CN108821973B - Clean production method of prolipofen - Google Patents
Clean production method of prolipofen Download PDFInfo
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- CN108821973B CN108821973B CN201810919302.7A CN201810919302A CN108821973B CN 108821973 B CN108821973 B CN 108821973B CN 201810919302 A CN201810919302 A CN 201810919302A CN 108821973 B CN108821973 B CN 108821973B
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- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Abstract
The invention discloses a method for cleanly producing Prussian lipid, which comprises the following steps: adding isopropanol A, fenofibric acid and 2-pyrrolidone hydrogen sulfate into a reaction container A; adding isopropanol B and aluminum isopropoxide into a reaction vessel B; and heating the reaction container A, distilling and collecting azeotrope of water and isopropanol generated by the esterification reaction in the reaction container A, adding the azeotrope into the reaction container B to remove water by using aluminum isopropoxide, condensing the isopropanol distilled out from the reaction container B, and returning the condensed isopropanol into the reaction container A for reaction to finally obtain the Prussian. The method takes the water generated in the esterification reaction process out of the reaction system in time, and after the water and isopropanol azeotrope are dewatered by the aluminum isopropoxide, the anhydrous isopropanol is distilled out and is continuously reused for the esterification reaction, so that the method not only ensures the rapid progress of the esterification reaction, but also reduces the generation of three wastes, improves the product quality, reduces the production cost, and has good economic benefit and environmental benefit.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for cleanly producing prolinol.
Background
The chemical name of the Prussian lipid is 2-methyl- [4- (4-chlorobenzoyl) phenoxy ] isopropyl propionate, which is a hypolipidemic, is mainly used for treating type IIa, IIb, III and IV hyperlipoproteinemia and has wide application.
The method has the defects of complex catalyst preparation, high cost, poor product quality, environmental pollution and the like in different degrees, and has long reaction time and poor water carrying effect due to the fact that cyclohexane, toluene, xylene and the like are used as water carrying agents in the reaction process, and high reaction temperature and more side reactions are caused due to the fact that high-boiling-point toluene and xylene are used as the water carrying agents, a large amount of energy is consumed for post-treatment, toxicity is high, and the product quality is influenced due to the fact that organic solvent residues of the puloformafen are high.
Disclosure of Invention
The invention aims to overcome the defects of the prior method, provides a method for cleanly producing the Prussian lipid, and solves the problems of complex catalyst preparation, high cost, poor product quality, environmental pollution and the like in the preparation method of the Prussian lipid in the prior art at different degrees.
In order to achieve the aim, the invention provides a method for cleanly producing the prolinol, which specifically comprises the following steps:
step 1, adding isopropanol A, fenofibric acid and 2-pyrrolidone hydrogen sulfate ([ Hnhp ] in sequence into a reaction container A with a condensation pipe A]HSO4) Then standby; wherein the mass ratio of the isopropanol A to the fenofibric acid to the 2-pyrrolidone hydrogen sulfate is 1.2-1.3: 1: 0.05 to 0.08;
adding isopropanol B and aluminum isopropoxide into a reaction vessel B with a condensation pipe B for later use; the mass ratio of the isopropanol B to the aluminum isopropoxide to the fenofibric acid is 1.2-1.3: 0.75-0.9: 1;
step 2, heating the reaction liquid in the reaction container A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the reaction container A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a reaction container B, heating the reaction liquid in the reaction container B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the reaction container B to absorb water in the distillate, carrying out hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the reaction container B, and returning the distilled isopropanol into the reaction container A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the reaction container A, and obtaining a concentrated solution after the distillation is finished;
adding cyclohexane with the mass being 65-75% of that of fenofibric acid into the concentrated solution for extraction, standing after extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, adding isopropanol C with the mass 1.4-1.6 times of that of fenofibric acid into the organic phase C, uniformly mixing, cooling to 20-25 ℃, crystallizing, performing suction filtration, washing a filter cake with isopropanol D with the mass 15.7% of that of fenofibric acid for 2-3 times, and drying to obtain the prolifene.
Preferably, in the step 3, the distillate is dripped into the reaction vessel B by using the dropping funnel A, the isopropanol distilled out of the reaction vessel B is dripped into the reaction vessel A by using the dropping funnel B to continue the reaction, and the dripping speeds of the dropping funnel A and the dropping funnel B are the same.
Preferably, the dropping funnel A has the same dropping speed as that of the azeotrope volatilized during the esterification reaction of the step 2 when distilled and collected.
Preferably, after the esterification reaction in the reaction vessel a is finished, the anhydrous isopropanol which is 85-95% of the fenofibric acid by mass is distilled out from the reaction vessel B under reduced pressure, then water which is 12.5% of the fenofibric acid by mass is added into the reaction vessel B, so that the aluminum isopropoxide which is not hydrolyzed by water absorption in the esterification reaction process is hydrolyzed into aluminum hydroxide, the water-containing isopropanol is recovered by reduced pressure distillation and reused for the dehydration reaction in the next reaction vessel B, and the aluminum hydroxide in the reaction vessel B is dried and calcined to obtain the aluminum oxide.
Preferably, the reaction vessel A and the reaction vessel B are both four-neck flasks.
Preferably, thermometers are provided in both the reaction vessel a and the reaction vessel B.
Preferably, the condensation pipe A and the condensation pipe B are straight condensation pipes.
Preferably, the organic phase B is subjected to rotary evaporation under the conditions of vacuum degree of-0.09 MPa to-0.1 MPa and rotating speed of 80 r/min.
Compared with the prior art, the invention has the beneficial effects that:
1) the invention adopts ionic liquid [ Hnhp]HSO4As a catalyst, the product is easy to separate from the catalyst after the catalytic esterification reaction, and the separated ionic liquid [ Hnhp]HSO4Can realize recycling after removing water through simple treatment, and does not influence the reaction effect and the product quality.
2) According to the invention, water generated in the esterification reaction process is timely taken out of the reaction system, so that the isopropanol and fenofibric acid are ensured to fully react, and the esterification reaction is efficiently promoted; the water and isopropanol azeotrope are distilled to obtain anhydrous isopropanol, which is then reused in esterification reaction after being dewatered by aluminum isopropoxide, so that the esterification reaction is carried out efficiently and quickly, the generation of three wastes is reduced, the product quality is improved, the production cost is reduced, and the method has good economic and environmental benefits.
Drawings
FIG. 1 is a process flow diagram of the present invention.
Detailed Description
In order that those skilled in the art will better understand that the method embodiments of the present invention may be practiced, the present invention will be further described with reference to the following specific examples and accompanying drawings, which are not intended to be limiting.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
FIG. 1 is a process flow diagram of the present invention, and it can be seen from FIG. 1 that the present invention takes out water generated in the esterification reaction process in time from the reaction system, so as to ensure that isopropanol and fenofibric acid fully react and efficiently promote the esterification reaction; the water and isopropanol azeotrope are dewatered by aluminum isopropoxide, and then anhydrous isopropanol is distilled out and continuously reused for esterification reaction.
The present invention will be further described with reference to the following specific examples, which are specifically shown in examples 1 to 4.
Example 1
A method for cleanly producing Prussian lipid comprises the following steps:
step 1, adding 76.6g of isopropanol A, 63.8g of fenofibric acid and 5.1g of 2-pyrrolidone hydrogen sulfate into a four-neck flask A with a thermometer, a straight condenser A and an electric stirrer for later use;
adding 80g of isopropanol B and 57.4g of aluminum isopropoxide into another four-neck flask B provided with a thermometer, a straight condenser tube B and an electric stirrer for later use;
step 2, heating the reaction liquid in the four-neck flask A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the four-neck flask A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a four-neck flask B, heating the reaction solution in the four-neck flask B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the four-neck flask B to absorb water in the distillate, performing hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the four-neck flask B, and returning the distilled isopropanol into the four-neck flask A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the four-neck flask A, and obtaining a concentrated solution after the distillation is finished;
adding 42g of cyclohexane into the concentrated solution for extraction, standing after the extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, then adding 95g of isopropanol C, uniformly mixing, cooling to 20-25 ℃ for crystallization, performing suction filtration by using a vacuum pump, washing a filter cake for 2 times by using 10g of isopropanol D, and drying to obtain 66.3g of the Prussian-oleofen, wherein the yield is 91.80%, the melting point is 80.1-80.8 ℃, and the purity is 99.97%.
Example 2
A method for cleanly producing Prussian lipid comprises the following steps:
step 1, adding 82g of isopropanol A, 63.8g of fenofibric acid and 3.2g of 2-pyrrolidone hydrogen sulfate into a four-neck flask A with a thermometer, a straight condenser A and an electric stirrer for later use;
adding 83g of isopropanol B and 53g of aluminum isopropoxide into another four-neck flask B provided with a thermometer, a straight condenser tube B and an electric stirrer for later use;
step 2, heating the reaction liquid in the four-neck flask A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the four-neck flask A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a four-neck flask B, heating the reaction solution in the four-neck flask B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the four-neck flask B to absorb water in the distillate, performing hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the four-neck flask B, and returning the distilled isopropanol into the four-neck flask A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the four-neck flask A, and obtaining a concentrated solution after the distillation is finished;
adding 44g of cyclohexane into the concentrated solution for extraction, standing after the extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, then adding 89g of isopropanol C, uniformly mixing, cooling to 20-25 ℃ for crystallization, performing suction filtration by using a vacuum pump, washing a filter cake for 2 times by using 10g of isopropanol D, and drying to obtain 66.1g of the Prussian-lipin, wherein the yield is 91.52%, the melting point is 80.0-80.8 ℃, and the purity is 99.98%.
Example 3
A method for cleanly producing Prussian lipid comprises the following steps:
step 1, adding 83g of isopropanol A, 63.8g of fenofibric acid and 4g of 2-pyrrolidone hydrogen sulfate into a four-neck flask A with a thermometer, a straight condenser A and an electric stirrer for later use;
76.5g of isopropanol B and 48g of aluminum isopropoxide are added into another four-neck flask B provided with a thermometer, a straight condenser tube B and an electric stirrer for standby;
step 2, heating the reaction liquid in the four-neck flask A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the four-neck flask A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a four-neck flask B, heating the reaction solution in the four-neck flask B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the four-neck flask B to absorb water in the distillate, performing hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the four-neck flask B, and returning the distilled isopropanol into the four-neck flask A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the four-neck flask A, and obtaining a concentrated solution after the distillation is finished;
adding 47g of cyclohexane into the concentrated solution for extraction, standing after extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, then adding 100g of isopropanol C, uniformly mixing, cooling to 20-25 ℃ for crystallization, performing suction filtration by using a vacuum pump, washing a filter cake for 2 times by using 10g of isopropanol D, and drying to obtain 65.8g of the Prussian-oleofen, wherein the yield is 91.10%, the melting point is 79.9-80.5 ℃, and the purity is 99.97%.
Example 4
A method for cleanly producing Prussian lipid comprises the following steps:
step 1, adding 80g of recovered isopropanol A, 63.8g of fenofibric acid and 4g of 2-pyrrolidone hydrogen sulfate into a four-neck flask A with a thermometer, a straight condenser A and an electric stirrer for later use;
adding 82g of recovered isopropanol B and 51g of aluminum isopropoxide into another four-neck flask B provided with a thermometer, a straight condenser tube B and an electric stirrer for later use;
step 2, heating the reaction liquid in the four-neck flask A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the four-neck flask A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a four-neck flask B, heating the reaction solution in the four-neck flask B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the four-neck flask B to absorb water in the distillate, performing hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the four-neck flask B, and returning the distilled isopropanol into the four-neck flask A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the four-neck flask A, and obtaining a concentrated solution after the distillation is finished;
adding 45g of recovered cyclohexane into the concentrated solution for extraction, standing after extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, then adding 102g of recovered isopropanol C, uniformly mixing, cooling to 20-25 ℃ for crystallization, performing suction filtration by using a vacuum pump, washing a filter cake for 2 times by using 10g of isopropanol D, and drying to obtain 66g of the Prussian-lipfen, wherein the yield is 91.38%, the melting point is 80.0-80.6 ℃, and the purity is 99.99%.
In examples 1 to 4, the organic phase B was subjected to rotary evaporation under a vacuum degree of-0.09 MPa to-0.1 MPa and a rotation speed of 80 r/min.
In the step 3, the distillate is dripped into a four-neck flask B by using a dropping funnel A, isopropanol distilled from the four-neck flask B is dripped into the four-neck flask A by using the dropping funnel B for continuous reaction, and the dripping speeds of the dropping funnel A and the dropping funnel B are the same; simultaneously, dropping funnel A's dropwise add speed is the same with the dropwise add speed when the azeotropic mixture distillation that volatilizees in the esterification reaction in-process of step 2 is collected, can make the speed that the azeotropic mixture that esterification reaction produced volatilizes four-neck flask A in the four-neck flask A like this and the speed that the isopropyl alcohol of distilling in the four-neck flask B added in the four-neck flask A keep in step to esterification reaction does not receive the influence of organic solvent volatilization loss in making four-neck flask A, and then guarantees going on smoothly of reaction.
After the esterification reaction in the four-neck flask A is finished, firstly carrying out reduced pressure distillation on the four-neck flask B to obtain anhydrous isopropanol with the mass equivalent to 85-95% of that of fenofibric acid, then adding 8g of water into the four-neck flask B to hydrolyze aluminum isopropoxide which does not absorb water and hydrolyze in the esterification reaction process into aluminum hydroxide, then carrying out reduced pressure distillation to recover water-containing isopropanol, reusing the water-containing isopropanol in the next batch of dehydration reaction in the four-neck flask B, and drying and calcining the aluminum hydroxide in the four-neck flask B to obtain aluminum oxide.
From the experimental data of the embodiments 1 to 4, it can be known that the method for preparing the proliferin has high yield and high purity, can greatly save the using amount of the isopropanol, improves the product quality, reduces the production cost, and has good economic benefit and environmental benefit.
It should be noted that, when the present invention relates to numerical ranges, it should be understood that two endpoints of each numerical range and any numerical value between the two endpoints can be selected, and since the steps and methods adopted are the same as those in embodiments 1 to 4, the present invention describes preferred embodiments in order to prevent redundancy, but once a person skilled in the art knows the basic inventive concept, other changes and modifications can be made to these embodiments. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (6)
1. A method for cleanly producing Prussian lipid is characterized by comprising the following steps:
step 1, sequentially adding isopropanol A, fenofibric acid and 2-pyrrolidone bisulfate into a reaction container A with a condenser A for later use; wherein the mass ratio of the isopropanol A to the fenofibric acid to the 2-pyrrolidone hydrogen sulfate is 1.2-1.3: 1: 0.05 to 0.08;
adding isopropanol B and aluminum isopropoxide into a reaction vessel B with a condensation pipe B for later use; wherein the mass ratio of the isopropanol B to the aluminum isopropoxide to the fenofibric acid is 1.2-1.3: 0.75-0.9: 1;
step 2, heating the reaction liquid in the reaction container A to 80 +/-1 ℃ under the stirring condition to perform esterification reaction, azeotroping water generated in the esterification reaction process with isopropanol A in the reaction container A, and distilling and collecting the volatilized azeotrope to obtain a distillate;
step 3, adding the distillate obtained in the step 2 into a reaction container B, heating the reaction liquid in the reaction container B to 80 +/-1 ℃ under the stirring condition, enabling aluminum isopropoxide in the reaction container B to absorb water in the distillate, carrying out hydrolysis reaction under the action of the absorbed water and the isopropanol to generate aluminum hydroxide, continuously distilling the isopropanol in the reaction container B, and returning the distilled isopropanol into the reaction container A for continuous reaction;
step 4, circularly repeating the steps 2-3 in the reaction process until the esterification reaction in the step 2 is carried out for 1.5 hours, stopping the reaction, then carrying out atmospheric distillation and reduced pressure distillation on the reaction liquid in the reaction container A, and obtaining a concentrated solution after the distillation is finished;
adding cyclohexane with the mass being 65-75% of that of fenofibric acid into the concentrated solution for extraction, standing after extraction is finished, and separating lower-layer ionic liquid to obtain an organic phase A;
adding a 10 mass percent sodium hydroxide aqueous solution into the organic phase A, adjusting the pH of the system to 8-9, and then separating a lower-layer water phase to obtain an organic phase B;
adding hot water at 65-70 ℃ into the organic phase B, washing to be neutral, and separating out a lower-layer water phase to obtain an organic phase C;
concentrating the organic phase C at 50-60 ℃ to remove the organic solvent, then adding isopropanol C with the mass 1.4-1.6 times of that of fenofibric acid into the organic phase C, uniformly mixing, cooling to 20-25 ℃, crystallizing, carrying out suction filtration, washing a filter cake with isopropanol D with the mass 15.7% of that of fenofibric acid for 2-3 times, and drying to obtain the prolifene;
in the step 3, the distillate is dripped into a reaction container B by using a dropping funnel A, isopropanol distilled from the reaction container B is dripped into the reaction container A by using the dropping funnel B for continuous reaction, and the dripping speeds of the dropping funnel A and the dropping funnel B are the same;
the dropping funnel A has the same dropping speed as that of the azeotrope volatilized in the esterification reaction process in the step 2 during distillation and collection.
2. The method for cleanly producing the pulullifene according to claim 1, wherein after the esterification reaction in the reaction vessel A is finished, anhydrous isopropanol which is equivalent to 85-95% of the mass of the fenofibric acid is firstly distilled out in the reaction vessel B under reduced pressure, then water which is equivalent to 12.5% of the mass of the fenofibric acid is added into the reaction vessel B, so that the aluminum isopropoxide which does not absorb water and hydrolyze in the esterification reaction process is hydrolyzed into aluminum hydroxide, then the water-containing isopropanol is recovered by reduced pressure distillation and is reused for the dehydration reaction in the next reaction vessel B, and the aluminum hydroxide in the reaction vessel B is dried and calcined to obtain the aluminum oxide.
3. The method for cleanly producing the prolipofen according to claim 1, characterized in that the reaction vessel A and the reaction vessel B are four-neck flasks.
4. The method for cleanly producing pullulan according to claim 3, wherein a thermometer is arranged in each of the reaction vessel A and the reaction vessel B.
5. The method for cleanly producing pullulan according to claim 1, wherein the condensation tube A and the condensation tube B are straight condensation tubes.
6. The method for clean production of the pullulan according to claim 1, wherein the organic phase B is subjected to rotary evaporation under the condition of vacuum degree of-0.09 to-0.1 MPa and rotation speed of 80 r/min.
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