CN106045941A - Method for preparing piperazine hydrochloride - Google Patents
Method for preparing piperazine hydrochloride Download PDFInfo
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- CN106045941A CN106045941A CN201610443691.1A CN201610443691A CN106045941A CN 106045941 A CN106045941 A CN 106045941A CN 201610443691 A CN201610443691 A CN 201610443691A CN 106045941 A CN106045941 A CN 106045941A
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- piperazine
- hydrochloric salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
Abstract
The invention discloses a method for preparing piperazine hydrochloride shown by a formula (1). The piperazine hydrochloride is prepared through the following steps of reacting anhydrous piperazine with excessive hydrogen chloride to obtain piperazine dihydrochloride, and reacting the piperazine dihydrochloride with an equivalent amount of the anhydrous piperazine. The method disclosed by the invention has the advantage that a basis is provided for the research and development of novel drugs, synthetic dyestuff, pesticides and the like. The formula (1) is shown in the description.
Description
(1) technical field
The present invention relates to the preparation method of a kind of piperazine mono-hydrochloric salts.
(2) background technology
The monosubstituted compound of piperazine becomes the key intermediate in numerous pharmaceutical synthesis due to its special structure, synthesizes piperazine
The monosubstituted compound of piperazine class has very important pharmacy value and economic worth.In the alkylated reaction of piperazine, owing to being company
String reaction, gains have monosubstituted, the disubstituted and mixture of reaction raw materials simultaneously；In order to obtain the N-monoalkylation of high yield
Product, it should proportioning raw materials, response time, reaction temperature, the reaction condition such as kind of addition catalyst are optimized.N-first
Base piperazine and NEP, as important bridged piperazine derivatives, are widely used industrial chemicals and medicine intermediate.Such as N-
Methyl piperazine can be used for the synthesis of quinolones levofloxacin, and NEP is synthesis veterinary drug anthracene Flucloxacillin, conjunction
Become dyestuff and the important intermediate of plant protection product.N-monoacyl bridged piperazine derivatives is the important intermediate of pharmaceutical synthesis.Due to
Piperazine has the amino that two activity are identical, so, if using general process for acylating to carry out acylation reaction, will obtain more
Double acylated piperazine by-products.Therefore, how the synthesis of N-monoacyl piperazine is it is crucial that to reduce the generation of double acylate.PH value,
Solvent, temperature are the major influence factors of monoacylated reaction.Generally use acylated again after first protecting an amino and remove-insurance
The method protected, such as formoxyl Protection Code, ethyoxyl Protection Code and one-tenth salt Protection Code etc..But these method reactions steps are many, instead
Answering condition wayward, yield is low.As can be seen here, the method synthesizing this compounds haves much room for improvement.The monosubstituted chemical combination of piperazines
The key of thing synthesis is just to try to avoid di-substituted generation, improves the productivity of monosubstituted thing.According to reactant and product thing
Change the difference of character, can select appropriate reaction path, suitable piperazine raw material, suitable reaction temperature and time, rationally
Post-processing approach reached high yield generate the monosubstituted thing of piperazines.
The preparation of the monosubstituted compound of piperazine, according to existing method yield is the most relatively low or cost is high, is difficult to control disubstitution product
Generation, so yield is the highest, such as document [Tang Wei, Zhao Zengren, Zhao Jin. science and education literary composition converge. the conjunction of the monosubstituted compound of piperazines
Become [J] .2008.02:196] report, the synthesis yield 44.2%-69% of the monosubstituted compound of benzyl diethylenediamine class, post processing cost
Height, waste residue is many, environmental pollution weight.
The production that there is not yet the preparation about piperazine mono-hydrochloric salts is reported.The inventive method yield is high, the three wastes are few, cost
Low.The present invention is that new drug research provides the foundation with exploitation.
(3) summary of the invention
It is an object of the present invention to provide the preparation method of a kind of piperazine mono-hydrochloric salts.
The object of the present invention is achieved like this:
The preparation of piperazine mono-hydrochloric salts:
Piperazine anhydrous (2) joins in polar solvent, and stirring and dissolving is passed through dry hydrogen chloride gas under room temperature, until not
Absorbing and continue ventilation 1 hour, filter, mother solution reuse, solid is dried after washing with a small amount of solvent, obtains piperazine dihydrochloride (3), will
(3) join in polar solvent with (2) waiting material amount, 0 DEG C～stirred under reflux temperature 12-24 hour, cold filtration, washing
It is dried to obtain piperazine mono-hydrochloric salts (1).
Described polar solvent is the alcohol of C1-C6, oxolane, Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF, preferably Isosorbide-5-Nitrae-dioxy
Six rings, acetonitrile, DMF, most preferably Isosorbide-5-Nitrae-dioxane.Polar solvent volumetric usage is calculated as 2-with the amount of formula (2) combinations of materials
10ml/mmol, preferably 4ml/mmol.
Piperazine dihydrochloride (3) is equal with Piperazine anhydrous (2) material amount.
Reaction temperature is 0 DEG C～reflux temperature, preferably reflux temperature.
Response time is 12-24 hour, preferably 18-24 hour, optimum 20-24 hour.
Described polar solvent is the alcohol of C1-C6, oxolane, Isosorbide-5-Nitrae-dioxane, acetonitrile, DMF, preferably Isosorbide-5-Nitrae-dioxy
Six rings, acetonitrile, DMF, most preferably acetonitrile.
Polar solvent volumetric usage is calculated as 2-10ml/mmol with the amount of formula (1) combinations of materials, preferably 4ml/mmol.
Compared with prior art, the beneficial effects are mainly as follows: the invention provides a kind of piperazine mono-salt acid
The preparation method of salt, for providing low cost, oligosaprobic former as the monosubstituted compound of piperazine of crucial medicine intermediate
Material and convenient method, for providing the foundation containing the new drug development of piperazine group.
(4) detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This:
Piperazine mono-hydrochloric salts compounds (1) of the present invention can be prepared in the following manner:
Embodiment 1
Piperazine mono-hydrochloric salts (1)
Adding 20mmol compound (2), 100mL Isosorbide-5-Nitrae-dioxane in 250mL round-bottomed flask, at 20 DEG C, stirring is logical
Enter dry hydrogen chloride, do not absorb after about 2 hours, continue the logical hydrogen chloride of stirring 1 hour, 3 hour filtration, 10mL are stirred at room temperature
Isosorbide-5-Nitrae-dioxane washing, merges washing liquid and filtrate recycle, and solid is dried to obtain piperazine dihydrochloride (3), and (3) are added 250mL
In round-bottomed flask, the Piperazine anhydrous (2) of the material amount such as addition and (3), add Isosorbide-5-Nitrae-dioxane 100mL, stir temperature rising reflux
React 12 hours, be cooled to room temperature, filter, 10mL Isosorbide-5-Nitrae-dioxane washing, merge washing liquid and filtrate recycle, solid is dried
Obtaining piperazine mono-hydrochloric salts (1), productivity 98%, standard silver nitrate titrates, records Cl-Content 28.95% (theoretical amount 28.98%).
Embodiment 2
Piperazine mono-hydrochloric salts (1)
Adding 20mmol compound (2), 200mL acetonitrile in 250mL round-bottomed flask, at 0 DEG C, stirring is passed through dry chlorination
Hydrogen, did not absorbed after about 4 hours, continues the logical hydrogen chloride of stirring 1 hour, 3 hour filtration is stirred at room temperature, and 10mL acetonitrile washs,
Merging washing liquid and filtrate recycle, solid is dried to obtain piperazine dihydrochloride (3), adds in 250mL round-bottomed flask by (3), add and
(3) Piperazine anhydrous (2) of material amount such as, adds acetonitrile 180mL, and stirring temperature rising reflux reacts 24 hours, is cooled to room temperature, mistake
Filter, 10mL acetonitrile washs, and merges washing liquid and filtrate recycle, and solid is dried to obtain piperazine mono-hydrochloric salts (1), productivity 96.2%, standard
Silver nitrate titration, records Cl-Content 28.92% (theoretical amount 28.98%).
Embodiment 3
Piperazine mono-hydrochloric salts (1)
250mL round-bottomed flask adds 20mmol compound (2), 120mL DMF, is stirred at room temperature and is passed through dry chlorination
Hydrogen, did not absorbed after about 3 hours, continues the logical hydrogen chloride of stirring 1 hour, is warming up to 3 hours cold filtrations of return stirring, 10mL
DMF washs, and merges washing liquid and filtrate recycle, and solid is dried to obtain piperazine dihydrochloride (3), and (3) are added 250mL round-bottomed flask
In, the Piperazine anhydrous (2) of the material amount such as addition and (3), add DMF 180mL, stirring temperature rising reflux reacts 20 hours, is cooled to
Room temperature, filters, and 10mL acetonitrile washs, and solid is dried to obtain piperazine mono-hydrochloric salts (1), productivity 97.5%, and standard silver nitrate titrates, and surveys
Obtain Cl-Content 29.02% (theoretical amount 28.98%).
Embodiment 4
Piperazine mono-hydrochloric salts (1)
250mL round-bottomed flask adds 20mmol compound (2), 40mL methanol, is stirred at room temperature and is passed through dry chlorination
Hydrogen, after not absorbing, continues the logical hydrogen chloride of stirring 1 hour, is warming up to 3 hours cold filtrations of return stirring, and 10mL methanol is washed
Washing, merge washing liquid and filtrate recycle, solid is dried to obtain piperazine dihydrochloride (3), (3) is added in 250mL round-bottomed flask, adds
With the Piperazine anhydrous (2) of the material amount such as (3), adding methanol 40mL, stirring temperature rising reflux reacts 24 hours, is cooled to room temperature, mistake
Filter, 10mL methanol washs, and solid is dried to obtain piperazine mono-hydrochloric salts (1), productivity 95.9%, and standard silver nitrate titrates, records Cl-Contain
Amount 28.89% (theoretical amount 28.98%).
Claims (6)
1. the preparation method of the piperazine mono-hydrochloric salts shown in a formula (1).
2. the preparation method of the piperazine mono-hydrochloric salts shown in a kind of formula (1) as claimed in claim 1, it is characterised in that with anhydrous
Piperazine (2) is passed through excess dry hydrogen chloride in polar solvent and prepares piperazine dihydrochloride formula (3).
3. the preparation method of the piperazine mono-hydrochloric salts shown in a kind of formula (1) as claimed in claim 1, it is characterised in that by (3)
Joining in polar solvent with (2) waiting material amount, 0 DEG C～stirred under reflux temperature 12-24 hour, cold filtration, washing is dry
Dry piperazine mono-hydrochloric salts (1).
4. polar solvent described in is one or more in C1-C6 alkylol, oxolane, Isosorbide-5-Nitrae-dioxane, DMF, preferably
Methanol, oxolane, Isosorbide-5-Nitrae-dioxane, DMF, most preferably Isosorbide-5-Nitrae-dioxane.
5. 0 DEG C～reflux temperature, preferably reflux temperature described in.
6. stirring 12-24 hour described in, preferably 20-24 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610443691.1A CN106045941A (en) | 2016-06-16 | 2016-06-16 | Method for preparing piperazine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610443691.1A CN106045941A (en) | 2016-06-16 | 2016-06-16 | Method for preparing piperazine hydrochloride |
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| CN106045941A true CN106045941A (en) | 2016-10-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610443691.1A Pending CN106045941A (en) | 2016-06-16 | 2016-06-16 | Method for preparing piperazine hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116120260A (en) * | 2023-01-06 | 2023-05-16 | 中国科学院宁波材料技术与工程研究所 | Preparation method and application of piperazine monohalogen salt |
| CN116143724A (en) * | 2023-01-06 | 2023-05-23 | 中国科学院宁波材料技术与工程研究所 | Preparation method and application of piperazine chloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3023211A (en) * | 1960-09-12 | 1962-02-27 | Jefferson Chem Co Inc | Method for the preparation of piperazine monohydrochloride |
| CN103254153A (en) * | 2013-05-24 | 2013-08-21 | 浙江苏泊尔制药有限公司 | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine |
| CN105237496A (en) * | 2015-10-27 | 2016-01-13 | 济南大学 | New method for synthesizing N-tertbutyloxycarbonyl piperazine |
-
2016
- 2016-06-16 CN CN201610443691.1A patent/CN106045941A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3023211A (en) * | 1960-09-12 | 1962-02-27 | Jefferson Chem Co Inc | Method for the preparation of piperazine monohydrochloride |
| CN103254153A (en) * | 2013-05-24 | 2013-08-21 | 浙江苏泊尔制药有限公司 | Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine |
| CN105237496A (en) * | 2015-10-27 | 2016-01-13 | 济南大学 | New method for synthesizing N-tertbutyloxycarbonyl piperazine |
Non-Patent Citations (3)
| Title |
|---|
| JIN WANG ET AL: "A Convenient Synthesis of N-Benzylpiperazine, 1-Aralkyl-4-benzylpiperazines and an Isostere of Idebenone", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》 * |
| 李贯良: "甲基哌嗪合成方法的改进", 《黄淮学刊》 * |
| 王国喜 等: "从哌嗪二盐酸盐合成肉桂基哌嗪", 《精细石油化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116120260A (en) * | 2023-01-06 | 2023-05-16 | 中国科学院宁波材料技术与工程研究所 | Preparation method and application of piperazine monohalogen salt |
| CN116143724A (en) * | 2023-01-06 | 2023-05-23 | 中国科学院宁波材料技术与工程研究所 | Preparation method and application of piperazine chloride |
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