CN101891692A - Preparation method of homopiperazine - Google Patents
Preparation method of homopiperazine Download PDFInfo
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- CN101891692A CN101891692A CN2010102631166A CN201010263116A CN101891692A CN 101891692 A CN101891692 A CN 101891692A CN 2010102631166 A CN2010102631166 A CN 2010102631166A CN 201010263116 A CN201010263116 A CN 201010263116A CN 101891692 A CN101891692 A CN 101891692A
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- high piperazine
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Abstract
The invention discloses a preparation method of homopiperazine, comprising the following steps of firstly, obtaining N-(2-formylethyl) formamide by carrying out reflux reaction on ethylenediamine and formylation reagent, wherein the molar ratio of the ethylenediamine to the formylation reagent is 1:2-4; secondly, obtaining 1,4-dicarboxy homopiperazine by reacting the N-(2-formylethyl) formamide with 1,3-propane dihalide under the alkaline condition, wherein the molar ratio of the N-(2-formylethyl) formamide to the 1,3-propane dihalide is 1:1.0-1.2; and thirdly, obtaining the homopiperazine by removing formyl of the 1,4-dicarboxy homopiperazine in alcohol hydrochloride solution. The invention has the advantages of cheap raw materials, simple synthesis technology, mild protection conditions, mild technological conditions, simple equipment and easy recovery and reuse of used solvent in the whole process.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate in particular to a kind of preparation method of high piperazine.
Background technology
The high piperazine of nitrogen heterocyclic ring has another name called 1, and 4-phenodiazine suberane is a medicine synthetic important intermediate, contained dinitrogen atom can with many organic compound reactions.High piperazine can be used for medicines such as synthetic high piperazine hydrochloride, marezine, Carbamzepine, quinolone and chloreyclizine.Replace piperazine synthesize the active obvious enhancing of antihistaminic agent behind the medicines such as marezine, curosajin according to people such as Armiger H [1] report with high piperazine.Ziegler[2] etc. the correlation research of pharmaceutical activity and structure is shown that the existence of high piperazine group significantly improves the activity of related drugs, thereby the research of high piperazine series compound is more and more come into one's own.
The preparation method of existing high piperazine mainly contains following several routes:
With N-(2-cyanoethyl) quadrol be raw material (
J. Org. Chem.26,1961,131-134), be catalyzer with Girdler G-49A, under pressurized with hydrogen, the hydrogenation ring-closure reaction generates high piperazine, 1.5 hours reaction times, high piperazine yield 32.4%.
The advantage of this technology is that reaction scheme is short, but because the pressure height, medium is an explosion hazard gases, and is relatively more dangerous, operates waywardly, and productivity ratio is lower.
2. with the N-(beta-hydroxy)-1, the 3-propylene diamine is a raw material, carries out in high-temperature high-pressure reaction kettle, catalyzer is Cu-Cr-Ba-Al
2O
3, feed stock conversion 93.2%, high piperazine yield 90%.
This byproduct of reaction is few, high piperazine yield height, but severe reaction conditions, and catalyzer is difficult for preparation, adopts the Japanese Patent of this technology more.Chemical engineering institute of China University Of Tianjin has developed this technology, and the selectivity of the cyclization effect of high piperazine is near 95%, and high piperazine ultimate yield is more than 90%.
With the quadrol that is easy to get be raw material (chemical reagent, 28(5), 2006,311-312), through sulfonylation, the synthetic high piperazine of sulfonylation 3 step reaction is taken off in cyclisation, total recovery can reach 78%.
In this synthetic method, the first step is reacted in aqueous sodium hydroxide solution, product yield 86%.Adopt the NaH/DMF system in the second step cyclization, added phase-transfer catalyst, can finish cyclization under comparatively gentle condition, crude product can directly carry out next step reaction; Take off alkylsulfonyl at last under the HBr/HOAc/PhOH reaction conditions, yield can reach 91%; This route raw material is easy to get, and simple to operate, yield is higher, is high piperazine and the high bridged piperazine derivatives synthetic route of using always; But raw material and solvent cost are higher, and very high to reclaiming requirement, price advantage is not obvious.
4. with 1,3-propylene diamine and ethylene glycol are raw material (JP2006306790), high-pressure hydrogenation reaction, reaction yield 23.5%.
This route raw material is simple and easy to, but temperature of reaction up to 150～400 ℃, complex process, yield has only 21%.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of the high piperazine that a kind of raw material is inexpensive, synthesis technique is simple, equipment is simple, cost is low.
The present invention solves the problems of the technologies described above the technical scheme of being taked: a kind of preparation method of high piperazine may further comprise the steps:
The first step:, obtain N-(2-formyl radical ethyl) methane amide with quadrol and formylation reagent back flow reaction, wherein, the mol ratio of quadrol and formylation reagent is 1:2～4;
Second step: under the basic solvent condition) methane amide and 1 with N-(2-formyl radical ethyl, the reaction of 3-dihalopropane, obtain 1, the high piperazine of 4-diformyl, wherein, N-(2-formyl radical ethyl) methane amide and 1, the mol ratio of 3-dihalopropane is 1:1.0～1.2;
The 3rd step: 1, the high piperazine of 4-diformyl is in the hydrochloric acid alcoholic solution, and the piptonychia acyl group obtains high piperazine.
Concrete, in the first step, the mol ratio of quadrol and formylation reagent can be 1:2,2.2,2.5,2.8,3,3.2,3.5,3.8 or 4;
In second step, N-(2-formyl radical ethyl) methane amide and 1, the mol ratio of 3-dihalopropane can be 1:1.0,1.02,1.05,1.08,1.1,1.12,1.15,1.18 or 1.2.
On the basis of such scheme, the formylation reagent that adopts in the first step is a kind of in ethyl formate, methyl-formiate or the formic acid.
On the aforesaid method basis, in the first step, the mol ratio of described quadrol and formylation reagent is preferably 1:3～3.5, reaction 2～5h, 20～60 ℃ of temperature of reaction make N-(2-formyl radical ethyl) methane amide.
On the aforesaid method basis, adopt in second step 1, the 3-dihalopropane is 1,3-propylene dichloride, 1-bromo-3-chloropropane, 1-chloro-3-iodopropane, 1,3-dibromopropane, 1-bromo-3-iodopropane or 1, a kind of in the 3-diiodo propane; The alkali of described formation alkaline condition is one or more in the hydride, oxyhydroxide, carbonate of basic metal or alkaline-earth metal.
On the aforesaid method basis, in second step, solvent is a dimethyl formamide, with N-(2-formyl radical ethyl) formamide soln slowly drops in the alkaliferous solvent, drips 1 again, and the 3-dihalopropane reacts.
On the aforesaid method basis, in second step, solvent and N-(2-formyl radical ethyl) the volume mass ratio of methane amide is 10～50:1, alkali and N-(2-formyl radical ethyl) the mol ratio 2.0～2.5:1 of methane amide.
On the aforesaid method basis, described N-(2-formyl radical ethyl) methane amide and 1, the mol ratio of 3-dihalopropane is 1:1.05～1.1,60～90 ℃ of temperature of reaction, reaction times 8～20h obtains 1, the high piperazine of 4-diformyl.
On the aforesaid method basis, in the hydrochloric acid alcoholic solution that adopts in the 3rd step, alcohol is a kind of in methyl alcohol, ethanol, the Virahol.
On the aforesaid method basis; in the 3rd step; concentrated hydrochloric acid is 1:1.5～2.5 with the volume ratio of alcohol in the hydrochloric acid alcoholic solution; hydrochloric acid alcoholic solution and 1, the volume mass ratio of the high piperazine of 4-diformyl is 5～8:1,50～70 ℃ of temperature of reaction; reaction times 3～7h; obtain high piperazine hydrochloride, with the ammoniacal liquor neutralization, the ethyl acetate extraction distillation obtains high piperazine.
Compare with the synthetic method of existing high piperazine, the invention has the beneficial effects as follows:
1) raw material is cheap;
2) synthesis technique is simple, and the protective condition gentleness is gone in last protection;
3) processing condition gentleness, equipment is simple;
4) solvent of using in the whole process all is easy to recycling;
In a word, present method raw material cheaply is easy to get, the production technique gentleness, and equipment is simple, and cost is low, and good using value is arranged.
Embodiment
The synthesis step of high piperazine:
The first step: the preparation of methane amide N-(2-formyl radical ethyl):
With the quadrol is raw material; with the formylation reagent reaction, wherein, quadrol 1mol; formylation reagent 2～4mol; best 3～3.5mol, reaction 2～5h, best 2～3h; 20～60 ℃ of temperature of reaction; 40～50 ℃ of optimal reaction temperatures form N-(2-formyl radical ethyl) methane amide, yield 80～95%.
Concrete steps are: under the nitrogen protection, the 227g ethyl formate slowly is added drop-wise in the quadrol of 60.0g, the dropping process remains on 20～30 ℃.Dropwise backflow 2h.After the cooling, the adularescent solid is separated out, and filters promptly to obtain product.Adopt re-crystallizing in ethyl acetate, obtain 108g N-(2-formyl radical ethyl) methane amide, yield 93%.Mp.?108～109℃（lit.?109～110℃）。
Second step: 1, the preparation of the high piperazine of 4-diformyl:
Under alkaline condition; N-(2-formyl radical ethyl) methane amide and 1; the reaction of 3-dihalopropane, wherein, N-(2-formyl radical ethyl) methane amide 1mol; 1; 3 dihalopropanes, 1.0～1.2mol, the best is 1.05～1.1mol, 10～50 times of volumes of dimethyl formamide (DMF) solvent; best 20～30 times of volumes; NaH consumption 2.0～2.5mol, best 2.1～2.3mol, 60～90 ℃ of temperature of reaction; best 60～65 ℃; reaction times 8～20h, optimum reacting time 8～10h obtains 1; the high piperazine of 4-diformyl, yield 40～60%.
Concrete steps are: under the nitrogen protection, with 113g N-(2-formyl radical ethyl) DMF(1500ml of methane amide) solution, slowly drop to the DMF(1000ml that contains 88g 60%NaH) in the suspension liquid, after stirring 30～60min under the room temperature, be warming up to 60～65 ℃, drip 212.1g 1, the 3-dibromopropane, after dropwising, insulation reaction 8～10h; After reaction finished, 70～80% DMF was reclaimed in underpressure distillation, will add water, ethyl acetate extraction in the reaction mixture then; anhydrous sodium sulfate drying concentrates, and 180～185 ℃ of (1mmHg) cuts are collected in distillation; obtain 70.2g 1, the high piperazine of 4-diformyl, yield 45%.
The 3rd step: the preparation of high piperazine:
1, the high piperazine 1g of 4-diformyl, the hydrochloric acid alcoholic solution is a concentrated hydrochloric acid: ethanol=1:2(v/v); the consumption of hydrochloric acid alcoholic solution is 5～8 times of volumes; 5～6 times of volumes of optimum amount, 50～70 ℃ of temperature of reaction, 55～60 ℃ of optimal reaction temperatures; reaction times 3～7h; optimum reacting time 5～6h obtains high piperazine hydrochloride, neutralizes with ammoniacal liquor; the ethyl acetate extraction distillation obtains high piperazine, yield 70～85%.
Concrete steps are: with 45g 1, the high piperazine of 4-diformyl is dissolved in 150ml ethanol, under the room temperature, adds the 75ml concentrated hydrochloric acid in this mixed solution, is incubated 50～60 ℃, reaction 5～6h, and concentrating under reduced pressure obtains yellow dope.With this solid 50ml water dissolution, be neutralized to pH=9 with ammoniacal liquor, ethyl acetate extraction distills behind the anhydrous sodium sulfate drying, obtains high piperazine crude product.73～75 ℃ of (30mmHg) cuts are collected in underpressure distillation, obtain the high piperazine of 22.5g, yield 78%.
Claims (9)
1. the preparation method of a high piperazine is characterized in that may further comprise the steps:
The first step:, obtain N-(2-formyl radical ethyl) methane amide with quadrol and formylation reagent back flow reaction, wherein, the mol ratio of quadrol and formylation reagent is 1:2～4;
Second step: under the basic solvent condition) methane amide and 1 with N-(2-formyl radical ethyl, the reaction of 3-dihalopropane, obtain 1, the high piperazine of 4-diformyl, wherein, N-(2-formyl radical ethyl) methane amide and 1, the mol ratio of 3-dihalopropane is 1:1.0～1.2;
The 3rd step: 1, the high piperazine of 4-diformyl is in the hydrochloric acid alcoholic solution, and the piptonychia acyl group obtains high piperazine.
2. the preparation method of high piperazine according to claim 1 is characterized in that: the formylation reagent that adopts in the first step is a kind of in ethyl formate, methyl-formiate, the formic acid.
3. the preparation method of high piperazine according to claim 1 and 2; it is characterized in that: in the first step, the mol ratio of described quadrol and formylation reagent is 1:3～3.5, and the reaction times is 2～5h; temperature of reaction is 20～60 ℃, makes N-(2-formyl radical ethyl) methane amide.
4. the preparation method of high piperazine according to claim 1, it is characterized in that: adopt in second step 1, the 3-dihalopropane is 1,3-propylene dichloride, 1-bromo-3-chloropropane, 1-chloro-3-iodopropane, 1,3-dibromopropane, 1-bromo-3-iodopropane or 1, a kind of in the 3-diiodo propane; The alkali of described formation alkaline condition is one or more in the hydride, oxyhydroxide, carbonate of basic metal or alkaline-earth metal.
5. the preparation method of high piperazine according to claim 4 is characterized in that: in second step, solvent is a dimethyl formamide; with N-(2-formyl radical ethyl) formamide soln slowly drops in the alkaliferous solvent; drip 1 again, the 3-dihalopropane reacts.
6. the preparation method of high piperazine according to claim 4; it is characterized in that: in second step; solvent and N-(2-formyl radical ethyl) the volume mass ratio of methane amide is 10～50:1, alkali and N-(2-formyl radical ethyl) the mol ratio 2.0～2.5:1 of methane amide.
7. according to the preparation method of claim 1 or 4 or 5 or 6 described high piperazines; it is characterized in that: methane amide and 1 described N-(2-formyl radical ethyl); the mol ratio of 3-dihalopropane is 1:1.05～1.1; 60～90 ℃ of temperature of reaction; reaction times 8～20h; obtain 1, the high piperazine of 4-diformyl.
8. the preparation method of high piperazine according to claim 1 is characterized in that: in the hydrochloric acid alcoholic solution that adopts in the 3rd step, alcohol is a kind of in methyl alcohol, ethanol, the Virahol.
9. according to the preparation method of claim 1 or 8 described high piperazines; it is characterized in that: in the 3rd step; concentrated hydrochloric acid is 1:1.5～2.5 with the volume ratio of alcohol in the hydrochloric acid alcoholic solution; hydrochloric acid alcoholic solution and 1, the volume mass ratio of the high piperazine of 4-diformyl is 5～8:1,50～70 ℃ of temperature of reaction; reaction times 3～7h; obtain high piperazine hydrochloride, with the ammoniacal liquor neutralization, the ethyl acetate extraction distillation obtains high piperazine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360330A (en) * | 2013-08-07 | 2013-10-23 | 刘怀振 | Synthetic method for homopiperazine |
| CN106699674A (en) * | 2016-11-23 | 2017-05-24 | 苏州百灵威超精细材料有限公司 | Method for preparing homopiperazine by utilizing ethyl trifluoroacetate |
| CN114957163A (en) * | 2022-02-12 | 2022-08-30 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
| CN116143712A (en) * | 2023-02-20 | 2023-05-23 | 南京杰运医药科技有限公司 | Synthesis method of N, N' -bis- (3-hydroxypropyl) homopiperazine |
| CN114957163B (en) * | 2022-02-12 | 2024-05-10 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
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| JP2006306790A (en) * | 2005-04-28 | 2006-11-09 | Koei Chem Co Ltd | Method for producing homopiperazine |
| CN101735159A (en) * | 2009-12-04 | 2010-06-16 | 大连凯飞精细化工有限公司 | Method for producing monoacetylated homopiperazine |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006306790A (en) * | 2005-04-28 | 2006-11-09 | Koei Chem Co Ltd | Method for producing homopiperazine |
| CN101735159A (en) * | 2009-12-04 | 2010-06-16 | 大连凯飞精细化工有限公司 | Method for producing monoacetylated homopiperazine |
Non-Patent Citations (3)
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| G.A.OLAH等: "甲酰试剂", 《化学试剂》 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360330A (en) * | 2013-08-07 | 2013-10-23 | 刘怀振 | Synthetic method for homopiperazine |
| CN106699674A (en) * | 2016-11-23 | 2017-05-24 | 苏州百灵威超精细材料有限公司 | Method for preparing homopiperazine by utilizing ethyl trifluoroacetate |
| CN106699674B (en) * | 2016-11-23 | 2019-06-18 | 苏州百灵威超精细材料有限公司 | A method of homopiperazine is prepared using Trifluoroacetic Acid Ethyl Ester |
| CN114957163A (en) * | 2022-02-12 | 2022-08-30 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
| CN114957163B (en) * | 2022-02-12 | 2024-05-10 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
| CN116143712A (en) * | 2023-02-20 | 2023-05-23 | 南京杰运医药科技有限公司 | Synthesis method of N, N' -bis- (3-hydroxypropyl) homopiperazine |
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Application publication date: 20101124 |