CN112939894A - Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine - Google Patents
Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine Download PDFInfo
- Publication number
- CN112939894A CN112939894A CN202110161808.8A CN202110161808A CN112939894A CN 112939894 A CN112939894 A CN 112939894A CN 202110161808 A CN202110161808 A CN 202110161808A CN 112939894 A CN112939894 A CN 112939894A
- Authority
- CN
- China
- Prior art keywords
- reaction
- piperazine
- hydroxyethyl
- hydroxypropyl
- raw material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine comprises the steps of adding piperazine serving as a first reaction raw material into water, adding a single-end-group protective agent, adding a second reaction raw material, adding an extracting agent, adjusting the pH value to 9-14 under the stirring condition, standing, and filtering and separating to obtain a water phase; transferring the water phase into a reaction kettle, sealing the reaction kettle, vacuumizing and introducing nitrogen into the reaction kettle; and obtaining the target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine after reaction. The invention uses piperazine, propylene oxide and ethylene oxide as raw materials, and the raw materials are cheap and easily available and have wide sources. Simple reaction, easy operation and high yield of target products. Meanwhile, the invention also provides a new green and economic thought for synthesizing the piperazine derivative with the asymmetric structure by taking piperazine as a raw material, and expands the application range of the piperazine derivative.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to an aqueous phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine, in particular to a method for preparing hydroxyalkyl piperazine derivatives by an aqueous phase single-end-group protection method.
Background
Piperazine and derivatives thereof are important chemical intermediates, can be used for synthesizing various fine chemical products such as medicines, dyes, surfactants and the like, have very wide application and have very important pharmaceutical value and economic value. For example, some piperazine derivatives have high biological activity in the multidrug, resistance to cancer and malaria treatment. In the hydroxyalkyl substitution reaction of piperazine, because the structure of the piperazine contains two symmetrical reactive active sites, a symmetrical dihydroxyalkyl piperazine byproduct is easily formed, so that the yield of the N-monohydroxyalkyl piperazine is low, and the cost for synthesizing the asymmetric piperazine derivative subsequently is increased. Therefore, the key point of synthesizing the asymmetric hydroxyalkyl piperazine by using piperazine and alkylene oxide as raw materials is to improve the yield of the intermediate N-monohydroxyalkyl piperazine and inhibit the generation of disubstituted compounds. At present, hydroxyalkyl piperazine as organic diamine also shows good desulfurization performance in the aspect of removing sulfur dioxide in flue gas, 1, 4-di (2-hydroxypropyl) piperazine with a symmetrical structure is industrially used, but the high melting point causes certain defects in the actual application process. Therefore, the asymmetric hydroxyalkyl piperazine 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine can effectively reduce the melting point and the loss of products and solvents while ensuring the desulfurization performance, and has wide industrial application prospect.
In the patents 201710732356.8, 201710732357.2, 201710732358.7, 201710732359.1, 201310199797.8 and 201610443468.7, piperazine dihydrochloride reacts with piperazine to prepare piperazine monohydrochloride, or piperazine monohydrochloride directly used as a raw material reacts with different reagents to synthesize piperazine hydrochloride containing different monosubstitution groups. The starting materials of the methods, namely piperazine monohydrochloride or piperazine dihydrochloride, have complex sources and higher cost.
Patent 201711416091.7 discloses a method for synthesizing a mono-BOC protected bisamino compound. The method comprises the steps of firstly carrying out a complex reaction by reacting an acidic compound with a diamino, and then adding a proper amount of BOC anhydride for reaction to obtain the product N-BOC piperazine. The method has simple reaction steps, but the temperature adjustable interval for generating the intermediate mono-ammonium salt by the inorganic acid/organic acid and the diamino compound is small and is not easy to control; and the patent does not mention the problem of how to carry out deprotection process treatment on the N-BOC piperazine ammonium salt intermediate.
Patent 201310673132.6 discloses a method for synthesizing 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine from N- (2-hydroxyethyl) piperazine. According to the method, N- (2-hydroxyethyl) piperazine is selected for direct propylene oxide reaction, no solvent is needed for participation, but high-purity N- (2-hydroxyethyl) piperazine is expensive and the production cost is high.
The literature, the research report on the synthesis and desulfurization performance of hydroxyalkyl piperazine by aqueous phase method, discloses: different organic acids and inorganic acids are adopted to provide hydrogen ions as a nitrogen end group protective agent, the pH value of a piperazine solution is adjusted to 7.5, and piperazine and epoxypropane are used as raw materials to react to synthesize N (-2-hydroxypropyl) piperazine. The preparation method is green and environment-friendly, the process is simple, but no deep research is carried out on subsequent deprotection and purification separation, the separation method is single, and the product loss is large.
Disclosure of Invention
The invention aims to provide an aqueous phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine.
In order to achieve the above objects and other related objects, the present invention provides the following technical solutions: a method for preparing 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine in an aqueous phase, which comprises the following steps:
step 1: adding a first reaction raw material piperazine into water, and then adding a single-end-group protective agent to react to obtain a first reaction system; the single-end-group protective agent is at least one of inorganic acid and organic acid;
step 2: adding a second reaction raw material into the first reaction system, and reacting to obtain a second reaction system;
and step 3: adding an extracting agent into the second reaction system, adjusting the pH value to 9-14 under the stirring condition, standing, and filtering and separating to obtain a water phase;
and 4, step 4: transferring the water phase into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing, and introducing nitrogen into the reaction kettle; raising the temperature in the reaction kettle to 28-32 ℃, introducing gas of a second reaction raw material into the reaction kettle under the stirring condition, reacting at the temperature of 20-80 ℃, concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is ended, extracting the residual liquid with an organic solvent, performing secondary reduced pressure distillation to remove the organic solvent, and performing column chromatography separation on the residue to obtain a target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine;
the second reaction raw material is ethylene oxide and propylene oxide.
The preferable technical scheme is as follows: the inorganic acid is at least one of sulfuric acid, hydrochloric acid and phosphoric acid; the organic acid is at least one of monobasic acid and polybasic acid with the carbon number less than 10.
The preferable technical scheme is as follows: the molar ratio of the piperazine to the hydrogen ions in the single-end-group protective agent is 1: 0.5-2.5; the mass ratio of piperazine to water is 1: 0.5-100; the reaction conditions of step 1 are: the temperature is 85-95 ℃, and the reaction time is 0.5-2 h.
The preferable technical scheme is as follows: the molar ratio of the reaction product piperazine monoammonium salt in the step 1 to the second reaction raw material is 1: 0.5-2.5; the reaction conditions of the step 2 are as follows: the reaction temperature is 25-60 ℃, and the reaction time is 2-8 h.
The preferable technical scheme is as follows: the extracting agent is one of six-membered ring organic solvents, and the mass ratio of the extracting agent to the propylene oxide is 1-10: 1.
the preferable technical scheme is as follows: and 4, replacing the air in the reaction kettle with nitrogen, vacuumizing to the pressure of-0.09 MPa in the reaction kettle, and introducing the nitrogen into the reaction kettle until the pressure in the reaction kettle is 0.05 MPa.
The preferable technical scheme is as follows: the molar ratio of the intermediate in the water phase to the second reaction raw material is 1: 0.5-1.5.
The preferable technical scheme is as follows: the organic solvent is at least one of dichloromethane, ethanol, propanol, diethyl ether and toluene; the mass ratio of the organic solvent to the second reaction raw material is 1-10: 1.
due to the application of the technical scheme, compared with the prior art, the invention has the advantages that:
1. the invention prepares 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine by a water-phase single-end-group protection method. Under the action of different inorganic acid or organic acid end group protective agents, piperazine firstly reacts with epoxypropane/ethylene oxide to generate an intermediate compound N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine, the intermediate compound N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine reacts with epoxyethane/epoxypropane after separation and deprotection processes, and 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine is prepared after separation and purification processes of reaction products. The method changes the activity of piperazine reaction sites, and has the advantages of simplicity, high efficiency, greenness and economy. Compared with the known method, the method has obvious advantages and wide potential application prospect.
2. The invention uses piperazine, propylene oxide and ethylene oxide as raw materials, and the raw materials are cheap and easily available and have wide sources. Simple reaction, easy operation and high yield of target products. Meanwhile, the invention also provides a new green and economic thought for synthesizing the piperazine derivative with the asymmetric structure by taking piperazine as a raw material, and expands the application range of the piperazine derivative.
Drawings
FIG. 1 is a gas chromatogram of the final product obtained in example 1.
FIG. 2 is a MS diagram of the final product obtained in example 1.
FIG. 3 shows the end product obtained in example 11H NMR spectrum.
FIG. 4 shows the end product obtained in example 113C NMR spectrum.
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
Please refer to fig. 1-4. It should be understood that the structures, ratios, sizes, and the like shown in the drawings and described in the specification are only used for matching with the disclosure of the specification, so as to be understood and read by those skilled in the art, and are not used to limit the conditions under which the present invention can be implemented, so that the present invention has no technical significance, and any structural modification, ratio relationship change, or size adjustment should still fall within the scope of the present invention without affecting the efficacy and the achievable purpose of the present invention. In addition, the terms "upper", "lower", "left", "right", "middle" and "one" used in the present specification are for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the terms is not to be construed as a scope of the present invention.
The preparation method takes piperazine, epoxypropane/ethylene oxide as main raw materials, water as a solvent and inorganic acid/organic acid as a single-end-group protective agent; under the action of a single-end-group protective agent of inorganic acid/organic acid, piperazine reacts with hydrogen ions in the solution to generate piperazine ammonium salt; piperazine ammonium salt firstly reacts with epoxypropane/epoxyethane to generate an intermediate N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine, the intermediate N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine reacts with epoxyethane/epoxypropane after separation and deprotection processes, and a reaction product is separated and purified to obtain 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine.
The gas chromatography detection conditions are as follows: the injection inlet temperature was 200 ℃, the column box temperature was 160 ℃, and the detector temperature was 200 ℃.
Example 1: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
(1) Dissolving 7.50g (0.0871mol) of piperazine in 100ml of water, adding 6.10g (0.0290mol) of citric acid under reflux condensation stirring, controlling the temperature to be 85-95 ℃ in the adding process, keeping the temperature and 90 ℃ after the adding is finished, and reacting for 1 h;
(2) continuously dropwise adding 5.06g (0.0871mol) of propylene oxide into the solution obtained in the step (1), controlling the temperature to be 28-32 ℃ in the dropwise adding process, keeping the temperature to be 30 ℃ after the dropwise adding is finished, and continuously reacting for 3 hours;
(3) adding an extractant benzene into the solution obtained in the step (2), adding barium hydroxide under full stirring to adjust the pH value to 9-14, standing, filtering and separating to obtain a water phase;
(4) and (4) transferring the solution obtained in the step (3) into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing to-0.09 MPa, repeating twice, and introducing nitrogen into the kettle to 0.05 MPa. After the temperature of the system reaches 30 ℃, 3.84g (0.0871mol) of ethylene oxide gas is slowly introduced into the kettle under the stirring state, the reaction temperature is controlled to be 25-35 ℃, the reaction pressure is kept stable by controlling the introduction rate of the ethylene oxide gas, and the reaction is carried out for 3 hours at constant temperature of 30 ℃. After the reaction is finished, the reaction solution is decompressed and concentrated to remove the solvent, residual liquid is extracted by dichloromethane, dichloromethane is removed by secondary decompression and distillation, and the residue is separated by column chromatography to obtain the target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine with the yield of 96.32%.
Example 2: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
The terminal group-protecting agent citric acid in example 1 was replaced with lactic acid (9.42g, 0.1045mol), and simultaneously the amount of propylene oxide added in step (2) of example 1 was 4.50g (0.0523mol), the reaction temperature was adjusted to 60 ℃, and the other conditions were the same as in example 1, whereby 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine, the objective product, was obtained in a yield of 95.68%.
Example 3: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
The terminal group protecting agent citric acid in example 1 was replaced with acetic acid (4.18g, 0.0697mol), and simultaneously the amount of ethylene oxide added in step (4) of example 1 was 2.69g (0.0610mol), the reaction temperature was lowered to 20 ℃ to obtain the objective product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine with a yield of 97.45%.
Example 4: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
The end group protecting agent citric acid in the example 1 is replaced by concentrated sulfuric acid 2.18g (0.0218mol), the reaction temperature is controlled to be 45 ℃, the other conditions are the same as the example 1, and the target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine is obtained, wherein the yield is 96.52%.
Example 5: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
(1) Dissolving 7.50g (0.0871mol) of piperazine in 100ml of water, adding 2.18g (0.0218mol) of concentrated sulfuric acid under reflux condensation stirring, controlling the temperature to be 50-60 ℃ in the adding process, keeping the temperature and 55 ℃ after the adding is finished, and reacting for 1.5 h.
(2) Transferring the solution obtained in the step (1) into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing to-0.09 MPa, repeating twice, and introducing nitrogen into the kettle to 0.05 MPa. After the temperature of the system reaches 40 ℃, 4.42g (0.1002mol) of ethylene oxide gas is slowly introduced into the kettle under the stirring state, the reaction temperature is controlled to be 35-45 ℃, the reaction pressure is kept stable by controlling the introduction rate of the ethylene oxide gas, and the reaction is carried out for 4 hours at the constant temperature of 40 ℃.
(3) And (3) after the reaction is ended, adding 100ml of benzene into the solution containing the N- (2-hydroxyethyl) piperazine amine salt obtained in the step (2), adding sodium hydroxide under full stirring to adjust the pH value to 9-14, reacting for 3 hours, standing, filtering and separating to obtain a water phase.
(4) Under the condition of reflux condensation and stirring, continuously dropwise adding 4.55g (0.0784mol) of propylene oxide into the water phase obtained in the step (3), controlling the temperature to be 20-30 ℃ in the dropwise adding process, keeping the temperature to be 25 ℃ after the dropwise adding is finished, and continuously reacting for 5 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was extracted with dichloromethane, and the dichloromethane was removed by secondary distillation under reduced pressure, and the residue was separated by column chromatography to obtain the target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine with a yield of 97.62%.
Example 6: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
The end group protecting agent concentrated sulfuric acid in the example 5 is replaced by succinic acid (5.14g, 0.0436mol), and the rest conditions are the same as the example 5, so that the target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine is obtained, and the yield is 95.58%.
Example 7: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
Preparation of 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine by aqueous phase single-end protection method: piperazine, epoxypropane/ethylene oxide are used as main raw materials, water is used as a solvent, and inorganic acid/organic acid is used as a single-end-group protective agent; under the action of a single-end-group protective agent of inorganic acid/organic acid, piperazine reacts with hydrogen ions in the solution to generate piperazine ammonium salt; the piperazine ammonium salt firstly reacts with propylene oxide/ethylene oxide to generate an intermediate N- (2-hydroxypropyl) piperazine salt/N- (2-hydroxyethyl) piperazine salt, the intermediate N- (2-hydroxypropyl) piperazine salt/N- (2-hydroxyethyl) piperazine salt reacts with ethylene oxide/propylene oxide after separation and deprotection processes, and the final product is determined to be 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine through gas phase-mass spectrometry, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum after separation and purification processes of reaction products. The chemical reaction equation of the method is as follows:
the preferred embodiment is: the inorganic acid comprises sulfuric acid, hydrochloric acid and phosphoric acid, and the organic acid comprises formic acid, acetic acid, oxalic acid and other monobasic and polybasic acids with carbon number less than ten. Preferably, the inorganic acid is sulfuric acid, and the organic acid is acetic acid.
The preferred embodiment is: the molar ratio of piperazine to hydrogen ions in organic acid or inorganic acid is 1: 2-2.5; the addition amount of water is 0.8-2 times of that of piperazine in terms of weight-volume ratio g/ml, the reaction temperature is 30-90 ℃, and the reaction time is 0.5-2 hours; the molar ratio of piperazine diammonium salt to piperazine is 1-20: 1, the addition amount of water is 0.8-2 times of that of piperazine diammonium salt in terms of weight-volume ratio g/ml, the reaction temperature is 95-120 ℃, and the reaction time is 1-3 hours.
The preferred embodiment is: in the step (1), the molar ratio of the inorganic acid/organic acid to the piperazine is n (H +): n (piperazine) is 1.1:1, the addition amount of water is 1.8 times of that of piperazine diammonium salt in terms of weight-volume ratio g/ml, the reaction temperature is 60 ℃, and the reaction time is 1H.
The preferred embodiment is: in the reaction process of the piperazine monoammonium salt and the propylene oxide/ethylene oxide, the molar ratio of the piperazine monoammonium salt to the propylene oxide/ethylene oxide is 1.6-2.2: 1; the reaction temperature is 25-60 ℃, and the reaction time is 2-8 h.
The preferred embodiment is: in the step (2), the molar ratio of the piperazine monoammonium salt to the propylene oxide/ethylene oxide is 1.8:1, the reaction temperature is 30 ℃, and the reaction time is 5 hours.
The preferred embodiment is: the deprotection and separation process of the N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine intermediate comprises the following steps: after the piperazine monoammonium salt reacts with the propylene oxide, the piperazine monoammonium salt is extracted, the pH value is adjusted, and the piperazine diammonium salt is recovered after filtration. Adding one of six-membered ring organic solvents such as benzene and cyclohexane into a reaction system, wherein the addition amount of the six-membered ring organic solvent is 1-10 times of that of propylene oxide according to the weight ratio of g/g; and adding alkali liquor to adjust the pH value of the solution to 9-14, wherein the mass fraction of the solution is 10% -35%, standing, filtering and separating to obtain a water phase.
The preferred embodiment is: in the deprotection process, benzene is selected as an organic solvent, and the addition amount of the benzene is 2 times of that of propylene oxide calculated according to the weight ratio g/g; the alkali liquor is preferably a sodium hydroxide solution with the mass fraction of 30%.
The preferred embodiment is: the reaction process of the mixed liquid containing the intermediate and the ethylene oxide/propylene oxide is that the molar ratio of the intermediate N- (2-hydroxypropyl) piperazine/N- (2-hydroxyethyl) piperazine to the ethylene oxide/propylene oxide is 1: 0.5-1.5; the reaction temperature is 20-80 ℃, and the reaction time is 1-10 h.
The preferred embodiment is: the separation and purification process of the final product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine comprises the steps of decompressing and concentrating reaction liquid after the reaction to remove solvent water, and adding one or more of dichloromethane, ethanol, propanol, ether and toluene into residual liquid, wherein the addition amount of the residual liquid is 1-10 times of that of propylene oxide in terms of weight ratio g/g; and (4) carrying out suction filtration, rectifying the filtrate under vacuum reduced pressure, and collecting fractions to obtain the 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine.
The preferred embodiment is: in the separation and purification process, the organic solvent is preferably dichloromethane, and the addition amount of the dichloromethane is 2 times of that of the propylene oxide in terms of weight ratio g/g.
The preferred embodiment is: in the separation and purification process, the temperature of the reduced pressure distillation is 125-165 ℃, and the vacuum degree is 450-675 mmHg.
Example 8: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
A method for preparing 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine in an aqueous phase, which comprises the following steps:
step 1: adding a first reaction raw material piperazine into water, and then adding a single-end-group protective agent to react to obtain a first reaction system; the single-end-group protective agent is inorganic acid;
step 2: adding a second reaction raw material into the first reaction system, and reacting to obtain a second reaction system;
and step 3: adding an extracting agent into the second reaction system, then regulating the pH value to 9 under the stirring condition, standing, and filtering and separating to obtain a water phase;
and 4, step 4: transferring the water phase into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing, and introducing nitrogen into the reaction kettle; raising the temperature in the reaction kettle to 28 ℃, introducing gas of a second reaction raw material into the reaction kettle under the stirring condition, reacting at the temperature of 20 ℃, concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is ended, extracting the residual liquid with an organic solvent, performing secondary reduced pressure distillation to remove the organic solvent, and separating the residue by column chromatography to obtain a target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine;
the second reaction raw material is ethylene oxide and propylene oxide.
The preferred embodiment is: the inorganic acid is sulfuric acid.
The preferred embodiment is: the molar ratio of the piperazine to the hydrogen ions in the single-end-group protective agent is 1: 0.5; the mass ratio of piperazine to water is 1: 0.5; the reaction conditions of step 1 are: the temperature is 85 ℃, and the reaction time is 0.5 h.
The preferred embodiment is: the molar ratio of the reaction product piperazine monoammonium salt in the step 1 to the second reaction raw material is 1: 0.5; the reaction conditions of the step 2 are as follows: the reaction temperature is 25 ℃, and the reaction time is 2 h.
The preferred embodiment is: the extracting agent is one of six-membered ring organic solvents, and the mass ratio of the extracting agent to the propylene oxide is 1:1.
the preferred embodiment is: and 4, replacing the air in the reaction kettle with nitrogen, vacuumizing to the pressure of-0.09 MPa in the reaction kettle, and introducing the nitrogen into the reaction kettle until the pressure in the reaction kettle is 0.05 MPa.
The preferred embodiment is: the molar ratio of the intermediate in the water phase to the second reaction raw material is 1: 0.5.
The preferred embodiment is: the organic solvent is dichloromethane; the mass ratio of the organic solvent to the second reaction raw material is 1:1.
example 9: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
A method for preparing 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine in an aqueous phase, which comprises the following steps:
step 1: adding a first reaction raw material piperazine into water, and then adding a single-end-group protective agent to react to obtain a first reaction system; the single-end-group protective agent is organic acid;
step 2: adding a second reaction raw material into the first reaction system, and reacting to obtain a second reaction system;
and step 3: adding an extracting agent into the second reaction system, then regulating the pH value to 14 under the stirring condition, standing, and filtering and separating to obtain a water phase;
and 4, step 4: transferring the water phase into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing, and introducing nitrogen into the reaction kettle; raising the temperature in the reaction kettle to 32 ℃, introducing gas of a second reaction raw material into the reaction kettle under the stirring condition, reacting at the temperature of 80 ℃, concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is ended, extracting the residual liquid with an organic solvent, performing secondary reduced pressure distillation to remove the organic solvent, and separating the residue by column chromatography to obtain a target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine;
the second reaction raw material is ethylene oxide and propylene oxide.
The preferred embodiment is: the organic acid is a monobasic acid.
The preferred embodiment is: the molar ratio of the piperazine to the hydrogen ions in the single-end-group protective agent is 1: 2.5; the mass ratio of piperazine to water is 1: 100, respectively; the reaction conditions of step 1 are: the temperature is 95 ℃ and the reaction time is 2 h.
The preferred embodiment is: the molar ratio of the reaction product piperazine monoammonium salt in the step 1 to the second reaction raw material is 1: 2.5; the reaction conditions of the step 2 are as follows: the reaction temperature is 60 ℃, and the reaction time is 8 h.
The preferred embodiment is: the extracting agent is one of six-membered ring organic solvents, and the mass ratio of the extracting agent to the propylene oxide is 10: 1.
the preferred embodiment is: and 4, replacing the air in the reaction kettle with nitrogen, vacuumizing to the pressure of-0.09 MPa in the reaction kettle, and introducing the nitrogen into the reaction kettle until the pressure in the reaction kettle is 0.05 MPa.
The preferred embodiment is: the molar ratio of the intermediate in the water phase to the second reaction raw material is 1: 1.5.
The preferred embodiment is: the organic solvent is ethanol; the mass ratio of the organic solvent to the second reaction raw material is 10: 1.
example 10: water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine
A method for preparing 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine in an aqueous phase, which comprises the following steps:
step 1: adding a first reaction raw material piperazine into water, and then adding a single-end-group protective agent to react to obtain a first reaction system; the single-end-group protective agent is inorganic acid;
step 2: adding a second reaction raw material into the first reaction system, and reacting to obtain a second reaction system;
and step 3: adding an extracting agent into the second reaction system, then regulating the pH value to 12 under the stirring condition, standing, and filtering and separating to obtain a water phase;
and 4, step 4: transferring the water phase into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing, and introducing nitrogen into the reaction kettle; raising the temperature in the reaction kettle to 30 ℃, introducing gas of a second reaction raw material into the reaction kettle under the stirring condition, reacting at the temperature of 50 ℃, concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is ended, extracting the residual liquid with an organic solvent, performing secondary reduced pressure distillation to remove the organic solvent, and separating the residue by column chromatography to obtain a target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine;
the second reaction raw material is ethylene oxide and propylene oxide.
The preferred embodiment is: the inorganic acid is hydrochloric acid.
The preferred embodiment is: the molar ratio of the piperazine to the hydrogen ions in the single-end-group protective agent is 1: 1.5; the mass ratio of piperazine to water is 1: 50; the reaction conditions of step 1 are: the temperature is 90 ℃ and the reaction time is 1 h.
The preferred embodiment is: the molar ratio of the reaction product piperazine monoammonium salt in the step 1 to the second reaction raw material is 1: 1.5; the reaction conditions of the step 2 are as follows: the reaction temperature is 40 ℃, and the reaction time is 5 h.
The preferred embodiment is: the extracting agent is one of six-membered ring organic solvents, and the mass ratio of the extracting agent to the propylene oxide is 5: 1.
the preferred embodiment is: and 4, replacing the air in the reaction kettle with nitrogen, vacuumizing to the pressure of-0.09 MPa in the reaction kettle, and introducing the nitrogen into the reaction kettle until the pressure in the reaction kettle is 0.05 MPa.
The preferred embodiment is: the molar ratio of the intermediate in the water phase to the second reaction raw material is 1:1.
The preferred embodiment is: the organic solvent is at least one of dichloromethane, ethanol, propanol, diethyl ether and toluene; the mass ratio of the organic solvent to the second reaction raw material is 5: 1.
the foregoing is illustrative of the preferred embodiment of the present invention and is not to be construed as limiting thereof in any way, and any modifications or variations thereof that fall within the spirit of the invention are intended to be included within the scope thereof.
Claims (8)
1. A water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine is characterized by comprising the following steps: comprises the following steps:
step 1: adding a first reaction raw material piperazine into water, and then adding a single-end-group protective agent to react to obtain a first reaction system; the single-end-group protective agent is at least one of inorganic acid and organic acid;
step 2: adding a second reaction raw material into the first reaction system, and reacting to obtain a second reaction system;
and step 3: adding an extracting agent into the second reaction system, adjusting the pH value to 9-14 under the stirring condition, standing, and filtering and separating to obtain a water phase;
and 4, step 4: transferring the water phase into a reaction kettle, sealing the reaction kettle, replacing air in the reaction kettle with nitrogen, vacuumizing, and introducing nitrogen into the reaction kettle; raising the temperature in the reaction kettle to 28-32 ℃, introducing gas of a second reaction raw material into the reaction kettle under the stirring condition, reacting at the temperature of 20-80 ℃, concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is ended, extracting the residual liquid with an organic solvent, performing secondary reduced pressure distillation to remove the organic solvent, and performing column chromatography separation on the residue to obtain a target product 1- (2-hydroxyethyl) 4- (2-hydroxypropyl) piperazine;
the second reaction raw material is ethylene oxide and propylene oxide.
2. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the inorganic acid is at least one of sulfuric acid, hydrochloric acid and phosphoric acid; the organic acid is at least one of monobasic acid and polybasic acid with the carbon number less than 10.
3. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the molar ratio of the piperazine to the hydrogen ions in the single-end-group protective agent is 1: 0.5-2.5; the mass ratio of piperazine to water is 1: 0.5-100; the reaction conditions of step 1 are: the temperature is 85-95 ℃, and the reaction time is 0.5-2 h.
4. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the molar ratio of the reaction product piperazine monoammonium salt in the step 1 to the second reaction raw material is 1: 0.5-2.5; the reaction conditions of the step 2 are as follows: the reaction temperature is 25-60 ℃, and the reaction time is 2-8 h.
5. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the extracting agent is one of six-membered ring organic solvents, and the mass ratio of the extracting agent to the propylene oxide is 1-10: 1.
6. the process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: and 4, replacing the air in the reaction kettle with nitrogen, vacuumizing to the pressure of-0.09 MPa in the reaction kettle, and introducing the nitrogen into the reaction kettle until the pressure in the reaction kettle is 0.05 MPa.
7. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the molar ratio of the intermediate in the water phase to the second reaction raw material is 1: 0.5-1.5.
8. The process for the aqueous phase preparation of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine according to claim 1, characterized in that: the organic solvent is at least one of dichloromethane, ethanol, propanol, diethyl ether and toluene; the mass ratio of the organic solvent to the second reaction raw material is 1-10: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110161808.8A CN112939894A (en) | 2021-02-05 | 2021-02-05 | Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110161808.8A CN112939894A (en) | 2021-02-05 | 2021-02-05 | Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112939894A true CN112939894A (en) | 2021-06-11 |
Family
ID=76242610
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110161808.8A Pending CN112939894A (en) | 2021-02-05 | 2021-02-05 | Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112939894A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113856751A (en) * | 2021-08-30 | 2021-12-31 | 中国海洋石油集团有限公司 | Catalyst, preparation method thereof and polymerization method of isocyanate |
| CN114870569A (en) * | 2022-04-11 | 2022-08-09 | 合肥工业大学 | Synthetic method of piperazine-based carbon trapping agent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103638779A (en) * | 2013-12-12 | 2014-03-19 | 合肥工业大学 | Renewable organic amine flue gas desulfurization agent and preparation method thereof |
-
2021
- 2021-02-05 CN CN202110161808.8A patent/CN112939894A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103638779A (en) * | 2013-12-12 | 2014-03-19 | 合肥工业大学 | Renewable organic amine flue gas desulfurization agent and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 潘飞等: "1-(2-羟乙基)-4-(2-羟丙基)哌嗪的合成与表征", 《高校化学工程学报》, vol. 30, no. 1, pages 142 - 148 * |
| 荆丹琳: "羟烷基哌嗪水相法合成及脱硫性能的研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑 (月刊)》, vol. 2020, no. 01, pages 016 - 186 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113856751A (en) * | 2021-08-30 | 2021-12-31 | 中国海洋石油集团有限公司 | Catalyst, preparation method thereof and polymerization method of isocyanate |
| CN114870569A (en) * | 2022-04-11 | 2022-08-09 | 合肥工业大学 | Synthetic method of piperazine-based carbon trapping agent |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112939894A (en) | Water phase preparation method of 1- (2-hydroxyethyl) -4- (2-hydroxypropyl) piperazine | |
| CN110668995A (en) | Tofacitinib citrate intermediate and preparation method of tofacitinib citrate | |
| CN113475740B (en) | Preparation method of chiral synthetic nicotine | |
| AU2005257478B2 (en) | Method for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl cyclopropane hydrochloride | |
| CN109824545A (en) | A kind of preparation method of trans- -4-N-Boc amino ring amine carboxylic acid | |
| WO2008139492A2 (en) | A process for the preparation of highly pure ranolazine base | |
| CN113549054B (en) | Vonoprazan fumarate intermediate and preparation method thereof | |
| CN109879780B (en) | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate | |
| JP4109893B2 (en) | Method for producing aziridines and N-vinylamides | |
| CN113582972A (en) | Method for synthesizing chiral nicotine from butyrolactone | |
| CN117843620B (en) | Purification preparation method of voronoi fumarate | |
| CN107673984B (en) | Preparation method of levetiracetam key intermediate (S) -2-aminobutanamide salt | |
| CN112552345A (en) | Preparation method of NK-1 receptor antagonist | |
| EP1899310B1 (en) | Stereoselective hydrogenation process for preparing cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-methoxy-5,6,7,8-tetrahydronaphthalene hydrochloride | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN111646991A (en) | Preparation method of avibactam sodium intermediate | |
| CN117843620A (en) | Purification preparation method of voronoi fumarate | |
| CN115745912B (en) | Method for preparing high-purity ranolazine | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| EP1727784B1 (en) | Improved process for preparation of gabapentin | |
| CN109912454B (en) | Synthesis method of mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile | |
| CN108003037B (en) | Synthesis process of N-methyl-5-hexene-1-amine | |
| CN109776359B (en) | Boc-1-amino-3, 6-dioxa-1, 8-octanediamine synthesis process | |
| CN106883138B (en) | The preparation method of tiger element | |
| CN114478439A (en) | Post-treatment process for synthesizing Boc-piperazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |