CN112375008A - Synthesis and purification method of arachidonic acid ethanolamine - Google Patents
Synthesis and purification method of arachidonic acid ethanolamine Download PDFInfo
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- CN112375008A CN112375008A CN202011330618.6A CN202011330618A CN112375008A CN 112375008 A CN112375008 A CN 112375008A CN 202011330618 A CN202011330618 A CN 202011330618A CN 112375008 A CN112375008 A CN 112375008A
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- arachidonic acid
- ethanolamine
- acid ethanolamine
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- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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Abstract
The invention discloses a method for synthesizing and purifying arachidonic acid ethanolamine, which is characterized by comprising the following steps: the separation and purification method comprises the steps of: the method comprises the steps of primary separation and primary purification of arachidonic acid, diacylchlorination, triamidation, decolorization, deodorization and molecular distillation purification. The invention mainly adopts the technology of purifying the arachidonic acid ethanolamine by multi-step and multi-stage molecular distillation process, thereby realizing the reduction of the consumption of the ethanolamine and improving the production efficiency of products. The process is suitable for industrial production. The reaction by-products are few, and the difficulty of later separation and purification is reduced. The two-stage or multi-stage purification process is beneficial to improving the quality of the product, reducing the smell of the product and increasing the purity of the product. Oxygen is isolated in the whole reaction process, so that the reaction loss can be reduced. The defects of the prior art are overcome.
Description
Technical Field
The invention relates to the technical field of synthesis and purification of fatty acid amide compounds, in particular to a method for synthesizing and purifying arachidonic acid ethanolamine.
Background
Arachidonic acid ethanolamine is one of the endogenous cannabinoids found in humans, and in recent years, arachidonic Acid Ethanolamine (AEA) is a cannabinoids of endogenous lipid signaling molecules, and has various effects of regulating appetite and lipid metabolism, protecting heart and nervous system, improving blood pressure and immune function, and the like.
The concentration of AEA in natural organism tissues is very small, the chemical structure is unstable, and the process of extracting AEA from the body is complex. Cannabis sativa (Cannabis) is a traditional drug that has a long history and is widely used in the world. As early as 4000 years ago, China has applied cannabis to daily life and medical treatment. However, the abuse of the cannabinoids worldwide causes adverse mental symptoms and addiction, and the like, which influences the enthusiasm for further research on the cannabis drugs. Until the 70's of the last century, the main active ingredient of cannabis, tetrahydrocannabinol (Δ 9-THC), was identified and purified, and after its medical use was confirmed, cannabis that had undergone multiple restricted uses was once again legally used in some states of the united states, and the first hot tide of cannabis studied historically appeared.
In 1992, AEA was discovered and isolated from porcine brain tissue by Deven et al, the scientist Israel. The first discovered ligand substance for the endocannabinoid receptor has a structure very similar to Δ 9-THC, and has similar physiological effects in vitro and in vivo experiments. In general, exertion of AEA physiological activity is often associated with cannabinoid receptors.
Cannabinoid receptor CB1 is mainly involved in the regulation of activities such as movement, memory and emotion and is used as a main drug target for obesity, alcohol dependence, Parkinson disease and the like; cannabinoid receptor CB2 type is involved in the regulation of body immunity, and has anti-inflammatory and analgesic effects. In addition, AEA is involved in the transduction of acute inflammatory pain signals through ion channels (TRPV1) acting on capsaicin receptors. Therefore, the concentration adaptability change of AEA under different physiological conditions of human body may have protective significance to human body.
Neurodegenerative diseases are caused by the loss of neurons in brain and spinal cord cells, resulting in dyskinesia and memory loss. AEA may exert neuroprotective effects by participating in processes such as glutamate transmission, oxidative stress and inflammatory responses. Melis et al also demonstrated that AEA can be involved in metabolism and immunoinflammatory responses by direct action on the classical nuclear receptors PPAR α and PPAR γ. The AEA can affect the learning and memory function when injected into a ventricle to cause cerebral edema and memory loss and a selective antagonist of CB1 (SR141716A) can improve the memory function of rodents, and the like. Thus, AEA may be used as a new target for the treatment of central nervous system diseases.
AEA regulates feeding behavior, glycolipid metabolism and energy balance through central and peripheral neural pathways. Most obese patients have endogenous ligand and CB1 receptor disorders, while the brain of an obese mouse under a high nutritional diet is accompanied by over-activation of the cannabis system, the expression of CB1 of hypothalamus and liver is increased, and the generation and accumulation of fat are aggravated. Animal studies have shown that blocking CB1 receptors in mouse adipose tissue induces free fatty acid oxidation and ameliorates hyperglycemia and hyperinsulinemia. Clinical studies of SR141716A find that the body mass, waist circumference and blood lipid and blood glucose indexes of patients are all obviously improved. In addition, changes in AEA content have important physiological implications for the pregnancy process. The AEA content in the antenatal venous blood of pregnant women is significantly lower than normal and rises sharply during labour, which may be related to the regulatory action of fatty acid amide hydrolase or the production of prostaglandins which are critical for labour. Feedback regulation between AEA and CB1 can reduce the suppression of uterine contraction caused by emotion of puerpera. The phenomenon of premature birth in pregnant rats lacking the CB1 receptor suggests that cannabis receptor signalling may be associated with human premature birth. Furthermore, the correlation between the AEA elevation and the labor of the pregnant woman may be a factor in regulating the embryo implantation window. The method provides a new idea for clinically searching new cannabis medicines applied to obstetrics and gynecology department.
In the actual production, due to the problems of low purity and oxidation of the arachidonic acid ethanolamine synthesis, the later application effect of the arachidonic acid ethanolamine is poor, and the invention mainly provides a technology for purifying the arachidonic acid ethanolamine by multiple steps.
Disclosure of Invention
The invention aims to provide a method for synthesizing and purifying arachidonic acid ethanolamine, which reasonably and effectively solves the problems of low purity, high oxidation degree and poor application effect of the synthesis and purification method of arachidonic acid ethanolamine in the prior art.
The invention adopts the following technical scheme:
a method for synthesizing and purifying arachidonic acid ethanolamine is characterized by comprising the following steps: the separation and purification method comprises the steps of:
the method comprises the following steps: preliminary isolation and preliminary purification of arachidonic acid
1.1, mixing arachidonic acid (ARA) grease, methanol or ethanol and urea in a reaction kettle according to a ratio and stirring, wherein the ARA grease comprises methanol or ethanol: the proportion range of the urea is 1:3:1 to 1:10:5, the ARA content in the ARA grease is 25 percent to 50 percent, the methanol or ethanol content is more than 75 percent,
1.2, heating the mixed materials to 60-80 ℃, refluxing and preserving heat for more than 0.5 hour,
1.3, cooling to below 4 ℃, preserving heat for more than 1 hour,
1.4 detecting the arachidonic acid content of the supernatant, and centrifuging when the content is more than 60%
1.5 centrifuging and keeping supernatant, adding inorganic acid to adjust pH to 1-3, concentrating under reduced pressure, recovering methanol/ethanol, concentrating to remove methanol/ethanol, stopping concentrating, wherein the inorganic acid comprises sulfuric acid, hydrochloric acid, phosphoric acid, etc., wherein the hydrochloric acid is the most preferred, and preparing concentrated solution;
1.6 washing the concentrated solution with pure water until the pH value is 6-8, dehydrating the oil layer to obtain primarily purified arachidonic acid,
step two: acyl chloride
2.1, adding 2-6ml DMF per kg fatty acid, stirring, slowly dripping oxalyl chloride at room temperature, controlling the temperature of the materials at 25-30 ℃,
2.2, dropwise adding 2ml of methanol into the reaction solution 2, using phosphomolybdic acid to develop color on an arachidonic acid control dot plate, completely reacting without arachidonic acid dots, and completing acyl chlorination to prepare an acyl chlorination reaction solution;
step three: amidation
And 3.1, according to the mass of the reaction liquid after acyl chlorination, preparing ethanolamine according to the ratio of 2-5:1, preparing a solvent of the reaction liquid with the volume ratio of more than 1.5 times, putting the ethanolamine and the solvent into a reaction kettle, starting stirring, and stirring at the speed of 30-200 rpm.
The solvent comprises one of organic solvents such as hexane, ethyl acetate, acetone, dichloromethane and the like,
3.2, slowly dripping the acyl chlorination reaction liquid, and controlling the temperature to be 30-35 ℃. Keeping the pH to be alkaline in the dropping process, if the pH is neutral, adding ethanolamine properly,
3.3, stirring for more than 0.5 hour after dripping, and washing with pure water until the pH value is neutral;
step four: decolorizing, deodorizing and purifying by molecular distillation
4.1, adding a decolorant into the mixed solution of the arachidonic acid ethanolamine after washing for decoloration, decoloring for 30-90min under the condition that the vacuum degree is not more than 5 torr, preparing a decolored solution,
the decolorizing agent comprises one or more of active carbon, activated clay and attapulgite, the use amount of the decolorizing agent is 1-5% of arachidonic acid ethanolamine,
4.2, separating the decolorant by using plate-frame or centrifugation technology and the like to obtain decolored mixed liquor;
4.3, decompressing and concentrating the decolored solution to recover the solvent to prepare a concentrated solution, wherein the concentrated solution is a crude product of arachidonic acid ethanolamine to complete the synthesis of arachidonic acid ethanolamine,
4.4, the crude product of arachidonic acid ethanolamine can be directly deodorized by steam, residual ethyl acetate and odor substances are removed, the finished product of arachidonic acid ethanolamine is obtained,
4.5, the crude product of arachidonic acid ethanolamine or finished product of arachidonic acid ethanolamine can be purified by molecular distillation,
4.6, multi-stage molecular distillation purification can be carried out, the purity of the crude product of arachidonic acid ethanolamine or finished product of arachidonic acid ethanol can be improved by 10 to 30 percent,
4.7, wherein the stripping deodorization and molecular distillation process can be carried out only one or in combination; the synthesis and purification method of the arachidonic acid ethanolamine is formed.
Further, the technological parameters of the method for synthesizing and purifying arachidonic acid ethanolamine are as follows: an arachidonic acid ethanolamine product by a steam stripping deodorization and molecular distillation process, wherein the arachidonic acid ethanolamine content is not less than 60%, the arachidonic acid ethanolamine content is not less than 80% by a multistage molecular distillation process, the peroxidation value of the arachidonic acid ethanolamine is not higher than 5mmol/kg, the anisidine value is not higher than 20, the color is not higher than Y40R10, and the solvent residue is not higher than 1%. The beneficial technical effects of the invention are as follows:
the invention aims to provide a method for synthesizing and purifying arachidonic acid ethanolamine, which reasonably and effectively solves the problems of low purity, high oxidation degree and poor application effect of the synthesis and purification method of arachidonic acid ethanolamine in the prior art.
The invention mainly adopts the technology of purifying the arachidonic acid ethanolamine by multi-step and multi-stage molecular distillation process, thereby realizing the reduction of the consumption of the ethanolamine and improving the production efficiency of products. The process is suitable for industrial production. The reaction by-products are few, and the difficulty of later separation and purification is reduced. The two-stage or multi-stage purification process is beneficial to improving the quality of the product, reducing the smell of the product and increasing the purity of the product. Oxygen is isolated in the whole reaction process, so that the reaction loss can be reduced. The defects of the prior art are overcome.
Drawings
FIG. 1 is a process flow diagram of the present invention.
Detailed Description
The invention will be better understood by the following description of embodiments thereof, but the applicant's specific embodiments are not intended to limit the invention to the particular embodiments shown, and any changes in the definition of parts or features and/or in the overall structure, not essential changes, are intended to define the scope of the invention.
Example (b):
example 1
Arachidonic acid purification
1.1A glass reactor was mixed with 200g of an oil and fat having an arachidonic acid content of 42.5%, 1000mL of anhydrous methanol and 400g of urea in a predetermined ratio and stirred.
1.2 heating the mixed material to 75 +/-2 ℃, and refluxing and preserving heat for 1 hour.
1.3 the temperature is reduced to 4 +/-1 ℃, the temperature is preserved for 3 hours, and the stirring speed is kept at 8 rpm.
1.4 centrifuging and keeping supernatant, adding hydrochloric acid into the centrifugate to adjust ph to 2, decompressing and concentrating, and recovering methanol. Concentrating until methanol is removed, and stopping concentrating.
1.5 washing the concentrate with water to pH 6.5 and dehydrating the oil layer to obtain purified arachidonic acid 103 g.
1.6 detection of arachidonic acid content 73.5%
Bis-acylchlorination
2.1 under nitrogen atmosphere, add 3ml DMF into 100g purified arachidonic acid, stir, slowly drop oxalyl chloride at room temperature, control the temperature of the material at 28 + -1 deg.C.
2.2 the reaction solution 2 was taken out and 2ml of methanol was added dropwise to the reaction solution, and the reaction was completed on an arachidonic acid control plate, and the plate was developed with phosphomolybdic acid without arachidonic acid spots.
(III) amidation
3.1 weighing 400g ethanolamine, adding 400mL ethyl acetate to start stirring, the stirring speed is 180rpm.
3.2 slowly adding the reaction solution of acyl chloride dropwise, and controlling the temperature to be 32 +/-2 ℃.
3.3 after the completion of the dripping, the mixture was stirred for 0.5 hour and washed with pure water until ph became neutral.
Fourthly, refining
4.1 adding 5g of activated carbon and 5g of activated clay into the cleaned arachidonic acid ethanolamine with ethyl acetate, and decoloring for 60 min;
3.4 the arachidonic acid ethanolamine with ethyl acetate is filtered in a laboratory, the active carbon and the active clay are removed, and the filtrate is decompressed, concentrated and the ethyl acetate is recovered to obtain 112g of arachidonic acid ethanolamine.
4.2 the obtained arachidonic acid ethanolamine is deodorized in a laboratory by a reduced pressure stripping mode, and residual solvents and odor substances in the product are removed.
Fifthly, products
The sample is detected, the content of the arachidonic acid ethanolamine in the product is 71.3 percent, the peroxide value is 3.5mmol/kg, the anisidine value is 13.7, the color is Y20R4.5, and the solvent residue is less than 1mg/kg.
Example 2
Purification of arachidonic acid
1.1 mixing 50kg of fat and oil with arachidonic acid content of 42.5%, 200L of absolute ethanol and 200kg of urea in a reaction kettle in proportion and stirring.
1.2 heating the mixed material to 70 +/-2 ℃, and refluxing and preserving heat for 2 hours.
1.3 under the protection of nitrogen atmosphere, gradually cooling to minus 7 +/-3 ℃, preserving heat for 5 hours, and keeping the stirring speed at 5 rpm.
1.4 using an explosion-proof centrifuge to centrifuge and retain supernatant, adding sulfuric acid into the centrifugate to adjust ph to 1.5, decompressing and concentrating, and recovering ethanol. Concentrating until ethanol is removed, and stopping concentrating.
1.5 washing the concentrate with water to pH 6.8 and dehydrating the oil layer to obtain purified arachidonic acid 22.3 kg.
1.6 detection result shows that the content of arachidonic acid is 76.5 percent
Di, acyl chlorination
2.1 under nitrogen atmosphere, 22kg of purified arachidonic acid was added with 2L of DMF, stirred and oxalyl chloride was slowly added dropwise at room temperature, controlling the temperature of the batch at 28. + -. 2 ℃.
2.2 the reaction solution 2 was taken out and 2ml of methanol was added dropwise to the reaction solution, and the reaction was completed on an arachidonic acid control plate, and the plate was developed with phosphomolybdic acid without arachidonic acid spots.
Tris, amidation
3.1 weighing 50kg ethanolamine, adding 40L ethyl acetate, starting stirring at 90rpm
3.2 slowly pumping the reaction solution of acyl chlorination, and controlling the temperature to be 32 +/-2 ℃.
3.3 after the completion of the dropwise addition, the mixture was stirred for 2 hours and then washed with pure water until ph became neutral.
Fourthly, refining
4.1 adding 500g of activated carbon and 250g of silicon dioxide into the cleaned arachidonic acid ethanolamine with ethyl acetate, and decoloring for 90min under the condition that the vacuum degree is not more than 5 torr;
3.4 filtering the arachidonic acid ethanolamine with ethyl acetate by an explosion-proof filter to remove active carbon and silicon dioxide, decompressing and concentrating the filtrate to recover ethyl acetate to obtain 23.6kg of arachidonic acid ethanolamine with the content of 65.3 percent.
4.2 the obtained arachidonic acid ethanolamine is deodorized in a laboratory by a reduced pressure stripping mode, and residual solvents and odor substances in the product are removed.
4.3 deodorized arachidonic acid ethanol amine is distilled through 3 grades of molecules to obtain 16.5kg of arachidonic acid ethanol amine product.
Fifthly, products
The sample is detected, the content of the arachidonic acid ethanolamine in the product is 83.2 percent, the peroxide value is 2.1mmol/kg, the anisidine value is 12.3, the color is Y20R3.2, and the solvent residue is less than 1mg/kg.
Example 3
Purification of arachidonic acid
1.1 in a reaction vessel, 200g of an oil and fat containing 50.3% of arachidonic acid, 600mL of absolute ethanol and 600g of urea were mixed in proportion and stirred.
1.2 heating the mixed material to 75 +/-2 ℃, and refluxing and preserving heat for 1 hour.
1.3 under the protection of nitrogen atmosphere, gradually cooling to 0 +/-3 ℃, preserving heat for 3 hours, and keeping the stirring speed at 6 rpm.
1.4 using a laboratory filter to pump and filter, reserving filtrate, adding sulfuric acid into the filtrate to adjust ph to 1.2, decompressing and concentrating, and recovering ethanol. Concentrating until ethanol is removed, and stopping concentrating.
1.5 washing the concentrate with water to a pH of 6.8 and dehydrating the lipid layer to obtain 95kg of purified arachidonic acid.
1.6 detection of arachidonic acid content 83.3%
Di, acyl chlorination
2.1 to the purified arachidonic acid, 2.5mL of DMF was added under nitrogen atmosphere, stirred, and oxalyl chloride was added slowly dropwise at room temperature, controlling the batch temperature at 28. + -. 2 ℃.
2.2 the reaction solution 2 was taken out and 2ml of methanol was added dropwise to the reaction solution, and the reaction was completed on an arachidonic acid control plate, and the plate was developed with phosphomolybdic acid without arachidonic acid spots.
Tris, amidation
3.1 weighing 200g ethanolamine, adding 400mL hexane, starting stirring at 120rpm
3.2 slowly pumping the reaction solution of acyl chlorination, and controlling the temperature to be 32 +/-2 ℃.
3.3 after the completion of the dropwise addition, the mixture was stirred for 2 hours and then washed with pure water until ph became neutral.
Fourthly, refining
4.1 adding 5g of activated carbon and 5g of silicon dioxide into the washed arachidonic acid ethanolamine with hexane, and decoloring for 40min under the condition that the vacuum degree is not more than 5 torr;
3.4 filtering the arachidonic acid ethanolamine with hexane through an explosion-proof filter to remove activated carbon and silicon dioxide, and concentrating the filtrate under reduced pressure to recover the arachidonic acid ethanolamine with hexane.
4.2 the obtained arachidonic acid ethanolamine is deodorized in a laboratory by a reduced pressure stripping mode, and residual solvents and odor substances in the product are removed to obtain 98g of arachidonic acid ethanolamine.
Fifthly, products
The sample is detected, the content of the arachidonic acid ethanolamine in the product is 82.2 percent, the peroxide value is 4.1mmol/kg, the anisidine value is 15.6, the color is Y30R3.5, and the solvent residue is less than 1mg/kg.
Example 4
Purification of arachidonic acid
1.1 in a reaction vessel, 80kg of an oil and fat containing 35.5% of arachidonic acid, 600L of methanol and 300kg of urea were mixed in proportion and stirred.
1.2 heating the mixed material to 70 +/-2 ℃, and refluxing and preserving heat for 5 hours.
1.3 under the protection of nitrogen atmosphere, gradually cooling to-4 +/-3 ℃, preserving heat for 8 hours, and keeping the stirring speed at 5 rpm.
1.4 using an explosion-proof centrifuge to centrifuge and retain supernatant, adding sulfuric acid into the centrifugate to adjust ph to 1.5, decompressing and concentrating, and recovering methanol. Concentrating until methanol is removed, and stopping concentrating.
1.5 washing the concentrate with water to pH 6.8 and dehydrating the oil layer to obtain purified arachidonic acid 35.5 kg.
1.6 detection result shows that the content of arachidonic acid is 65.6 percent
Di, acyl chlorination
2.1 under nitrogen atmosphere, 35.5kg of purified arachidonic acid was added with 3L of DMF, stirred, and oxalyl chloride was slowly added dropwise at room temperature, controlling the temperature of the batch at 28. + -. 2 ℃.
2.2 the reaction solution 2 was taken out and 2ml of methanol was added dropwise to the reaction solution, and the reaction was completed on an arachidonic acid control plate, and the plate was developed with phosphomolybdic acid without arachidonic acid spots.
Tris, amidation
3.1 weighing 80kg ethanolamine, adding 60L ethyl acetate, starting stirring at 50rpm
3.2 slowly pumping the reaction solution of acyl chlorination, and controlling the temperature to be 32 +/-2 ℃.
3.3 after the completion of the dropwise addition, the mixture was stirred for 2 hours and then washed with pure water until ph became neutral.
Fourthly, refining
4.1 adding 300g of activated carbon, 250g of silicon dioxide and 300g of activated clay into the cleaned arachidonic acid ethanolamine with ethyl acetate, and decoloring for 90min under the condition that the vacuum degree is not more than 5 torr;
3.4 filtering the arachidonic acid ethanolamine with ethyl acetate by an explosion-proof filter, removing active carbon, silicon dioxide and activated clay, decompressing and concentrating the filtrate and recovering ethyl acetate to obtain 37.6kg of arachidonic acid ethanolamine with the content of 63.2 percent.
4.2 the obtained arachidonic acid ethanolamine is deodorized in a laboratory by a reduced pressure stripping mode, and residual solvents and odor substances in the product are removed.
4.3 deodorized arachidonic acid ethanol amine is distilled by 3 grades of molecules to obtain 20.3kg of arachidonic acid ethanol amine product.
Fifthly, products
The sample is detected, the content of the arachidonic acid ethanolamine in the product is 85.7 percent, the peroxide value is 2.0mmol/kg, the anisidine value is 9.5, the color is Y30R2.5, and the solvent residue is less than 1mg/kg.
The synthesis and purification method of the arachidonic acid ethanolamine is completed.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it is therefore intended that all such changes and modifications as fall within the true spirit and scope of the invention be considered as within the following claims.
Claims (2)
1. A method for synthesizing and purifying arachidonic acid ethanolamine is characterized by comprising the following steps: the separation and purification method comprises the steps of:
the method comprises the following steps: preliminary isolation and preliminary purification of arachidonic acid
1.1, mixing arachidonic acid (ARA) grease, methanol or ethanol and urea in a reaction kettle according to a ratio and stirring, wherein the ARA grease comprises methanol or ethanol: the proportion range of the urea is 1:3:1 to 1:10:5, the ARA content in the ARA grease is 25 to 60 percent, the methanol or ethanol content is more than 75 percent,
1.2, heating the mixed materials to 60-80 ℃, refluxing and preserving heat for more than 0.5 hour,
1.3, cooling to below 4 ℃, preserving heat for more than 1 hour,
1.4 detecting the arachidonic acid content of the supernatant, and centrifuging when the content is more than 60%
1.5 centrifuging and keeping supernatant, adding inorganic acid to adjust pH to 1-3, concentrating under reduced pressure, recovering methanol/ethanol, concentrating to remove methanol/ethanol, stopping concentrating, wherein the inorganic acid comprises sulfuric acid, hydrochloric acid, phosphoric acid, etc., wherein the hydrochloric acid is the most preferred, and preparing concentrated solution;
1.6 washing the concentrated solution with pure water until the pH value is 6-8, dehydrating the oil layer to obtain primarily purified arachidonic acid,
step two: acyl chloride
2.1, adding 2-6ml DMF per kg fatty acid, stirring, slowly dripping oxalyl chloride at room temperature, controlling the temperature of the materials at 25-30 ℃,
2.2, dropwise adding 2ml of methanol into the reaction solution 2, using phosphomolybdic acid to develop color on an arachidonic acid control dot plate, completely reacting without arachidonic acid dots, and completing acyl chlorination to prepare an acyl chlorination reaction solution;
step three: amidation
And 3.1, according to the mass of the reaction liquid after acyl chlorination, preparing ethanolamine according to the ratio of 2-5:1, preparing a solvent of the reaction liquid with the volume ratio of more than 1.5 times, putting the ethanolamine and the solvent into a reaction kettle, starting stirring, and stirring at the speed of 30-200 rpm.
The solvent comprises one of organic solvents such as hexane, ethyl acetate, acetone, dichloromethane and the like,
3.2, slowly dripping the acyl chlorination reaction liquid, and controlling the temperature to be 30-35 ℃. Keeping the pH to be alkaline in the dropping process, if the pH is neutral, adding ethanolamine properly,
3.3, stirring for more than 0.5 hour after dripping, and washing with pure water until the pH value is neutral;
step four: decolorizing, deodorizing and purifying by molecular distillation
4.1, adding a decolorant into the mixed solution of the arachidonic acid ethanolamine after washing for decoloration, decoloring for 30-90min under the condition that the vacuum degree is not more than 5 torr, preparing a decolored solution,
the decolorizing agent comprises one or more of active carbon, activated clay and attapulgite, the use amount of the decolorizing agent is 1-5% of arachidonic acid ethanolamine,
4.2, separating the decolorant by using plate-frame or centrifugation technology and the like to obtain decolored mixed liquor;
4.3, decompressing and concentrating the decolored solution to recover the solvent to prepare a concentrated solution, wherein the concentrated solution is a crude product of arachidonic acid ethanolamine to complete the synthesis of arachidonic acid ethanolamine,
4.4, the crude product of arachidonic acid ethanolamine can be directly deodorized by steam, residual ethyl acetate and odor substances are removed, the finished product of arachidonic acid ethanolamine is obtained,
4.5, the crude product of arachidonic acid ethanolamine or finished product of arachidonic acid ethanolamine can be purified by molecular distillation,
4.6, multi-stage molecular distillation purification can be carried out, the purity of the crude product of arachidonic acid ethanolamine or finished product of arachidonic acid ethanol can be improved by 10 to 30 percent,
4.7, wherein the stripping deodorization and molecular distillation process can be carried out only one or in combination; the synthesis and purification method of the arachidonic acid ethanolamine is formed.
2. The method for synthesizing and purifying arachidonic acid ethanolamine according to claim 1, wherein the technological parameters of the method for synthesizing and purifying arachidonic acid ethanolamine are as follows: an arachidonic acid ethanolamine product by a steam stripping deodorization and molecular distillation process, wherein the arachidonic acid ethanolamine content is not less than 60%, the arachidonic acid ethanolamine content is not less than 80% by a multistage molecular distillation process, the peroxidation value of the arachidonic acid ethanolamine is not higher than 5mmol/kg, the anisidine value is not higher than 20, the color is not higher than Y40R10, and the solvent residue is not higher than 1%.
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