阅读说明：本技术 乙交酯的制备方法 (Process for preparing glycolide ) 是由 王睿 朱煜 周芬 熊金根 于 2018-07-06 设计创作，主要内容包括：本发明涉及一种乙交酯的制备方法,主要解决现有技术中存在的收集过程中乙交酯容易发生副反应的问题。通过采用乙交酯的制备方法,其特征在于,包括：解聚反应时,将解聚反应产生的乙交酯与溶剂混合形成液体混合物,并将所形成的液体混合物的温度保持在65～95℃；然后在剪切条件下冷却所得的液体混合物,得到乙交酯晶体的步骤；其中,所述溶剂与乙交酯互不相溶的技术方案,较好地解决了该问题,可用于高纯度乙交酯的工业化生产中。(The invention relates to a preparation method of glycolide, which mainly solves the problem that the glycolide is easy to generate side reaction in the collection process in the prior art. A method for producing glycolide, which comprises: during depolymerization, mixing glycolide generated by the depolymerization reaction with a solvent to form a liquid mixture, and keeping the temperature of the formed liquid mixture at 65-95 ℃; then cooling the obtained liquid mixture under a shearing condition to obtain glycolide crystals; the technical scheme that the solvent and the glycolide are not mutually soluble solves the problem well, and can be used for industrial production of high-purity glycolide.)

1. A method for preparing glycolide, comprising: mixing glycolide generated by depolymerization reaction with a solvent to form a liquid mixture during depolymerization reaction, and keeping the temperature of the formed liquid mixture at 65-95 ℃; then cooling the obtained liquid mixture under a shearing condition to obtain glycolide crystals; wherein the solvent is immiscible with glycolide.

2. The process for the preparation of glycolide according to claim 1, characterized by comprising the steps of:

(1) adding glycolic acid aqueous solution and a catalyst into a reaction kettle, carrying out polycondensation reaction, and distilling to remove water at normal pressure;

(2) under the vacuum condition, continuously reacting until the reactant is solidified into milk white, and obtaining glycolic acid oligomer;

(3) carrying out depolymerization reaction on the obtained glycolic acid oligomer to generate glycolide; putting the product glycolide obtained in the depolymerization process into a collection tank filled with a solvent immiscible with glycolide, and keeping the temperature of the collection tank at 65-95 ℃ until the reaction is finished to obtain a liquid mixture;

(4) after the depolymerization reaction is finished, the collected liquid mixture is cooled and sheared to separate out glycolide crystals, glycolide crystals are obtained by filtration, and refined glycolide is obtained by washing and drying.

3. The process for preparing glycolide according to claim 2, wherein the reaction temperature for the removal of water by heating and distillation in step (1) is in the range of 110 ℃ to 180 ℃.

4. The method for preparing glycolide according to claim 2, wherein the catalyst used in step (1) is one of stannous chloride, stannous octoate, zinc oxide, zinc acetylacetonate, and iron acetylacetonate.

5. The method for producing glycolide according to claim 2, wherein the vacuum condition in the step (2) is in the range of 100Pa to 8000 Pa.

6. The method for preparing glycolide according to claim 2, wherein the depolymerization reaction in the step (3) is carried out at a reaction pressure of 100 to 3000Pa and a reaction temperature of 220 to 280 ℃.

7. The process for preparing glycolide according to claim 2, wherein the solvent immiscible with glycolide in step (3) is an organic solvent having a melting point of less than 70 ℃ and a boiling point of more than 150 ℃.

8. The process for producing glycolide according to claim 7, wherein the organic solvent is an alcohol solvent having 6 or more and 12 or less carbon atoms.

9. The process for preparing glycolide according to claim 2, wherein the volume of the solvent immiscible with glycolide in the step (3) is 0.5 to 5 times the volume of glycolide.

10. The process for the preparation of glycolide according to claim 2, wherein the temperature of the collection tank in the step (3) is maintained at a temperature of from 70 ℃ to 80 ℃.

Technical Field

The invention relates to a preparation method of glycolide.

Background

Glycolide is a cyclic ester produced by dehydration of two molecules of glycolic acid, and is a monomer for producing polyglycolic acid (PGA). Polyglycolic acid is an important biodegradable polyester material, can be degraded into glycolic acid under the catalytic action of biological enzyme and participates in the metabolism of a human body, so that the polyglycolic acid is widely used in the fields of biomedical materials such as surgical sutures, artificial tissues, drug controlled release and the like. The synthesis methods of polyglycolic acid are roughly divided into two types, one route is obtained by direct polycondensation of glycolic acid, which is also called a one-step method, and the polymer obtained by the method is generally low in molecular weight and poor in processing strength, and is not suitable for the field of medical materials; another method is that glycolic acid is firstly condensed to obtain polyglycolic acid with not high molecular weight, then the polyglycolic acid is depolymerized to obtain glycolide, and then the polyglycolic acid is prepared by polymerization of the glycolide, the route is called as a two-step method, the polymer with high molecular weight can be obtained, and the method is mainly used for preparing medical operation line materials, and a specific preparation method is as follows:

(1) firstly, glycolic acid is gradually heated under normal pressure to carry out polycondensation reaction and remove water generated by the reaction, and after the water yield reaches a certain degree, water is further removed under the reduced pressure condition to obtain a polycondensation product with higher molecular weight.

(2) Heating glycolic acid prepolymer and catalyst such as stannous chloride to 230-280 deg.C under reduced pressure, collecting glycolide vapor generated by reaction, and cooling to obtain yellow solid crude product, referred to as crude glycolide.

The crude glycolide obtained by the above reaction usually contains various impurities such as water, glycolic acid oligomer, and the like, and it is necessary to obtain glycolide having a purity satisfying the polymerization requirement by purification and purification. In order to industrially purify glycolide by transfer, it is necessary to heat, store and transfer glycolide in the form of a liquid phase, and glycolide is likely to undergo side reactions such as hydrolysis and self-polymerization under heating conditions, which lowers the yield of glycolide, and the by-products produced thereby also increase the burden on the subsequent purification process.

Wuyu, CN101616907, discloses a method for producing glycolide, in which polyglycolic acid obtained by polycondensation is heated together with a high-boiling depolymerization solvent such as diethylene glycol dibutyl ether to be distilled off, liquid separation is performed at 90 ℃, and then the depolymerization solvent remaining in glycolide is removed from the glycolide phase obtained by rinsing the liquid separation with n-hexane. The method improves the heat dissipation effect of the depolymerization process. However, a large amount of high boiling point solvent and glycolide need to be distilled out together, so that more energy is consumed, and the economic and environment-friendly concept is not met.

Disclosure of Invention

The invention aims to solve the technical problems of more side reactions such as self polymerization, hydrolysis and the like during the preparation of glycolide in the prior art and high content of terminal carboxyl groups of the obtained glycolide, and provides a preparation method of glycolide.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for preparing glycolide, comprising: during depolymerization reaction (namely during depolymerization reaction), glycolide generated by the depolymerization reaction is mixed with a solvent to form a liquid mixture, and the temperature of the formed liquid mixture is kept at 65-95 ℃; then cooling the obtained liquid mixture under a shearing condition to obtain glycolide crystals; wherein the solvent is immiscible with glycolide.

In the above technical solution, the preparation method preferably comprises the following steps:

(1) adding a glycolic acid aqueous solution and a catalyst into a reaction kettle, carrying out polycondensation reaction, and distilling to remove water at normal pressure;

(2) under the vacuum condition, continuously reacting until the reactant is solidified into milk white, and obtaining glycolic acid oligomer;

(3) carrying out depolymerization reaction on the obtained glycolic acid oligomer to generate glycolide; putting the product glycolide obtained in the depolymerization process into a collection tank filled with a solvent immiscible with glycolide, and keeping the temperature of the collection tank at 65-95 ℃ until the reaction is finished to obtain a liquid mixture;

(4) after the depolymerization reaction is finished, the collected liquid mixture is cooled and sheared to separate out glycolide crystals, glycolide crystals are obtained by filtration, and then refined glycolide is obtained by washing and drying

In the above technical solution, the reaction temperature range for removing water by distillation in the step (1) is preferably 110 to 180 ℃.

In the above technical scheme, the catalyst used in the step (1) is preferably one of stannous chloride, stannous octoate, zinc oxide, zinc acetylacetonate and iron acetylacetonate.

In the above-mentioned embodiment, the vacuum condition in the step (2) is in the range of 100Pa to 8000Pa, preferably 3000Pa to 5000 Pa.

In the above-mentioned technical means, the reaction pressure of the depolymerization reaction in the step (3) is preferably 100 to 3000Pa, more preferably 1000 to 3000 Pa; the reaction temperature is preferably 220 to 280 ℃ and more preferably 240 to 270 ℃.

In the above technical solution, the solvent immiscible with glycolide in the step (3) is preferably an organic solvent having a melting point of 70 ℃ or higher and a boiling point of 150 ℃ or higher; more preferably, the solvent is an alcohol solvent having 6 to 12 carbon atoms, such as n-hexanol, n-heptanol, and n-octanol, or polyethylene glycol.

In the above technical solution, the volume of the solvent immiscible with glycolide in the step (3) is preferably 0.5 to 5 times, and more preferably 1 to 2 times the volume of glycolide.

In the above technical solution, the temperature of the collection tank body in the step (3) is preferably maintained at 70-80 ℃.

In the above technical scheme, in the step (4), the mixture of glycolide and the solvent is cooled to a temperature not higher than 20 ℃ to ensure that glycolide is fully crystallized and precipitated, and the shearing can be in a stirring manner or the like.

The impurities in the glycolide are mainly water, glycolic acid and oligomers thereof, so the impurity content in the glycolide can be characterized by utilizing a method for measuring the content of terminal carboxyl groups in the glycolic acid. The content of terminal carboxyl in glycolide before and after refining can be measured by an acid-base titration method. The operation thereof is described below. The glycolide sample is dissolved in about 20mL of dry dimethyl sulfoxide, and a few drops of bromophenol blue indicator solution are dropped into the dried dimethyl sulfoxide after the glycolide sample is dissolved, so that the solution is yellow. Titration was carried out with a solution of sodium hydroxide in benzyl alcohol at a concentration of 0.01632mol/L, and the end point was when the solution changed from yellow to green in color. The carboxyl end group content in glycolide was calculated by calculating the volume of sodium hydroxide solution used when the titration endpoint was reached.

By adopting the technical scheme of the invention, the generated crude glycolide is collected in the depolymerization reaction processIn the collecting tank, mixing with immiscible solvent, maintaining temperature, and crystallizing to greatly reduce the carboxyl end group content of crude glycolide, increase the yield, and make the carboxyl end group content of refined glycolide up to 10^-6mol.g^-1And a better technical effect is achieved.

The invention is further illustrated by the following examples.

Detailed Description

[ example 1 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask, and water produced in the reaction was distilled off by gradually raising the temperature at normal pressure within a temperature range of 110 to 180 ℃. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceeded, glycolide was distilled off continuously, 300ml of n-octanol was added to the collection bottle, and stirring was started to allow thorough mixing of the liquid phase glycolide and the solvent. The collection tank was kept at 70 ℃ for 4 hours, the depolymerization reaction was stopped, and a portion of the crude glycolide sample was taken for acid-base titration. And then slowly cooling the liquid in the collecting tank, and cooling the system to 10 ℃ under the condition of keeping the stirring rotating speed unchanged, and crystallizing and separating out glycolide. Filtering the cooled solid-liquid mixture, rinsing the filter cake with methanol for 3 times, filtering, drying the obtained glycolide crystals to obtain 282g of glycolide with the yield of 88%, wherein the terminal carboxyl group content of the crude glycolide is 3.63 multiplied by 10^-4mol.g^-1The carboxyl end group content of the refined glycolide was 7.10X 10^-6mol.g^-1。

[ example 2 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask, and water produced in the reaction was distilled off by gradually raising the temperature at normal pressure within a temperature range of 110 to 180 ℃. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceedsWhile glycolide is continuously distilled off, 300ml of dodecanol is added into a collecting bottle, and stirring is started to fully mix the liquid-phase glycolide and the solvent. The collection tank was kept at 70 ℃ for 4 hours, the depolymerization reaction was stopped, and a portion of the crude glycolide sample was taken for acid-base titration. And then slowly cooling the liquid in the collecting tank, and cooling the system to 10 ℃ under the condition of keeping the stirring rotating speed unchanged, and crystallizing and separating out glycolide. The cooled solid-liquid mixture was filtered, and the cake was rinsed 3 times with methanol, and the resulting glycolide crystals were dried after filtration to obtain 279g of glycolide with a yield of 87%. Wherein the carboxyl end group content of the crude glycolide is 4.12X 10^-4mol.g^-1The carboxyl end group content of the refined glycolide is 7.65 multiplied by 10^-6mol.g^-1。

[ example 3 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask, and water produced in the reaction was distilled off by gradually raising the temperature at normal pressure within a temperature range of 110 to 180 ℃. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceeded, glycolide was distilled off continuously, 300ml of polyethylene glycol 400 was added to the collection bottle, and stirring was started to allow thorough mixing of the liquid phase glycolide and the solvent. The collection tank was kept at 70 ℃ for 4 hours, the depolymerization reaction was stopped, and a portion of the crude glycolide sample was taken for acid-base titration. And then slowly cooling the liquid in the collecting tank, and cooling the system to 10 ℃ under the condition of keeping the stirring rotating speed unchanged, and crystallizing and separating out glycolide. Filtering the cooled solid-liquid mixture, rinsing the filter cake with methanol for 3 times, filtering, drying the obtained glycolide crystals to obtain 282g of glycolide with the yield of 88%, wherein the terminal carboxyl group content of the crude glycolide is 3.44 multiplied by 10^-4mol.g^-1mol.g^-1The carboxyl end group content of the refined glycolide was 6.82X 10^-6mol.g^-1。

[ example 4 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask under normal pressureGradually raising the temperature within the temperature range of 110-180 ℃, heating and distilling to remove the water generated in the reaction. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceeded, glycolide was distilled off continuously, 400ml of polyethylene glycol 400 was added to the collection bottle, and stirring was started to allow thorough mixing of the liquid phase glycolide and the solvent. The collection tank temperature was maintained at 70 ℃ for 4 hours. Stopping the depolymerization reaction, and taking a part of crude glycolide samples for acid-base titration. And then slowly cooling the liquid in the collecting tank, and cooling the system to 10 ℃ under the condition of keeping the stirring rotating speed unchanged, and crystallizing and separating out glycolide. Filtering the cooled solid-liquid mixture, rinsing the filter cake with methanol for 3 times, filtering, and drying the obtained glycolide crystals to obtain glycolide 260g with yield of 81%, wherein the terminal carboxyl group content of the crude glycolide is 3.95 × 10^-4mol.g^-1The carboxyl end group content of the refined glycolide is 8.03 multiplied by 10^-6mol.g^-1。

[ COMPARATIVE EXAMPLE 1 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask, and water produced in the reaction was distilled off by gradually raising the temperature at normal pressure within a temperature range of 110 to 180 ℃. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceeds, glycolide is continuously distilled off. Keeping the temperature of the glycolide at 90 ℃ for 4 hours after the glycolide enters the collection tank, and taking a part of crude glycolide samples for acid-base titration. After the depolymerization reaction was stopped, 300ml of isopropanol was added to the collection tank for recrystallization. Filtering the cooled solid-liquid mixture, rinsing the filter cake with methanol for 3 times, filtering, and drying the obtained glycolide crystals to obtain 208g of glycolide with a yield of 65%, wherein the end carboxyl group content of the crude glycolide is 12.21 × 10^-4mol.g^-1The carboxyl end group content of the refined glycolide was 68.1X 10^-6mol.g^-1。

[ COMPARATIVE EXAMPLE 2 ]

600g of 70% glycolic acid aqueous solution and 2g of stannous octoate were added to a three-neck flask, and water produced in the reaction was distilled off by gradually raising the temperature at normal pressure within a temperature range of 110 to 180 ℃. Then vacuumizing to reduce the system pressure to 5kPa, and increasing the reaction temperature to 200 ℃ to continue the reaction for 2h to obtain the glycolic acid oligomer. The temperature was raised to 260 ℃ and the vacuum degree was increased to 1kpa, and the obtained glycolic acid oligomer was subjected to depolymerization reaction. As the reaction proceeds, glycolide is continuously distilled off. After the glycolide enters the collection tank, the temperature is kept at 75 ℃ for 4 hours, and part of the crude glycolide sample is taken for acid-base titration. After the depolymerization reaction was stopped, 300ml of isopropanol was added to the collection tank for recrystallization. Filtering the cooled solid-liquid mixture, rinsing the filter cake with methanol for 3 times, filtering, and drying the obtained glycolide crystals to obtain 237g of glycolide with yield of 74%, wherein the content of terminal carboxyl groups of the crude glycolide is 8.79X 10^-4mol.g^-1The carboxyl end group content of the refined glycolide was 29.5X 10^-6mol.g^-1。