CN103159700A - Piperazine citrate preparation process - Google Patents
Piperazine citrate preparation process Download PDFInfo
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- CN103159700A CN103159700A CN2011104062747A CN201110406274A CN103159700A CN 103159700 A CN103159700 A CN 103159700A CN 2011104062747 A CN2011104062747 A CN 2011104062747A CN 201110406274 A CN201110406274 A CN 201110406274A CN 103159700 A CN103159700 A CN 103159700A
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Abstract
The present invention relates to a piperazine citrate preparation method, and further provides a piperazine citrate with characteristics of safe quality and good stability. The preparation method comprises that: citric acid and anhydrous piperazine are completely dissolved and filtered, and form a salt in a reaction kettle under an appropriate reaction condition, and cooling crystallization, centrifugation, washing and vacuum drying are performed after the complete reaction to obtain the product. The preparation process has characteristics of simpleness, easy operation, extremely small three-waste generation, high yield, low cost, high product purity, and easy industrial production, wherein the yield is up to more than 90%. In the prior art, the piperazine citrate preparation process comprises adopting citric acid and piperazine hexahydrate as raw materials, adopting water as a solvent, and carrying out dissolving, salt forming, alcohol precipitation, centrifugation and drying, and has disadvantages of complex process, large wastewater generation and low yield. With the present invention, the disadvantages in the prior art are overcome.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of preparation technology of piperazine citrate, the present invention provides the piperazine citrate of a kind of quality safety, good stability simultaneously.
Background technology
Piperazine citrate (Piperazine Citrate) another name is piperazine citrate, is present comparatively ideal one of ascarid medicine that drives.The advantages such as the effective in cure height of this medical instrument, toxicity is low, usage is easy are by numerous medical workers are commonly used.This medical instrument has the effect of paralysis Ascaris Suum muscle, its mechanism may be for piperazine at polypide neuromuscular junction performance cholinolytic effect, the excitation of blockage of acetylcholine to Ascaris Suum muscle, or change the polypide muscle cell membrane to the permeability of ion, the transmission of the impulsion that affects the nerves; Also can suppress the generation of succinate, reduce the supply of energy, block nerves neuromuscular junction place can not assign impulsion.Thereby roundworm is thrown off from the position of parasitism, excrete with intestinal peristalsis.Roundworm does not show excitation before paralysis, therefore use this product safer.This product to roundworm larva of a tapeworm or the cercaria of a schistosome worm without effect, also very faint to the action of muscles of mammal.This product also can be used for driving away pinworm but its mechanism of action is still not too clear and definite in addition.
Traditional preparation technology of piperazine citrate is for take Citric Acid and Uricida as raw material, take water as solvent, makes through dissolving, salify, alcohol precipitation, centrifugal, drying, and its technique is loaded down with trivial details, produce that waste liquid amount is large, yield is low.
Summary of the invention
The present invention aims to provide the piperazine citrate preparation technology that a kind of yield is high, purity is high, pollution is little, cost is low, easy and simple to handle, and this technique is fit to large-scale production, can satisfy the requirement of field of medicaments.
Manufacture craft of the present invention comprises the following steps:
(1) dissolving: fully dissolve respectively Citric Acid, Piperazine anhydrous with solvent, the Citric Acid solvent temperature is 20 ℃ ~ 60 ℃, and preferred 45 ℃, the time is 10 minutes ~ 60 minutes, preferred 30 minutes; The Piperazine anhydrous solvent temperature is 20 ℃ ~ 40 ℃, and preferred 25 ℃, the time is 10 minutes ~ 40 minutes, preferred 20 minutes;
(2) filter: after Citric Acid, Piperazine anhydrous fully dissolve, be filtered to respectively in reactor and header tank through the titanium rod;
(3) crystallization: filter complete after, open the interior stirring of reactor and be warming up to simultaneously 40 ℃ ~ 90 ℃, preferred 60 ℃, open the header tank valve, slowly drip in Piperazine anhydrous solution and reactor and react with citric acid soln, time for adding is 20 minutes ~ 90 minutes, dropwises rear insulation 1 hour ~ 4 hours, preferred 3 hours, cooling crystallization;
(4) centrifugal drying: the reactor reaction product is washed then vacuum-drying to the piperazine citrate filter cake and is namely got piperazine citrate through centrifugal acquisition piperazine citrate filter cake.
In above dissolution process, the solvent of dissolving Citric Acid and Piperazine anhydrous is one or more mixtures in 1,2-ethylene dichloride, methylene dichloride, ethanol, acetone, preferred alcohol.
Solvent in above dissolution process and the mass ratio of Citric Acid are 20:1 ~ 5:1, preferred 10:1; The mass ratio of solvent and Piperazine anhydrous is 15:1 ~ 5:1, preferred 8:1.
In above filtration procedure, the filter footpath of titanium rod strainer is 0.45um ~ 10um, preferred 1.0um.
Cooling crystallization temperature in above crystallisation process is 0 ℃ ~ 40 ℃, and preferred 20 ℃, the crystallization time is 2 hours ~ 6 hours, preferred 4 hours.
The lotion that cleans the piperazine citrate filter cake in above centrifugal process is one or more mixtures in 1,2-ethylene dichloride, methylene dichloride, ethanol, acetone, preferred alcohol.
In above process of vacuum drying, temperature is 50 ℃ ~ 85 ℃, preferred 60 ℃, and vacuum tightness is-0.06MPa ~-0.09MPa, be 2 hours ~ 6 hours time of drying.
Reaction principle of the present invention is as follows:
C
6H
8O
7?+?C
4H
10N
2?———>（C
4H
10N
2）
3·2C
6H
8O
7·5H
2O
Wherein in reaction process, the mol ratio of Citric Acid and Piperazine anhydrous is 3:1 ~ 1:3.
Advantage of the present invention: the inventive method prepares piperazine citrate, reacts to be synthesis under normal pressure, and technique is simple, and equipment requirements is not high, and Technological Economy is reasonable, and facility investment is few, and is easy to operate and safe.Do not need to add catalyzer in whole reaction process, reactant need not re-refine and purity very high.The generation quantity of three wastes is few, almost non-environmental-pollution.React also recyclable applying mechanically of ethanol used, thereby greatly reduce production costs.The reaction process difficulty is low, and is easy and simple to handle.Yield of the present invention is up to more than 90%, and product content can reach more than 99%, has overcome the defective that technique is loaded down with trivial details, the generation waste liquid amount is large, yield is low that traditional technology has.Piperazine citrate is used for medical wide range, and tablet, oral liquor and other types of formulations listing are arranged on the market, and piperazine citrate also can be used as veterinary drug, and good market prospect is fit to large-scale production.
Embodiment
Following enforcement can illustrate in greater detail the present invention, but does not limit in any form the present invention.
Embodiment 1
The ethanolic soln 4000ml that adds the 384.2g Citric Acid in the reactor of a 10000ml is heated to 45 ℃; Drip the ethanolic soln 3000ml of 258.5g Piperazine anhydrous in the reactor.Time for adding is 30 minutes.After dropwising, insulated and stirred reaction 2 hours stops stirring cooling crystallization, centrifugal drying.Get piperazine citrate 582g, content 99.2%, yield 90.6%.
Embodiment 2
The ethanolic soln 4500ml that adds the 384.2g Citric Acid in the reactor of a 10000ml is heated to 60 ℃; Drip the ethanolic soln 3000ml of 258.5g Piperazine anhydrous in the reactor.Time for adding is 40 minutes.After dropwising, insulated and stirred reaction 3 hours stops stirring cooling crystallization, centrifugal drying.Get piperazine citrate 595g, content 99.7%, yield 92.6%.
Embodiment 3
The acetone soln 5000ml that adds the 384.2g Citric Acid in the reactor of a 10000ml is heated to 50 ℃; Drip the acetone soln 2500ml of 258.5g Piperazine anhydrous in the reactor.Time for adding is 30 minutes.After dropwising, insulated and stirred reaction 3 hours stops stirring cooling crystallization, centrifugal drying.Get piperazine citrate 588g, content 99.4%, yield 91.5%.
Embodiment 4
The dichloromethane solution 4000ml that adds the 384.2g Citric Acid in the reactor of a 10000ml is heated to 60 ℃; Drip the dichloromethane solution 4000ml of 258.5g Piperazine anhydrous in the reactor.Time for adding is 50 minutes.After dropwising, insulated and stirred reaction 3 hours stops stirring cooling crystallization, centrifugal drying.Get piperazine citrate 590g, content 99.8%, yield 91.8%.
Claims (8)
1. the preparation technology of a piperazine citrate is characterized in that comprising the following steps:
Dissolving: fully dissolve Citric Acid, Piperazine anhydrous with solvent, the Citric Acid solvent temperature is 20 ℃ ~ 60 ℃, and preferred 45 ℃, the time is 10 minutes ~ 60 minutes, preferred 30 minutes; The Piperazine anhydrous solvent temperature is 20 ℃ ~ 40 ℃, and preferred 25 ℃, the time is 10 minutes ~ 40 minutes, preferred 20 minutes;
Filter: after Citric Acid, Piperazine anhydrous fully dissolve, be filtered to respectively in reactor and header tank through the titanium rod;
Crystallization: filter complete after, open the interior stirring of reactor and be warming up to simultaneously 40 ℃ ~ 90 ℃, preferred 60 ℃, open the header tank valve, slowly drip Piperazine anhydrous solution in reactor with the citric acid soln reaction, time for adding is 20 minutes ~ 90 minutes, dropwises rear insulation 1 hour ~ 4 hours, preferred 3 hours, cooling crystallization;
Centrifugal drying: the reactor reaction product is washed then vacuum-drying to the piperazine citrate filter cake and is namely got piperazine citrate through centrifugal acquisition piperazine citrate filter cake.
2. according to claim 1 method, the solvent that it is characterized in that dissolving Citric Acid and Piperazine anhydrous are one or more mixtures in 1,2-ethylene dichloride, methylene dichloride, ethanol, acetone, preferred alcohol.
3. the preparation technology of a kind of piperazine citrate according to claim 1, it is characterized in that: the solvent in described dissolution process and the mass ratio of Citric Acid are 20:1 ~ 5:1, preferred 10:1; The mass ratio of solvent and Piperazine anhydrous is 15:1 ~ 5:1, preferred 8:1.
4. the preparation technology of a kind of piperazine citrate according to claim 1 is characterized in that: in described filtration procedure, the filter footpath of titanium rod strainer is 0.45um ~ 10um, preferred 1.0um.
5. the preparation technology of a kind of piperazine citrate according to claim 1, it is characterized in that: the crystallisation by cooling temperature in described crystallisation process is 0 ℃ ~ 40 ℃, preferred 20 ℃, crystallization time is 2 hours ~ 6 hours, preferred 4 hours.
6. the preparation technology of a kind of piperazine citrate according to claim 1, it is characterized in that: the lotion that cleans the piperazine citrate filter cake in described centrifugal process is 1, one or more mixtures in 2-ethylene dichloride, methylene dichloride, ethanol, acetone, preferred alcohol.
7. the preparation technology of a kind of piperazine citrate according to claim 1, it is characterized in that: in described process of vacuum drying, temperature is 50 ℃ ~ 85 ℃, preferred 60 ℃, vacuum tightness is-0.06MPa ~-0.09MPa, be 2 hours ~ 6 hours time of drying.
8. the preparation technology of a kind of piperazine citrate according to claim 1, it is characterized in that: in described reaction process, the mol ratio of Citric Acid and Piperazine anhydrous is 3:1 ~ 1:3.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110406274.7A CN103159700B (en) | 2011-12-09 | 2011-12-09 | A kind of preparation technology of piperazine citrate |
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| CN201110406274.7A CN103159700B (en) | 2011-12-09 | 2011-12-09 | A kind of preparation technology of piperazine citrate |
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| CN103159700B CN103159700B (en) | 2016-03-16 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1046057B (en) * | 1955-08-17 | 1958-12-11 | Bayer Ag | Process for the preparation of a neutral piperazinium salt |
| CS235223B1 (en) * | 1982-05-07 | 1985-05-15 | Lubor Jozefini | Method of tripiperazine dicitrean preparation |
| CN101555235A (en) * | 2009-05-20 | 2009-10-14 | 湖南康普制药有限公司 | Manufacture process of piperazine ferulate |
-
2011
- 2011-12-09 CN CN201110406274.7A patent/CN103159700B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1046057B (en) * | 1955-08-17 | 1958-12-11 | Bayer Ag | Process for the preparation of a neutral piperazinium salt |
| CS235223B1 (en) * | 1982-05-07 | 1985-05-15 | Lubor Jozefini | Method of tripiperazine dicitrean preparation |
| CN101555235A (en) * | 2009-05-20 | 2009-10-14 | 湖南康普制药有限公司 | Manufacture process of piperazine ferulate |
Non-Patent Citations (3)
| Title |
|---|
| J.J HEFFERREN ET AL.: "preparation and properties of citric and tartaric acid salts of piperazine", 《JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION》, vol. 44, no. 11, 23 September 2006 (2006-09-23), pages 679 - 682 * |
| V.KRISHNAN,A.MUTHUKUMARAN ET AL.,: "synthesis of piperazine & its salts", 《INDIAN JOURNAL OF TECHNOLOGY》, vol. 13, 31 March 1975 (1975-03-31), pages 129 * |
| 朱葆佺: "《新编药物合成反应路线图设计与制备工艺新技术实务全书》", 31 March 2005, 天津电子出版社, article "第六篇 药物中间体的合成工艺，第二章 杂环类医药中间体合成工艺，第一节，哌嗪及其衍生物", pages: 1096 * |
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| CN103159700B (en) | 2016-03-16 |
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Denomination of invention: Preparation process of piperazine citrate Effective date of registration: 20210730 Granted publication date: 20160316 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
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Denomination of invention: Preparation process of piperazine citrate Effective date of registration: 20211028 Granted publication date: 20160316 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021980011259 |