 4,7-dichloroquinoline 39.6g, Piperazine anhydrous 4.3g in reaction flask, open and stir, be warming up to back flow reaction 8 hours, after having reacted, distill out ethanol, add 5% dilute hydrochloric acid solution 200ml, stir 30 minutes, be cooled to 20 ~ 25 DEG C, filtering separation solid.Proceeded to by filter cake in reaction flask, add 5% sodium hydroxide solution 100ml, 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Filter cake proceeds in reaction flask, adds 5% dilute hydrochloric acid solution 100ml, and 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Use 5% sodium hydroxide solution more respectively, 5% dilute hydrochloric acid solution pulls an oar 3 times; Be transferred in reaction flask by the solid of separation, add purified water 200ml, 20 ~ 25 DEG C are stirred 1 hour, and filtering separation solid, 60 DEG C of drying under reduced pressure obtain PIPERAQUINE derivative III 4.5g.According to the testing conditions of related substance HPLC under piperaquine phosphate item in " Chinese Pharmacopoeia " 2015 editions, detect collection of illustrative plates as Fig. 1.
The preparation of embodiment 2 PIPERAQUINE derivative III
Add 100ml methyl alcohol, 4,7-dichloroquinoline 59.6g, Piperazine anhydrous 4.3g in reaction flask, open and stir, be warming up to back flow reaction 8 hours, after having reacted, distill out methyl alcohol, add 5% dilute hydrochloric acid solution 200ml, stir 30 minutes, be cooled to 20 ~ 25 DEG C, filtering separation solid.Proceeded to by filter cake in reaction flask, add 5% sodium hydroxide solution 100ml, 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Filter cake proceeds in reaction flask, adds 5% dilute hydrochloric acid solution 100ml, and 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Use 5% sodium hydroxide solution more respectively, 5% dilute hydrochloric acid solution pulls an oar 3 times; Be transferred in reaction flask by the solid of separation, add purified water 200ml, 20 ~ 25 DEG C are stirred 1 hour, and filtering separation solid, 60 DEG C of drying under reduced pressure obtain PIPERAQUINE derivative III 5.2g.
The preparation of embodiment 3 PIPERAQUINE derivative III
Add 100ml methyl alcohol, 4,7-dichloroquinoline 39.6g, Piperazine anhydrous 4.3g in reaction flask, open and stir, be warming up to back flow reaction 8 hours, after having reacted, distill out methyl alcohol, add 5% dilute hydrochloric acid solution 200ml, stir 30 minutes, be cooled to 20 ~ 25 DEG C, filtering separation solid.Proceeded to by filter cake in reaction flask, add 5% sodium hydroxide solution 100ml, 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Filter cake proceeds in reaction flask, adds 5% dilute hydrochloric acid solution 100ml, and 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Use 5% sodium hydroxide solution more respectively, 5% dilute hydrochloric acid solution pulls an oar 3 times; Be transferred in reaction flask by the solid of separation, add purified water 200ml, 20 ~ 25 DEG C are stirred 1 hour, and filtering separation solid, 60 DEG C of drying under reduced pressure obtain PIPERAQUINE derivative III 4.1g.
The preparation of embodiment 4 PIPERAQUINE derivative III
Add 100ml ethanol, 4,7-dichloroquinoline 49.5g, Piperazine anhydrous 4.3g in reaction flask, open and stir, be warming up to back flow reaction 8 hours, after having reacted, distill out ethanol, add 5% dilute hydrochloric acid solution 200ml, stir 30 minutes, be cooled to 20 ~ 25 DEG C, filtering separation solid.Proceeded to by filter cake in reaction flask, add 5% sodium hydroxide solution 100ml, 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Filter cake proceeds in reaction flask, adds 5% dilute hydrochloric acid solution 100ml, and 20 ~ 25 DEG C are stirred 1 hour, filtering separation solid; Use 5% sodium hydroxide solution more respectively, 5% dilute hydrochloric acid solution pulls an oar 3 times; Be transferred in reaction flask by the solid of separation, add purified water 200ml, 20 ~ 25 DEG C are stirred 1 hour, and filtering separation solid, 60 DEG C of drying under reduced pressure obtain PIPERAQUINE derivative III 4.7g.
Detail the present invention above, comprise its preferred embodiment.But it should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention and/or improve in the scope of described claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a preparation method for PIPERAQUINE derivative III, reaction equation is as follows:
。
2. preparation method according to claim 1, specifically comprises the steps:
A) in alcoholic solvent, add 4,7-dichloroquinoline, Piperazine anhydrous reaction;
B) after having reacted, steam solvent, add dilute hydrochloric acid, separate solid;
C) sig water making beating is used, separate solid by b) obtaining solid;
D) dilute hydrochloric acid making beating is used, separate solid by c) obtaining solid;
E) repeat c) successively, d) operate 3 times;
F) purified water making beating is used, separate solid by e) obtaining solid;
G) separate solid is carried out drying.
3. preparation method according to claim 2, is characterized in that: the mol ratio of 4,7-dichloroquinoline and Piperazine anhydrous is 4 ~ 6:1.
4. preparation method according to claim 2, is characterized in that: alcoholic solvent comprises methyl alcohol, ethanol.
5. PIPERAQUINE derivative III according to claim 1, is characterized in that: PIPERAQUINE derivative III is for the quality control of PIPERAQUINE and salt thereof.
6. PIPERAQUINE derivative III according to claim 1, is characterized in that: PIPERAQUINE derivative III is for the quality control of piperaquine phosphate and preparation thereof.
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| CN201510730934.5A CN105330601A (en) | 2015-11-03 | 2015-11-03 | Preparation method of piperaquine derivative |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289423A (en) * | 2008-06-17 | 2008-10-22 | 广州中医药大学 | 7-chlorine -4-(1- piperazinyl)chinoline and applications thereof in preparation of anti-malaria medicaments |
| CN101293871A (en) * | 2008-06-17 | 2008-10-29 | 广州中医药大学 | 7-chlorine-4-[4'-(7''-chloroquine-4''-base)diethylenediamine-1'-base]quinoline and uses 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 |
| CN101440063A (en) * | 2008-12-19 | 2009-05-27 | 重庆康乐制药有限公司 | Preparation of piperaquini phosphatis |
| CN103360309A (en) * | 2013-08-02 | 2013-10-23 | 重庆邮电大学 | Synthetic method for piperaquine phosphate intermediate 7-chloro-4-(1-piperazino)quinoline |
| US20140200346A1 (en) * | 2011-06-06 | 2014-07-17 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Novel Process for the Synthesis of 7-Chloro-4-(piperazin-1-yl)-quinoline |
| CN104402815A (en) * | 2014-09-15 | 2015-03-11 | 桂林南药股份有限公司 | Control method of piperaquine phosphate impurity |
-
2015
- 2015-11-03 CN CN201510730934.5A patent/CN105330601A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101289423A (en) * | 2008-06-17 | 2008-10-22 | 广州中医药大学 | 7-chlorine -4-(1- piperazinyl)chinoline and applications thereof in preparation of anti-malaria medicaments |
| CN101293871A (en) * | 2008-06-17 | 2008-10-29 | 广州中医药大学 | 7-chlorine-4-[4'-(7''-chloroquine-4''-base)diethylenediamine-1'-base]quinoline and uses thereof |
| CN101440063A (en) * | 2008-12-19 | 2009-05-27 | 重庆康乐制药有限公司 | Preparation of piperaquini phosphatis |
| US20140200346A1 (en) * | 2011-06-06 | 2014-07-17 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Novel Process for the Synthesis of 7-Chloro-4-(piperazin-1-yl)-quinoline |
| CN103360309A (en) * | 2013-08-02 | 2013-10-23 | 重庆邮电大学 | Synthetic method for piperaquine phosphate intermediate 7-chloro-4-(1-piperazino)quinoline |
| CN104402815A (en) * | 2014-09-15 | 2015-03-11 | 桂林南药股份有限公司 | Control method of piperaquine phosphate impurity |
Non-Patent Citations (6)
| Title |
|---|
| FANG YAN,等: "Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS,ESI-MS and NMR", 《MALARIA JOURNAL》 * |
| JOSEPH MD FORTUNAK，等: "An Efficient, Green Chemical Synthesis of the Malaria Drug, Piperaquine", 《TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
| TARA SINGH,等: "Antimalarials. 7-Chloro-4-(substituted amino)quinolines", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| VAIJANATH G. DONGRE，等: "Characterization and quantitative determination of impurities in piperaquine phosphate by HPLC and LC/MS/MS", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 国家药典委员会: "《中华人民共和国药典》", 30 June 2015 * |
| 张小松,等: "磷酸哌喹有关物质的检测研究", 《中国药事》 * |
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Application publication date: 20160217 |