CN103254153A - Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine - Google Patents
Preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine Download PDFInfo
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Abstract
The invention discloses a preparation method of high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine, which comprises the following preparation steps: 1) reacting piperazine and piperazine dihydrochloride in solvent to prepare piperazine monohydrochloride; 2) reacting the piperazine monohydrochloride and 2-(2-chloroethoxy)ethanol in solvent; 3) after the reaction is finished, filtering to recover piperazine dihydrochloride, and drying for repeated use; 4) evaporating the filtrate to remove the solvent, thus obtaining a high-purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine crude product; and 5) performing vacuum reduced pressure rectification on the 1-[2-(2-hydroxyethoxy)ethyl]piperazine crude product, and collecting the 1-[2-(2-hydroxyethoxy)ethyl]piperazine fraction to obtain the high-purity product. The invention effectively solves the problem that the disubstituted compound impurity content is high and improves the product purity; and the cost of the raw materials is low, the process cost is greatly lowered, and the process is greener and more environment-friendly, thereby ensuring that the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine; Be specifically related to prepare intermediate 1-[2-(2-hydroxy ethoxy) ethyl of anti-spiritual class disease therapeuticing medicine quetiapine fumarate] preparation method of piperazine.
Background technology
1-[2-(2-hydroxy ethoxy) ethyl] piperazine, be called for short HEEP, outward appearance is colourless to light yellow viscous liquid, the CAS registration number is [13349-82-1], molecular structure such as general formula I:
General formula I
Synthetic quetiapine fumarate has the report of multiple route, but route the most practical, that economic worth is arranged most is the use dibenzo [b that reports among the patent EP240228, f] [1,4] sulphur azatropylidene-11-ketone is through making the scheme of Quetiapine with key intermediate HEEP condensation behind the chloro, and HEEP is most important intermediate in the Quetiapine preparation process.
The simplest synthetic route of HEEP is to be that starting material and 2-(2-chloroethoxy) ethanol condensation reaction takes place under alkaline condition makes with the piperazine.Reaction formula is as follows.
But this synthetic method is owing to send on the piperazine two imido grpup chemical environments identical, the condensation reaction meeting produces a large amount of di-substituted impurity that waits, total recovery has only 55%, gas phase purity is lower than 85%, for addressing this problem, need adopt the repeatedly mode of rectifying removal of impurities, each purification approximately will be lost the finished product of 5-8%, cause the products production cost very high like this, lack competitive power in market.
Some researchs think that this may be that the halogen reactive behavior causes too by force, and reaction is improved, and use Tosyl chloride (TsCl) and glycol ether reaction, generate the glycol ether ester of sulfonylation, and it is comparatively easy to make next step form single substituent control condition.Reaction formula is as follows.
But this method does not have the basic problem that solves reaction yet, at first is that glycol ether ester and the piperazine reaction of sulfonylation still has dibasic problem.Secondly; Tosyl chloride (TsCl) and glycol ether reaction itself also can produce the situation of disulfonylization; the raw material of the glycol ether ester of the sulfonylation that uses itself just has dibasic problem; also can produce corresponding impurity; with the downward prepared in reaction HEEP of such raw material, the impurity situation of back is more complicated.
For solving dibasic problem, patent Be556239 has reported a kind of method, as raw material, with 2-(2-chloroethoxy) ethanol condensed again hydrolysis makes HEEP under the alkaline condition with the piperazinecarboxylic acid ethyl ester.Reaction formula is as follows.
This route is one side of protection piperazine earlier; avoided the generation of disubstitution product impurity; but starting raw material piperazinecarboxylic acid ethyl ester is difficult to obtain; raw materials cost is higher; secondly reaction scheme prolongs relatively; total recovery is low, and the insufficient of hydrolysis reaction also will introduce new impurity simultaneously, and these have all limited the suitability for industrialized production of this route.
All have different defectives among the above multiple preparation method, or impurity such as piperazine raw material, two substituted-piperazinyl, hydroxyethyl piperazine exceed standard seriously in the product, or raw material sources are difficult to obtain, cost is higher, lacks the market competitiveness.
Summary of the invention
The object of the present invention is to provide a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine; The present invention has solved the high problem of di-substituted foreign matter content in the existing commercially available prod effectively, and product purity increases substantially; And cost of material is cheap, wide material sources, and the technology cost significantly reduces; The piperazine dihydrochloride that reaction treatment reclaims is reusable, makes three wastes treatment capacity reduce greatly, makes technology environmental protection more, is fit to suitability for industrialized production.
For achieving the above object, technical scheme of the present invention is:
A kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step:
1) adopts piperazine and piperazine dihydrochloride in solvent, to react and produce the piperazine mono-hydrochloric salts;
2) utilize the piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol that prepare in the step 1) in solvent, to react;
3) reaction finishes after-filtration recovery piperazine dihydrochloride, can reuse after drying;
4) the step 3) filtrate filtered is steamed namely obtain highly purified 1-[2-(2-hydroxy ethoxy) ethyl after desolventizing] piperazine (HEEP) crude product;
5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, collect 1-[2-(2-hydroxy ethoxy) ethyl] piperazine (HEEP) cut namely gets high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product.
The adding mol ratio of piperazine and piperazine dihydrochloride is 1:0.8-1.2 in the described step 1); Solvent adopts a kind of in water and the alcoholic solvent in the described step 1); And the add-on of solvent is calculated with envelope-bulk to weight ratio mL/g, is 1.8-2.2 times of piperazine add-on.
The adding mol ratio of described piperazine and piperazine dihydrochloride is preferably 1:0.91.And the add-on of solvent is calculated with envelope-bulk to weight ratio mL/g, is 2.0 times of piperazine add-on.
Described alcoholic solvent adopts a kind of in methyl alcohol, ethanol, the Virahol.
Described step 2) the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is (1.8-2.2) in: 1; Described step 2) solvent adopts a kind of in polar solvent and the non-polar solvent in; And the add-on of solvent is calculated with weight ratio g/g, is 1.2-2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Described step 2) temperature of reaction in is 40-120 ℃; Reaction times is 2-8 hour.
The adding mol ratio of described piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is preferably 1.82:1; And the add-on of solvent is calculated with weight ratio g/g, is 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Temperature of reaction is preferably 80 ℃; Reaction times is preferably 5.5 hours.
Described polar solvent adopts a kind of in water and the alcoholic solvent; Described non-polar solvent adopts a kind of in methylene dichloride, chloroform, hexanaphthene, normal hexane, toluene, the dimethylbenzene.
Described alcoholic solvent adopts a kind of in methyl alcohol, ethanol, the Virahol.
The rectification under vacuum temperature is 120-160 ℃ in the described step 5), and vacuum tightness is 10-30mmHg.
The reaction equation that the present invention relates to is as follows:
The invention has the beneficial effects as follows: 1, the present invention is the main raw material reaction that feeds intake by using the piperazine mono-hydrochloric salts; the influence of namely having protected the end on the piperazine ring not reacted, thus high serious problems of di-substituted foreign matter content in the existing commercially available prod solved effectively.The crude product purity of its HEEP of preparation method provided by the invention can reach more than 98%, has improved product purity, and has also improved transformation efficiency and the yield of reaction, and yield can reach more than 75%, makes the technology cost significantly reduce.
2, the raw material of piperazine mono-hydrochloric salts can use piperazine dihydrochloride and piperazine to produce easily; be that starting raw material is compared with glycol ether ester or the piperazinecarboxylic acid ethyl ester of the tosylation of existing bibliographical information; this cost of material is cheap, and wide material sources are fit to suitability for industrialized production.
3, the piperazine dihydrochloride of reaction treatment recovery can need not to handle, and only can repeat after the drying to apply mechanically, and makes three wastes treatment capacity reduce greatly, makes technology environmental protection more.
Description of drawings
Fig. 1 is 1-[2-(2-hydroxy ethoxy) ethyl that the present invention prepares] infrared spectrogram of piperazine;
Fig. 2 is 1-[2-(2-hydroxy ethoxy) ethyl that the present invention prepares] mass spectrum of piperazine;
Fig. 3 is 1-[2-(2-hydroxy ethoxy) ethyl that the present invention prepares] the nucleus magnetic hydrogen spectrum figure of piperazine;
Fig. 4 is 1-[2-(2-hydroxy ethoxy) ethyl that the present invention prepares] the nuclear-magnetism carbon spectrogram of piperazine;
Fig. 5 is the gas chromatogram of the embodiment of the invention 1;
Fig. 6 is the gas chromatogram of the embodiment of the invention 2;
Fig. 7 is the gas chromatogram of the embodiment of the invention 3;
Fig. 8 is the gas chromatogram of the embodiment of the invention 4;
Fig. 9 is the gas chromatogram of the embodiment of the invention 5.
Embodiment
A kind of high purity 1-[2-of present embodiment (2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the adding mol ratio of piperazine and piperazine dihydrochloride is 1:0.91(piperazine dihydrochloride 168g(1.06mol); Piperazine 100g(1.16mol)), (add-on of methyl alcohol is calculated with envelope-bulk to weight ratio mL/g in methyl alcohol, be 2.0 times of piperazine add-on) be heated with stirring to back flow reaction 1.2 hours, be cooled to 13 ℃, suction filtration, filter cake is drained with small amount of methanol washing, and filter cake was 75 ℃ of dryings 5.5 hours; Obtain the about 245g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts for preparing in the step 1) and 2-(2-chloroethoxy) ethanol in the 500ml reaction flask, add solvent reaction, wherein the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 1.82:1(piperazine mono-hydrochloric salts 90g(734.5mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) solvent adopts polar solvent methyl alcohol in; And the add-on of methyl alcohol is calculated with weight ratio g/g, is 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 80 ℃; Insulation reaction is 5.5 hours under this temperature.3) after reaction finishes, be lower than 60 ℃ of underpressure distillation and remove the about 50g of half quantity of methyl alcohol, be cooled to 18 ℃, filter, filter cake washs with small amount of methanol and is piperazine dihydrochloride, 53 ℃ of dryings after 7.5 hours with regard to recyclable recycling.4) the step 3) filtrate filtered slowly is heated to 95 ℃, namely obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl behind vacuum decompression distillation for removing methanol and the residual piperazine] piperazine (HEEP) crude product.5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=148 ℃, vacuum tightness=15mmHg) is colorless transparent viscous liquid, 53.8g, molar yield 76.9% is high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product.Analytical results sees that shown in Fig. 1-5,3390.81 absorption peak can be confirmed the hydroxyl among the HEEP in Fig. 1 infrared spectra, and 1119.10 can confirm the ehter bond among the HEEP, can obtain containing in the sample HEEP molecular structure conclusion of ethoxy ethanol structure thus.174 molecular ion peak can obviously be confirmed the molecular weight of HEEP in Fig. 2 mass spectrum, and 84 peak shows the piperazine fragment peak, and can obtain sample thus is the conclusion of the HEEP of molecular weight 174 really.3.71 is fignal centers of hydroxyl hydrogen in Fig. 3 nucleus magnetic hydrogen spectrum, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on the piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on the piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.Fig. 5 records purity (GC) 99.7%.
Embodiment 2
A kind of high purity 1-[2-of present embodiment (2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step: 1) in reaction flask, add the piperazine dihydrochloride after piperazine and embodiment 1 reclaim; Wherein the adding mol ratio of the piperazine dihydrochloride after piperazine and the recovery is 1:0.91(piperazine dihydrochloride 180g(1.06mol); Piperazine 100g(1.16mol)), (add-on of ethanol is calculated with envelope-bulk to weight ratio mL/g in ethanol, be 1.8 times of piperazine add-on) be heated with stirring to back flow reaction 1.2 hours, be cooled to 13 ℃, suction filtration, filter cake is drained with small amount of ethanol washing, and filter cake was 85 ℃ of dryings 5.5 hours; Obtain the about 238g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts for preparing in the step 1) and 2-(2-chloroethoxy) ethanol in the 500ml reaction flask, add solvent reaction, wherein the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 1.93:1(piperazine mono-hydrochloric salts 95g(774.6mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) solvent adopts polar solvent water in; And the add-on of water is calculated with weight ratio g/g, is 1.2 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 78 ℃; Insulation reaction is 6.5 hours under this temperature.3) after reaction finished, the about 40g of half water yield was removed in 75 ℃ of underpressure distillation, is cooled to 18 ℃, filtration, filter cake is piperazine dihydrochloride, 65 ℃ of dryings after 7.5 hours with regard to recyclable recycling.4) the step 3) filtrate filtered slowly is heated to 95 ℃, namely obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl behind vacuum decompression dephlegmate and the residual piperazine] piperazine (HEEP) crude product.5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=155 ℃, vacuum tightness=17mmHg) is colorless transparent viscous liquid, 55.4g, molar yield 79.2%, be high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product, analytical results is seen Fig. 1-4 and shown in Figure 6,3390.81 absorption peak can be confirmed the hydroxyl among the HEEP in Fig. 1 infrared spectra, 1119.10 can confirm the ehter bond among the HEEP, can obtain containing in the sample HEEP molecular structure conclusion of ethoxy ethanol structure thus.174 molecular ion peak can obviously be confirmed the molecular weight of HEEP in Fig. 2 mass spectrum, and 84 peak shows the piperazine fragment peak, and can obtain sample thus is the conclusion of the HEEP of molecular weight 174 really.3.71 is fignal centers of hydroxyl hydrogen in Fig. 3 nucleus magnetic hydrogen spectrum, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on the piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on the piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.Fig. 6 records purity (GC) 99.7%.
Embodiment 3
A kind of high purity 1-[2-of present embodiment (2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the adding mol ratio of piperazine and piperazine dihydrochloride is 1:0.8(piperazine dihydrochloride 158g(0.93mol); Piperazine 100g(1.16mol)), (add-on of water is calculated with envelope-bulk to weight ratio mL/g, is 2.2 times of piperazine add-on) was heated with stirring to back flow reaction 1 hour in water, was cooled to 10 ℃, suction filtration, and filter cake was 70 ℃ of dryings 5 hours; Obtain the about 225g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts for preparing in the step 1) and 2-(2-chloroethoxy) ethanol in the 500ml reaction flask, add solvent reaction, wherein the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.0:1(piperazine mono-hydrochloric salts 98.4g(802.8mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) solvent adopts polar solvent ethanol in; And the add-on of ethanol is calculated with weight ratio g/g, is 2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 40 ℃; Insulation reaction is 2 hours under this temperature.3) after reaction finishes, be lower than 60 ℃ of underpressure distillation and remove the about 30g of half amount of alcohol, be cooled to 15 ℃, filter, filter cake washs with small amount of ethanol and is piperazine dihydrochloride, 50 ℃ of dryings after 7 hours with regard to recyclable recycling.4) the step 3) filtrate filtered slowly is heated to 90 ℃, namely obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl behind vacuum decompression distillation for removing methanol and the residual piperazine] piperazine (HEEP) crude product.5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=120 ℃, vacuum tightness=10mmHg) is colorless transparent viscous liquid, 54.7g, molar yield 78.2% is high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product.Analytical results is seen Fig. 1-4 and shown in Figure 7, and 3390.81 absorption peak can be confirmed the hydroxyl among the HEEP in Fig. 1 infrared spectra, and 1119.10 can confirm the ehter bond among the HEEP, can obtain containing in the sample HEEP molecular structure conclusion of ethoxy ethanol structure thus.174 molecular ion peak can obviously be confirmed the molecular weight of HEEP in Fig. 2 mass spectrum, and 84 peak shows the piperazine fragment peak, and can obtain sample thus is the conclusion of the HEEP of molecular weight 174 really.3.71 is fignal centers of hydroxyl hydrogen in Fig. 3 nucleus magnetic hydrogen spectrum, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on the piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on the piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.8% by Fig. 7.
Embodiment 4
A kind of high purity 1-[2-of present embodiment (2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step: 1) in reaction flask, add the piperazine dihydrochloride after piperazine and embodiment 3 reclaim; Wherein the adding mol ratio of the piperazine dihydrochloride after piperazine and the recovery is 1:1.2(piperazine dihydrochloride 236g(1.39mol); Piperazine 100g(1.16mol)), (add-on of Virahol is calculated with envelope-bulk to weight ratio mL/g in Virahol, be 2.1 times of piperazine add-on) in be heated with stirring to back flow reaction 1.5 hours, be cooled to 20 ℃, suction filtration, filter cake is drained with a small amount of washed with isopropyl alcohol, and filter cake was 90 ℃ of dryings 6 hours; Obtain the about 250g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts for preparing in the step 1) and 2-(2-chloroethoxy) ethanol in the 500ml reaction flask, add solvent reaction, wherein the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.2:1(piperazine mono-hydrochloric salts 102.1g(883.1mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) solvent adopts the polar solvent Virahol in; And the add-on of Virahol is calculated with weight ratio g/g, is 1.8 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 120 ℃; Insulation reaction is 8 hours under this temperature.3) after reaction finished, the about 60g of half Virahol amount was removed in 80 ℃ of underpressure distillation, is cooled to 20 ℃, filtration, filter cake is piperazine dihydrochloride after with a small amount of washed with isopropyl alcohol, 70 ℃ of dryings after 8 hours with regard to recyclable recycling.4) the step 3) filtrate filtered slowly is heated to 100 ℃, namely obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl behind vacuum decompression dephlegmate and the residual piperazine] piperazine (HEEP) crude product.5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=165 ℃, vacuum tightness=25mmHg) is colorless transparent viscous liquid, 55.8g, molar yield 79.7% is high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product.Analytical results is seen Fig. 1-4 and shown in Figure 8, and 3390.81 absorption peak can be confirmed the hydroxyl among the HEEP in Fig. 1 infrared spectra, and 1119.10 can confirm the ehter bond among the HEEP, can obtain containing in the sample HEEP molecular structure conclusion of ethoxy ethanol structure thus.174 molecular ion peak can obviously be confirmed the molecular weight of HEEP in Fig. 2 mass spectrum, and 84 peak shows the piperazine fragment peak, and can obtain sample thus is the conclusion of the HEEP of molecular weight 174 really.3.71 is fignal centers of hydroxyl hydrogen in Fig. 3 nucleus magnetic hydrogen spectrum, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on the piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on the piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.7% by Fig. 8.
A kind of high purity 1-[2-of present embodiment (2-hydroxy ethoxy) ethyl] preparation method of piperazine, comprise being prepared as follows step: 1) in reaction flask, add new piperazine dihydrochloride and piperazine; Wherein the adding mol ratio of piperazine and piperazine dihydrochloride is 1:1.05(piperazine dihydrochloride 193g(1.22mol); Piperazine 100g(1.16mol)), (add-on of water is calculated with envelope-bulk to weight ratio mL/g, is 1.9 times of piperazine add-on) was heated with stirring to back flow reaction 1.1 hours in water, was cooled to 12 ℃, suction filtration, and filter cake was 70 ℃ of dryings 5.3 hours; Obtain the about 232g of piperazine mono-hydrochloric salts.2) utilize the piperazine mono-hydrochloric salts for preparing in the step 1) and 2-(2-chloroethoxy) ethanol in the 500ml reaction flask, add solvent reaction, wherein the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 2.12:1(piperazine mono-hydrochloric salts 104.3g(851.0mmol); 2-(2-chloroethoxy) ethanol 50g(401.4mmol)); Described step 2) solvent adopts non-polar solvent methylene dichloride (described non-polar solvent methylene dichloride also can adopt a kind of replacement in chloroform, hexanaphthene, normal hexane, toluene, the dimethylbenzene, and the effect that plays is all identical) in; And the add-on of non-polar solvent is calculated with weight ratio g/g, is 2.2 times of 2-(2-chloroethoxy) amount of alcohol added; Stirring is warmed up to 100 ℃; Insulation reaction is 3 hours under this temperature.3) after reaction finished, the about 55g of half quantity of dichloromethane was removed in 70 ℃ of underpressure distillation, is cooled to 18 ℃, filtration, filter cake is piperazine dihydrochloride with a small amount of washed with dichloromethane, 52 ℃ of dryings after 7.4 hours with regard to recyclable recycling.4) the step 3) filtrate filtered slowly is heated to 94 ℃, namely obtains highly purified 1-[2-(2-hydroxy ethoxy) ethyl behind vacuum decompression distillation for removing methanol and the residual piperazine] piperazine (HEEP) crude product.5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine (HEEP) crude product, get middle runnings (cut temperature=160 ℃, vacuum tightness=20mmHg) is colorless transparent viscous liquid, 52.5g, molar yield 75.0%, be high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product, analytical results is seen Fig. 1-4 and shown in Figure 9,3390.81 absorption peak can be confirmed the hydroxyl among the HEEP in Fig. 1 infrared spectra, 1119.10 can confirm the ehter bond among the HEEP, can obtain containing in the sample HEEP molecular structure conclusion of ethoxy ethanol structure thus.174 molecular ion peak can obviously be confirmed the molecular weight of HEEP in Fig. 2 mass spectrum, and 84 peak shows the piperazine fragment peak, and can obtain sample thus is the conclusion of the HEEP of molecular weight 174 really.3.71 is fignal centers of hydroxyl hydrogen in Fig. 3 nucleus magnetic hydrogen spectrum, the 2.93rd, and imino-hydrogen peak, 2.91 and 2.51 is methylene radical hydrogen peaks on the piperazine ring, 2.57,3.69,3.63,3.61 is respectively four methylene radical hydrogen peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.In Fig. 4 nuclear-magnetism carbon spectrum the 45.4, the 54.4th, two groups of carbon on the piperazine ring, 58.4,61.5,67.6,72.5 is respectively four carbon peaks on the side chain.Can obtain the HEEP constructor thus should the conclusion of collection of illustrative plates.Record purity (GC) 99.7% by Fig. 9.
Claims (9)
1. a high purity 1-[2-(2-hydroxy ethoxy) ethyl] preparation method of piperazine, it is characterized in that comprising being prepared as follows step:
1) adopts piperazine and piperazine dihydrochloride in solvent, to react and produce the piperazine mono-hydrochloric salts;
2) utilize the piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol that prepare in the step 1) in solvent, to react;
3) reaction finishes after-filtration recovery piperazine dihydrochloride, can reuse after drying;
4) the step 3) filtrate filtered is steamed namely obtain highly purified 1-[2-(2-hydroxy ethoxy) ethyl after desolventizing] the piperazine crude product;
5) 1-[2-that step 4) is obtained (2-hydroxy ethoxy) ethyl] rectifying under vacuum decompression of piperazine crude product, collect 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine cut namely gets high purity 1-[2-(2-hydroxy ethoxy) ethyl] the piperazine product.
2. a kind of high purity 1-[2-as claimed in claim 1 (2-hydroxy ethoxy) ethyl] preparation method of piperazine, it is characterized in that the adding mol ratio of piperazine and piperazine dihydrochloride is 1:0.8-1.2 in the described step 1); Solvent adopts a kind of in water and the alcoholic solvent in the described step 1); And the add-on of solvent is calculated with envelope-bulk to weight ratio mL/g, is 1.8-2.2 times of piperazine add-on.
3. as a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl as described in the claim 2] preparation method of piperazine, the adding mol ratio that it is characterized in that described piperazine and piperazine dihydrochloride is 1:0.91; And the add-on of solvent is calculated with envelope-bulk to weight ratio mL/g, is 2.0 times of piperazine add-on.
4. as a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl as described in the claim 2] preparation method of piperazine, it is characterized in that described alcoholic solvent adopts a kind of in methyl alcohol, ethanol, the Virahol.
5. a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl according to claim 1] preparation method of piperazine, it is characterized in that described step 2) in the adding mol ratio of piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol be (1.8-2.2): 1; Described step 2) solvent adopts a kind of in polar solvent and the non-polar solvent in; And the add-on of solvent is calculated with weight ratio g/g, is 1.2-2.4 times of 2-(2-chloroethoxy) amount of alcohol added; Described step 2) temperature of reaction in is 40-120 ℃; Reaction times is 2-8 hour.
6. as a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl as described in the claim 5] preparation method of piperazine, it is characterized in that the adding mol ratio of described piperazine mono-hydrochloric salts and 2-(2-chloroethoxy) ethanol is 1.82:1; And the add-on of solvent is calculated with weight ratio g/g, is 2.0 times of 2-(2-chloroethoxy) amount of alcohol added; Temperature of reaction is 80 ℃; Reaction times is 5.5 hours.
7. as a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl as described in the claim 5] preparation method of piperazine, it is characterized in that described polar solvent adopts a kind of in water and the alcoholic solvent; Described non-polar solvent adopts a kind of in methylene dichloride, chloroform, hexanaphthene, normal hexane, toluene, the dimethylbenzene.
8. as a kind of high purity 1-[2-(2-hydroxy ethoxy) ethyl as described in the claim 7] preparation method of piperazine, it is characterized in that described alcoholic solvent adopts a kind of in methyl alcohol, ethanol, the Virahol.
9. by the described a kind of high purity 1-[2-of claim 1 (2-hydroxy ethoxy) ethyl] preparation method of piperazine, it is characterized in that the rectification under vacuum temperature is 120-160 ℃ in the described step 5), vacuum tightness is 10-30mmHg.
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| 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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Cited By (5)
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