CN101735159A - Method for producing monoacetylated homopiperazine - Google Patents
Method for producing monoacetylated homopiperazine Download PDFInfo
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- CN101735159A CN101735159A CN200910220605A CN200910220605A CN101735159A CN 101735159 A CN101735159 A CN 101735159A CN 200910220605 A CN200910220605 A CN 200910220605A CN 200910220605 A CN200910220605 A CN 200910220605A CN 101735159 A CN101735159 A CN 101735159A
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Abstract
The invention discloses a method for preparing monoacetylated homopiperazine. Corresponding homopiperazine bromate is prepared and neutralized under the alkaling condition by taking water as solvent; at about 0 DEG C, acetic anhydride is adopted for monoacetylated reaction. The invention starts from simple raw material to design and combine homopiperazine bromate which has reasonable route and is prepared by ethene diamine via sulfonylation, ring formation and removing sulfonyl; the homopiperazine bromate is alkalified and monoacetylated to finally generate the target product. The invention has moderate reaction condition, quick reaction, simple technology and easy operation, is suitable for industrial large-scale production, has high yield and high purity and satisfies the application requirements of pharmaceuticals industry and the like.
Description
Technical field:
The present invention relates to the method for making of the method for making of organic compound, particularly high piperazine.
Background technology:
Seven membered heterocyclic is polygon ring, their intermediate majority has intensive biological activity and pharmaceutical use, the high piperazine of nitrogen-containing heterocycle compound is a medicine synthetic important intermediate, contained dinitrogen atom can with many organic compound reactions, especially the structural modification of chemicals with transform in important role is arranged.High piperazine and high bridged piperazine derivatives thereof become important pharmaceutical intermediate, great potential with calmness, antipsychotic, anti-inflammatory and anti-nerve, be the staple product of forming a connecting link between chemical industry and the medicinal industry, be widely used in fields such as medicine, agricultural chemicals, tensio-active agent, energetic material.
High piperazine can be used N-(2-cyanoethyl) quadrol, N-(p-hydroxyl)-1, and amino compounds such as 3-propylene diamine, quadrol are that raw material synthesizes, and according to the difference of raw material, high piperazine has multiple synthetic route, as
1.1 it is synthetic by monoethanolamine (MEA)
This technology is catalyzer with Fe-Ni (Co), pressure 5.0MPa, and 300 ℃ of temperature, thanomin and liquefied ammonia reaction generate piperazine.This route raw material is easy to get, low price, and reaction product is piperazine and quadrol, but yield is low, and the yield of piperazine only is 25%, and the yield of coproduction quadrol is 45%.U.S. has this technology patent for Texaco and UnionCarbide company.
Early stage technology is to be that raw material is produced piperazine with the excess ammonia reaction with the monoethanolamine under pressurized with hydrogen, because the pressure height, medium is an explosion hazard gases, the very big danger that operates, and just there is the precedent that stops production because of blast in offshore company.
Succeeding in developing first with the solid acid in the world at present is the vapor phase process novel process of catalyzer, and this novel process makes thing science monoethanolamine steam under reduced pressure pass through solid acid catalyst in the time of 350～400 ℃, through the molecule inner dewatering reaction synthesizing piperazine.Compare with liquid phase method, the catalyzer of new process development is the solid acid that gasification silicon carries basic metal and trace acidic oxide compound composition, piperazine yield height, and catalyst life is long.China Zhejiang University has reported that under 15MPa by the research of thanomin and liquefied ammonia gas phase synthesizing piperazine, the piperazine yield only is 36%.
1.2 with oxyethane and quadrol is that raw material is synthetic
It is the raw material synthesizing piperazine that American I CTA company adopts oxyethane and quadrol, and reaction divided for three steps carried out.
Quadrol, oxyethane and solvent add in the condensation reactor by a certain percentage, and reaction generates N-beta-hydroxyethyl quadrol, and the catalysis in cyclization reactor of N-beta-hydroxyethyl quadrol and water, dehydration, cyclisation generate piperazine.Knockout tower is isolated Uricida, and the extracting rectifying dehydration obtains Piperazine anhydrous.
This operational path advantage is that raw material is easy to get, reaction conditions gentleness, yield height (82%), and the product of per step reaction all can be used as a finished product and sells, and can regulate product according to the market requirement.Shortcoming is that reaction needed for three steps finished complex process, long reaction time, facility investment expense height.Shaanxi Province just has a tame enterprise once to plan to introduce this technology, but because of various reasons and stranded.
1.3 with quadrol (EDA) is that raw material is synthetic
The catalyzer differential responses result who selects for use is also different.With the KZSM-5 zeolites as catalysts, temperature of reaction is 340 ℃, and through the reaction more than 3 days, the quadrol transformation efficiency reduces to 80% by 90% under gas phase condition, and the selectivity that generates piperazine and triethylene diamine remains on more than 95% substantially; If with H type zeolites as catalysts, under 330 ℃, 3 * 105Pa condition, 40% ethylenediamine solution contacts with catalyzer and reacts, and the piperazine yield is 36.95%, and selectivity is 57%; Perhaps with the CSZSM-5 zeolites as catalysts, under 340 ℃ condition, ethylenediamine solution and catalyzer contact reacts quadrol transformation efficiency are 55%, and generating the piperazine selectivity is the study on mechanism that the 55% Dalian Chemistry and Physics Institute and Fudan University have carried out molecular sieve catalytic quadrol system piperazine.
1.4 with the beta-hydroxyethyl quadrol is that raw material is synthetic
Catalyzer that this reaction is used is the Cu-Cr-Fe oxide compound, or the Cu-Cr-Mn oxide compound, pressure 8～26MPa, 110～300 ℃ of temperature of reaction, reaction times 2～40h, piperazine yield 78%～98%.The characteristics of this method are that by product is few, piperazine yield height, and shortcoming is that liquid phase rhythmic reaction, condition harshness, catalyzer are difficult to separate with reaction product.By beta-hydroxyethyl quadrol liquid phase reaction synthesizing piperazine, the yield of piperazine reaches 87% in the compressive reaction still in University Of Tianjin.
1.5 with the diethylenetriamine is that raw material is synthetic
About 175～225 ℃ of temperature of reaction, pressure is 20.4～34.0MPa, as if being catalyzer with Ni-Mgo, the Piperazine anhydrous productive rate can reach 81%, if make catalyzer with Reynolds Ni, the piperazine productive rate only has about 50%.But the polyamine compounds price is higher, and it is higher therefore to produce the Piperazine anhydrous cost with this method.
1.6 by two pure and mild quadrols is that raw material is synthetic
Under the condition of Ru3 (CO) 12 and Bu3P existence, ethylene glycol and quadrol generation cyclisation, condensation reaction, the yield that generates piperazine is 60%～90%, is oxy-compound at this method catalyzer, difficult realization industrialization.
Summary of the invention
The objective of the invention is to overcome above-mentioned not enough problem, the method for the high piperazine of a kind of manufacture order ethanoyl is provided, the reaction conditions gentleness is swift in response, and technology is simple, and is easy to operate.
The technical scheme that the present invention is adopted for achieving the above object is: the method for the high piperazine of a kind of manufacture order ethanoyl; by preparing corresponding high piperazine bromate; then with water as solvent; under alkaline condition, high piperazine hydrochlorate is neutralized; in temperature is about 0 ℃, takes acetic anhydride to carry out the single acetyl glycosylation reaction.Concrete reaction formula is as follows:
Described quadrol adds Tosyl chloride in basic solution; react intermediate product 1; after separating, add alkali lye, phase-transfer catalyst and toluene in the intermediate product 1; intermediate product 1 with bromine chloro thing parent's point substitution reaction takes place and ring closure reaction gets intermediate product 2; under the catalysis of acetic acid, phenol and bromic acid, intermediate product 2 generates the bromate of high piperazine, after the bromate of high piperazine alkalizes in water tank; in aqueous phase acid anhydrides acylations, obtain product.
Described the first step system intermediate product 1: in the time of 10-20 ℃, the aqueous solution of quadrol is added in the reactor, stir, in reaction system, add normal 10～20% aqueous sodium hydroxide solutions of 2-2.5, when being cooled to temperature 10-20 ℃, add Tosyl chloride in batches, ratio 2～2.5 equivalents of quadrol and Tosyl chloride, stirring reaction 5-6 hour, filtered 1-2 days, filter cake is pulled an oar with ethanol at 60 ℃, stirred 30 minutes, be cooled to room temperature and filter once more, the filter cake washing with alcohol, infrared drying to constant weight gets white solid intermediate product 1;
The second step system intermediate product 2: with intermediate product 1 (0.5～2 equivalent and intermediate product ratio), Tetrabutyl amonium bromide (with intermediate product 1 to 0.1～2 equivalents), toluene is (with intermediate product 1 to 6～8, M/V), 5% aqueous sodium hydroxide solution (with the intermediate product ratio be 3～8 equivalents) add in the reactor successively, rise to 76 ℃ under the stirring state, the bromine chlorine alkane solution that will be dissolved in the toluene adds in the reaction solution under this temperature, bromine chlorine alkane and intermediate product 1 are than being 0.5～3 equivalent, in 95-100 ℃ of backflow 8-9 hour, detect through TLC, react completely, reduce to room temperature, filter the water ethyl acetate extraction, with organic phase and toluene layer merging saturated common salt water washing, the vacuum rotary steam concentrated solution is cooled to 0-5 ℃ under agitation condition, filter, filter cake merges the back and adopts the IR bake drying, gets a white products intermediate product 2;
The bromate of the high piperazine of the 3rd step system: with intermediate product 2, Glacial acetic acid (with intermediate product 2 than being 0.5～2 equivalent), phenol (with intermediate product 2 than being 0.5～2 equivalent), 40% hydrogen bromide (with intermediate product 2 to the 8～15 equivalents) aqueous solution adds in the reactor successively, in 111 ℃ of back flow reaction 12 hours, after the TLC demonstration reacts completely, reduce to room temperature, solution is with toluene band water, being threaded to volume is thick liquid, add acetone, in temperature is 0-5 ℃ of stirring, filter, get the bromate of the high piperazine of a white solid;
The 4th step synthetic product: the bromate of high piperazine is soluble in water; with ethyl acetate extraction 3-4 time; water is under 0 ℃ of stirring condition; add 5～10 normal NaOH in batches; controlled temperature is below 10 ℃; stirred 30 minutes; be cooled to 0 ℃ and controlled temperature and be no more than 0 ℃; drip acid anhydrides to aqueous phase, the bromate of high piperazine and the equivalence ratio of acid anhydrides 1～5 equivalent stirred 4-5 hour; reaction solution extracts with extraction agent; separate two acylates, add the NaOH solid in the aqueous solution to regulate pH=10-11, water extracts with extraction agent once more; sample presentation is analyzed; GC shows to have only single acylate, and product obtains the high piperazine of a colourless liquid product monoacylphosphine by underpressure distillation.
Described the 4th step synthetic product: it is solvent that the bromate of high piperazine is taked ethanol respectively, and hydrochloric acid is catalyzer; The equivalence ratio 1 of the sodium hydroxide of adjustment usefulness and the bromate of high piperazine: 1-1: 2, wherein 1: 2 equivalence ratio is better.
Extraction agent in described the 4th step synthetic product adopts methylene dichloride, ethyl acetate, and toluene or chloroform etc., preferred chloroform, effect of extracting is fine.
The present invention is from simple raw material, and the synthetic route of design is reasonable, through sulfonylation, closes ring by quadrol, takes off the bromate that alkylsulfonyl becomes high piperazine, and alkalization is monoacylated, finally generates target product.The reaction conditions gentleness of this invention is swift in response, and technology is simple, and is easy to operate.Be suitable for large-scale industrial production, the productive rate height, the purity height satisfies the application demand of pharmaceutical industries etc.
Embodiment
Embodiment 1
The first step system intermediate product 1: in the time of 10-20 ℃, with quadrol (70g, water 1.17mol) (163ml) solution is added in the 2L four-hole bottle successively, stirs, in reaction system, add aqueous sodium hydroxide solution (114g, 2.85mol, 746ml water), lower the temperature 10-20 ℃ the time, add Tosyl chloride (496.6g in batches, 2.6mol), finish, stirred 5-6 hour.Filter 1-2 days (although reaction solution is more sticking, be difficult for filtering, but will filter as far as possible, because inorganic salt are arranged in the solution), filter cake is pulled an oar with ethanol at 60 ℃, stirred 30 minutes, and when being cooled to room temperature, filtered once more, the filter cake washing with alcohol, infrared drying gets white solid intermediate product (318g) to constant weight, and productive rate is 72.6%.
The second step system intermediate product 2: intermediate product 1 (36.8g, 0.1mol), Tetrabutyl amonium bromide (8g, 0.025mol), toluene (400ml), 5% aqueous sodium hydroxide solution (400ml) adds in the 2L four-hole bottle successively, rises to 76 ℃ under the stirring state, (18.9g, 0.12mol) solution is added dropwise in the reaction solution under this temperature will to be dissolved in bromine chlorine alkane in the 100ml toluene.In 95-100 ℃ of backflow 8-9 hour, detect through TLC, react completely.Reduce to room temperature, filter, the water ethyl acetate extraction is with organic phase and toluene layer merging saturated aqueous common salt washed twice.Vacuum rotary steam concentrated solution to volume is 100ml, is cooled to 0 ~-5 ℃ under agitation condition, filters, and twice filter cake merged, and the IR bake drying gets a white intermediate product 2 (33.6g), productive rate (82%).
The bromate of the high piperazine of the 3rd step system: intermediate product 2 (160g, 0.39mol), the 195ml Glacial acetic acid, 195ml phenol, 40% aqueous solution of hydrogen bromide of 1L adds in the 2L four-hole bottle successively, in 111 ℃ of backflows, reacts 12 hours.The TLC demonstration reacts completely.Reduce to room temperature, solution is with toluene band water, and being threaded to volume is thick liquid, adds proper amount of acetone, is 0 ~-5 ℃ of stirring in temperature, filter, the bromate (95.7g) of the high piperazine of a white solid, productive rate is 94%.
The 4th step synthetic product: (78g 0.3mol) is dissolved in the 50ml water bromate, uses ethyl acetate extraction 3-4 time, and water is under 0 ℃ of stirring condition, and (24g 0.6mol) adds NaOH in batches, makes its temperature below 10 ℃.Stirred 30 minutes, and under 0 ℃ of condition, dripped acetic anhydride (14ml), make temperature not surpass 0 ℃ in the process of dropping, stirred 4-5 hour to aqueous phase.Reaction solution chloroform extraction, purpose separate two acylates, and the aqueous solution adds the NaOH solid to regulate PH=10-11, and water is used chloroform extraction once more, the sample presentation analysis, and GC shows to have only single acylate.Product obtains a colourless liquid by underpressure distillation.Recycle, weighing products are 20g, productive rate 49%.
Claims (6)
1. the method for the high piperazine of manufacture order ethanoyl, it is characterized in that: by preparing corresponding high piperazine bromate, then with water as solvent, under alkaline condition high piperazine hydrochlorate being neutralized, is 0 ℃ in temperature, takes acetic anhydride to carry out the single acetyl glycosylation reaction.
2. the method for the high piperazine of a kind of manufacture order ethanoyl according to claim 1; it is characterized in that: quadrol adds Tosyl chloride in basic solution; react intermediate product 1; after separating, add alkali lye, phase-transfer catalyst and toluene in the intermediate product 1; intermediate product 1 with bromine chloro thing parent's point substitution reaction takes place and ring closure reaction gets intermediate product 2; under the catalysis of acetic acid, phenol and bromic acid; intermediate product 2 generates the bromate of high piperazine; after the bromate of high piperazine alkalizes in water tank; in aqueous phase acid anhydrides acylations, obtain product.
3. the method for the high piperazine of a kind of manufacture order ethanoyl according to claim 1 and 2, it is characterized in that: the first step system intermediate product 1: in the time of 10-20 ℃, the aqueous solution of quadrol is added in the reactor, stir, in reaction system, add normal 10～20% aqueous sodium hydroxide solutions of 2-2.5, when being cooled to temperature 10-20 ℃, add Tosyl chloride, ratio 2～2.5 equivalents of quadrol and Tosyl chloride, stirring reaction 5-6 hour in batches, filtered 1-2 days, filter cake is pulled an oar with ethanol at 60 ℃, stirs 30 minutes, is cooled to room temperature and filters once more, the filter cake washing with alcohol, infrared drying to constant weight gets white solid intermediate product 1;
The second step system intermediate product 2: with intermediate product 1, with the normal Tetrabutyl amonium bromide in intermediate product 1 to 0.1～2, with intermediate product 1 to 6～8, the toluene of M/V, with the intermediate product ratio be that 3～8 normal 5% aqueous sodium hydroxide solutions add in the reactor successively, rise to 76 ℃ under the stirring state, the bromine chlorine alkane solution that will be dissolved in the toluene adds in the reaction solution under this temperature, bromine chlorine alkane and intermediate product 1 are than being 0.5～3 equivalent, in 95-100 ℃ of backflow 8-9 hour, detect through TLC, react completely, reduce to room temperature, filter the water ethyl acetate extraction, with organic phase and toluene layer merging saturated common salt water washing, the vacuum rotary steam concentrated solution is cooled to 0-5 ℃ under agitation condition, filter, filter cake merges the back and adopts the IR bake drying, gets a white products intermediate product 2;
The bromate of the high piperazine of the 3rd step system: with intermediate product 2, with intermediate product 2 than be 0.5～2 normal Glacial acetic acid, with intermediate product 2 than being 0.5～2 normal phenol, adding in the reactor successively with normal 40% aqueous solution of hydrogen bromide in intermediate product 2 to 8～15, in 111 ℃ of back flow reaction 12 hours, after the TLC demonstration reacts completely, reduce to room temperature, solution is with toluene band water, being threaded to volume is thick liquid, add acetone, in temperature is 0-5 ℃ of stirring, filter, get the bromate of the high piperazine of a white solid;
The 4th step synthetic product: the bromate of high piperazine is soluble in water; with ethyl acetate extraction 3-4 time; water is under 0 ℃ of stirring condition; add 5～10 normal NaOH in batches; controlled temperature is below 10 ℃; stirred 30 minutes; be cooled to 0 ℃ and controlled temperature and be no more than 0 ℃; drip acid anhydrides to aqueous phase, the bromate of high piperazine and the equivalence ratio of acid anhydrides 1～5 equivalent stirred 4-5 hour; reaction solution extracts with extraction agent; separate two acylates, add the NaOH solid in the aqueous solution to regulate pH=10-11, water extracts with extraction agent once more; sample presentation is analyzed; GC shows to have only single acylate, and product obtains the high piperazine of a colourless liquid product monoacylphosphine by underpressure distillation.
4. the method for the high piperazine of a kind of manufacture order ethanoyl according to claim 3 is characterized in that: the 4th step synthetic product: it is solvent that the bromate of high piperazine is taked ethanol respectively, and hydrochloric acid is catalyzer.
5. the method for the high piperazine of a kind of manufacture order ethanoyl according to claim 3 is characterized in that: the 4th step synthetic product: the equivalence ratio 1 of the sodium hydroxide of adjustment usefulness and the bromate of high piperazine: 1-1: 2.
6. the method for the high piperazine of a kind of manufacture order ethanoyl according to claim 3 is characterized in that: the extraction agent in the 4th step synthetic product adopts methylene dichloride, ethyl acetate, toluene or chloroform.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891692A (en) * | 2010-08-26 | 2010-11-24 | 上海立科药物化学有限公司 | Preparation method of homopiperazine |
| CN104744382A (en) * | 2015-02-12 | 2015-07-01 | 渭南畅通药化科技有限公司 | Preparation method of homopiperzine |
| CN113372329A (en) * | 2021-06-15 | 2021-09-10 | 华东理工大学 | Preparation method of fasudil hydrochloride compound |
| 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 |
-
2009
- 2009-12-04 CN CN200910220605A patent/CN101735159A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891692A (en) * | 2010-08-26 | 2010-11-24 | 上海立科药物化学有限公司 | Preparation method of homopiperazine |
| CN104744382A (en) * | 2015-02-12 | 2015-07-01 | 渭南畅通药化科技有限公司 | Preparation method of homopiperzine |
| CN113372329A (en) * | 2021-06-15 | 2021-09-10 | 华东理工大学 | Preparation method of fasudil hydrochloride compound |
| CN113372329B (en) * | 2021-06-15 | 2022-10-18 | 华东理工大学 | Preparation method of fasudil hydrochloride compound |
| 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: 20100616 |