CN107868074B - Purification method of glycolide - Google Patents
Purification method of glycolide Download PDFInfo
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- CN107868074B CN107868074B CN201610850811.XA CN201610850811A CN107868074B CN 107868074 B CN107868074 B CN 107868074B CN 201610850811 A CN201610850811 A CN 201610850811A CN 107868074 B CN107868074 B CN 107868074B
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Abstract
The invention relates to a purification method of glycolide, which mainly solves the problem that impurities with large molecular weight are difficult to remove in the recrystallization process in the prior art. A refining method by using glycolide comprises the following steps: 1) dissolving a crude glycolide product obtained by depolymerization reaction in a solvent I, and filtering to remove insoluble substances; 2) heating and distilling the collected filtrate to remove the solvent I to obtain solid-phase crude glycolide; 3) mixing and stirring the crude glycolide obtained in the step 2) by using a solvent II, filtering the solid-liquid mixture to collect a filter cake, repeating the operation for at least 3 times, and then drying the filter cake in vacuum to obtain a refined glycolide product; wherein the solvent I is at least one of dichloromethane, tetrahydrofuran, acetone, ethyl acetate and 1, 4-dioxane; the solvent II is at least one of alcohols, ethers, esters and ketones, so that the problem is solved well, and the method can be used in industrial production of glycolide.
Description
Technical Field
The invention relates to a method for purifying glycolide.
Background
Glycolide is a cyclic ester formed by the dehydration of two molecules of glycolic acid, an important compound that can be used to prepare polyglycolic acid and its copolymers. Polyglycolic acid and copolymers thereof have biodegradability, can be finally degraded to obtain carbon dioxide and water, have excellent gas barrier property and mechanical strength, and are widely applied to the field of biomedical materials such as surgical sutures, artificial tissues, drug controlled release systems and the like. Therefore, research into polyglycolic acid and glycolide has attracted much attention in recent years.
To obtain polyglycolic acid having a high molecular weight, glycolide is obtained by a two-step reaction using glycolic acid as a raw material. Polyglycolic acid having a molecular weight of several tens of thousands to several hundreds of thousands can be obtained by ring-opening polymerization of glycolide. One method for the preparation of glycolide from glycolic acid is listed below:
(1) first, glycolic acid is gradually heated to a temperature of not higher than 180 ℃ under normal pressure to carry out polycondensation reaction and water generated in the reaction is removed, and after the water yield reaches a certain degree, water is further removed under reduced pressure (generally lower than 15mmHg) to obtain a polycondensation product with a higher molecular weight.
(2) Under reduced pressure (generally less than 5mmHg), glycolic acid prepolymer and catalyst, such as stannous chloride, are heated together to 230 ℃ to 280 ℃, glycolide vapor generated by the reaction is collected, and yellow solid crude product, which is called crude glycolide in the patent, is obtained after cooling.
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.
The purification methods of glycolide reported in the current patents include a solvent absorption method, a gas-assisted evaporation method, a recrystallization method and the like. Among them, recrystallization is often used, and a method of repeatedly recrystallizing crude glycolide with an organic solvent such as isopropyl alcohol or ethyl acetate is more common. For example, US patent nos. 5223630, CN100999516, and CN101054371 have reported recrystallization purification methods of glycolide.
The recrystallization method can effectively remove small-molecule impurities present in crude glycolide, but glycolic acid oligomers having a relatively large molecular weight are also vaporized together with glycolide in the depolymerization reaction. Such impurities show a greater difference in solubility at different temperatures than glycolide, i.e., a certain solubility at high temperatures and a very low solubility at room temperature. And thus difficult to separate from glycolide by recrystallization. Such impurities with large molecular weight are mostly polymers of glycolic acid, and active hydrogen carried by terminal carboxyl groups of the polymers can generate polymerization inhibition on glycolide. The existence of a very small amount of active hydrogen in the ring-opening polymerization process of glycolide can greatly influence the molecular weight of the obtained polymer, and the polyglycolic acid which needs to meet the application requirements of surgical sutures and the like needs to meet the requirements of the intrinsic viscosity number of more than or equal to 1 and the mass-average molecular weight of more than one hundred thousand. Therefore, how to remove these impurities becomes an important issue in the glycolide purification process.
Pfeiri reported in US4650851 that glycolide was dissolved in dichloromethane, and then mixed with neutral alumina and stirred, and then filtered and the solvent was evaporated, and this method is complicated in operation and difficult to scale up, and the decrease in acid impurities and the mixing and stirring time are greatly related and difficult to control. There are other patents reporting the control of the acid content of the product by adding another substance to react with the glycolic acid oligomer at the time of depolymerization reaction to inhibit its incorporation into the crude glycolide, as Mitsubishi chemical reports in patent US5900491 the method of adding orthoformate at the time of depolymerization to inhibit the acid impurity content in crude lactide, but there are no reports related to the preparation of glycolide. Dupont also reports in U.S. Pat. No. 4,193,93 that the proportion of oligomer impurities is reduced after obtaining a block copolymer by reacting polyglycolic acid with polyether, but there is no report on whether these methods can be applied to industrial scale production.
Disclosure of Invention
The invention aims to solve the problem that impurities with higher molecular weight in a glycolide crude product are difficult to separate, and provides a purification method of glycolide.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for purifying glycolide, comprising:
(1) dissolving a crude glycolide product obtained by depolymerization reaction in a solvent I, and filtering to remove insoluble substances;
(2) heating and distilling the collected filtrate to remove the solvent I to obtain solid-phase crude glycolide;
(3) mixing and stirring the crude glycolide obtained in the step (2) by using a solvent II, filtering the solid-liquid mixture to collect a filter cake, repeating the operation for at least 3 times, and drying the filter cake in vacuum to obtain a refined glycolide product;
wherein the solvent I is at least one of dichloromethane, tetrahydrofuran, acetone, ethyl acetate and 1, 4-dioxane; the solvent II is at least one of alcohols, ethers, esters and ketones.
In the above technical scheme, the solvent I is preferably a mixture I of two or more of dichloromethane, tetrahydrofuran, acetone, ethyl acetate, and 1, 4-dioxane; further preferably, the mixture I contains acetone, and the volume fraction of the acetone is not less than 50%.
In the above technical solution, when the solvent I is preferably a mixture I of two or more of dichloromethane, tetrahydrofuran, acetone, ethyl acetate, and 1, 4-dioxane, the two or more solvents may perform a synergistic purification effect, and the content of terminal carboxyl groups in the refined glycolide may be much less than that of the solvent I, for example, the mixture I in which the volume ratio of acetone to ethyl acetate is 1: 1; even when a mixture I of acetone to ethyl acetate in a volume ratio of 1:1 is combined with a solvent II selected from absolute ethanol, the effect is better.
In the above technical solution, the volume usage of the solvent I is preferably 1.1-2 times of the required usage for dissolving the crude glycolide.
In the above technical solution, the step (2) of heating and distilling the collected filtrate to remove the solvent I is preferably performed under the protection of inert gas.
In the above technical scheme, the solvent II is preferably a mixture II of two or more of alcohols, ethers, esters and ketones; further, the solvent II is preferably a mixture of alcohol and ethyl acetate or alcohol and acetone; more preferably a mixture of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-butyl ether, methyl ethyl ketone and ethyl acetate.
In the above technical solution, the amount of the solvent II is preferably 1-2 times of the mass of the crude glycolide.
In the technical scheme, the mixing and stirring time of the crude glycolide and the solvent II in the step (3) is preferably 0.5-3 h; the stirring process is preferably carried out under inert gas.
In the above technical solution, the time for vacuum drying in the step (3) is preferably not less than 4 h.
In the above technical solution, the "inert gas" may be one of various inert gases commonly used in the art, such as nitrogen, helium, argon, etc.
Since the high-molecular-weight impurities in glycolide are usually glycolic acid oligomers having a degree of polymerization of 4 or more, the effect of removing the high-molecular-weight impurities in glycolide can be characterized by a method for measuring the content of terminal carboxyl groups in 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 end carboxyl content in the refined glycolide is 8.96 multiplied by 10-6mol.g-1. The content of impurities with molecular weight far lower than that of impurities with large molecular weight in the prior art, and a better technical effect is obtained.
The invention is further illustrated by the following examples.
Detailed Description
[ example 1 ]
400g of glycolic acid was added to a three-necked flask, and the reaction mixture was heated to 90 ℃ under normal pressure to completely melt the reaction mixture, after which the system was heated from 90 ℃ to 200 ℃ over 2 hours and reacted at that temperature for 2 hours, during which time water produced in the reaction was distilled off. Then vacuumizing to reduce the system pressure to 5kPa, and continuing the reaction for 2h until the reactants are solidified into milk white to obtain the glycolic acid oligomer. 2.0g of stannous octoate was added to the oligomer, the temperature was raised to 260 ℃ and the vacuum was increased to 100 pa. As the reaction proceeds, light yellow liquid is distilled off continuously, and a yellow solid, namely the crude glycolide product, is obtained after cooling. After 3h the reaction was stopped and the crude product was collected in calculated yield of 92%. The carboxyl end group content in the crude glycolide was determined to be 7.90X 10 by acid-base titration-4mol.g-1。
The product, crude glycolide (280g), was dissolved in 600g of acetone, stirred at room temperature until a homogeneous transparent solution formed, and the insoluble matter was removed by filtration over a quartz sand funnel. Collecting filtrate, and removing the most big part with rotary evaporatorAnd (3) partially dissolving the solvent, adding the solid after removing the solvent into a round-bottom flask, adding 250g of absolute ethyl alcohol, mechanically stirring for 1h, performing suction filtration by using a quartz sand funnel, performing suction filtration to half-dry, transferring the filter cake into the flask again, adding 250g of absolute ethyl alcohol, and stirring for 1 h. The washing-filtration procedure was repeated three times and the collected solid was dried under vacuum at 60 ℃ for 5h to give 216g of white crystals in a total yield of 70.8%. The content of terminal carboxyl in the refined glycolide is 1.48 multiplied by 10 measured by acid-base titration-5mol.g-1。
[ example 2 ]
The crude glycolide was prepared as in example 1.
The product, crude glycolide (277g), was dissolved in 600g of acetone, stirred at room temperature until a homogeneous transparent solution formed, and the insoluble matter was removed by filtration over a quartz sand funnel. Collecting the filtrate, removing most of the solvent by using a rotary evaporator, adding the solid from which the solvent is removed into a round-bottom flask, adding 250g of anhydrous methanol, mechanically stirring for 1h, performing suction filtration by using a quartz sand funnel, transferring the filter cake to the flask again after the filter cake is half-dried, adding 250g of anhydrous methanol, and stirring for 1 h. After repeating the washing-filtering step three times, the collected solid was vacuum dried at 60 ℃ for 5 hours to obtain 221g of white crystals in a total yield of 72.3%. The content of terminal carboxyl in the refined glycolide is 1.15 multiplied by 10 measured by acid-base titration-5mol.g-1。
[ example 3 ]
The crude glycolide was prepared as in example 1.
The crude glycolide (278g) was dissolved in a mixed solvent of 400g of acetone and 400g of ethyl acetate, stirred at room temperature until a uniform transparent solution was formed, and then filtered with a quartz sand funnel to remove powdery insoluble substances. Collecting the filtrate, removing most of the solvent by using a rotary evaporator, adding the solid from which the solvent is removed into a round-bottom flask, adding 250g of absolute ethyl alcohol, mechanically stirring for 1h, performing suction filtration by using a quartz sand funnel, transferring the filter cake to the flask again after the filter cake is half-dried, adding 250g of absolute ethyl alcohol, and stirring for 1 h. Repeating the washing-filtering steps for three times, and vacuum drying the collected solid at 60 deg.C for 5h to obtain212g of white crystals were obtained, and the total yield was 69.6%. Acid-base titration is utilized to measure that the content of terminal carboxyl in the refined glycolide is 8.96 multiplied by 10-6mol.g-1。
[ example 4 ]
The crude glycolide was prepared as in example 1.
The crude glycolide (280g) was dissolved in a mixed solvent of 400g of acetone and 400g of ethyl acetate, stirred at room temperature until a uniform transparent solution was formed, and then filtered through a quartz sand funnel to remove powdery insoluble substances. Collecting the filtrate, removing most of the solvent by using a rotary evaporator, adding the solid from which the solvent is removed into a round-bottom flask, adding 250g of anhydrous methanol, mechanically stirring for 1h, performing suction filtration by using a quartz sand funnel, transferring the filter cake to the flask again after the filter cake is half-dried, adding 250g of anhydrous methanol, and stirring for 1 h. After repeating the washing-filtering step three times, the collected solid was vacuum dried at 60 ℃ for 5 hours to obtain 214g of white crystals in a total yield of 70.2%. The content of terminal carboxyl in the refined glycolide is 1.01 multiplied by 10 measured by acid-base titration-5mol.g-1。
[ COMPARATIVE EXAMPLE 1 ]
The crude glycolide was prepared as in example 1.
278g of the crude glycolide obtained was recrystallized from 400mL of ethyl acetate, heated to 70 ℃ to give a clear solution, filtered hot, and the filtrate obtained was allowed to stand and cooled to room temperature. And filtering and drying the solid-liquid mixture with the precipitated crystals, and repeating the recrystallization process for three times. The obtained solid was dried under vacuum at 60 ℃ for 5 hours to obtain 187g of white crystals, the total yield being 61.2%. The content of terminal carboxyl in the refined glycolide is 1.36 multiplied by 10 measured by acid-base titration-4mol.g-1。
[ COMPARATIVE EXAMPLE 2 ]
The crude glycolide was prepared as in example 1.
278g of the obtained crude glycolide is mixed with 400g of absolute ethyl alcohol, then the mixture is mechanically stirred for 1 hour, after the stirring is finished, the mixture is filtered to be semi-dry, and the filter cake is mixed with 250g of absolute ethyl alcohol again. After repeating the washing-filtration step three times, the obtained solid was dried under vacuum at 60 ℃ for 5 hours to obtain white crystals 227g, total yield 74.2%. The carboxyl end group content in the refined glycolide is measured to be 9.77 multiplied by 10 by acid-base titration-5mol.g-1。
Claims (6)
1. A refining method of glycolide comprises the following steps:
(1) dissolving a crude glycolide product obtained by depolymerization reaction in a solvent I, and filtering to remove insoluble substances;
(2) heating and distilling the collected filtrate to remove the solvent I to obtain solid-phase crude glycolide;
(3) mixing and stirring the crude glycolide obtained in the step (2) by using a solvent II, filtering the solid-liquid mixture to collect a filter cake, repeating the operation for at least 3 times, and drying the filter cake in vacuum to obtain a refined glycolide product;
wherein the solvent I is a mixture I of more than two of acetone, ethyl acetate and 1, 4-dioxane, the mixture I contains acetone, and the volume fraction of the acetone is not less than 50%; the solvent II is ethanol.
2. The method for purifying glycolide according to claim 1, wherein the solvent I is used in an amount of 1.1 to 2 times by volume as much as the amount of the dissolved crude glycolide.
3. The method for purifying glycolide according to claim 1, wherein the step (2) of heating and distilling the collected filtrate to remove the solvent I is carried out under an inert gas atmosphere.
4. The method according to claim 1, wherein the amount of the solvent II is 1 to 2 times the mass of the crude glycolide.
5. The method for refining glycolide according to claim 1, wherein the mixing and stirring time of the crude glycolide and the solvent II in the step (3) is 0.5 to 3 hours; the stirring process is protected by inert gas.
6. The method for refining glycolide according to claim 1, wherein the time for vacuum drying in the step (3) is not less than 4 hours.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111087381B (en) * | 2018-10-23 | 2021-03-26 | 中国石油化工股份有限公司 | Refining treatment method of glycolide |
| CN114478468B (en) * | 2020-10-26 | 2023-08-08 | 中国石油化工股份有限公司 | Method for refining glycolide and glycolide obtained by same |
| CN114790188A (en) * | 2021-01-26 | 2022-07-26 | 惠生工程（中国）有限公司 | Refining and purifying method of crude glycolide |
| CN115246812A (en) * | 2021-04-28 | 2022-10-28 | 上海浦景化工技术股份有限公司 | Method for refining glycolide |
| CN115246811A (en) * | 2021-04-28 | 2022-10-28 | 上海浦景化工技术股份有限公司 | Continuous production method of purified glycolide |
| CN115504957A (en) * | 2021-06-23 | 2022-12-23 | 中国石油化工股份有限公司 | Glycolide refining method and glycolide obtained by same |
| CN114149403B (en) * | 2021-11-17 | 2024-01-26 | 中国五环工程有限公司 | Mixed crystal form glycolide and preparation method and application thereof |
| CN114014835A (en) * | 2021-12-09 | 2022-02-08 | 内蒙古久泰新材料有限公司 | Glycolide purification process |
| CN115124501B (en) * | 2022-08-30 | 2023-02-03 | 深圳市迈启生物材料有限公司 | Method and device for preparing glycolide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223630A (en) * | 1989-10-10 | 1993-06-29 | E. I. Du Pont De Nemours And Company | Glycolide purification process |
| CN100999516A (en) * | 2006-01-12 | 2007-07-18 | 中南大学 | Purifying process of glycolide |
| CN101054371A (en) * | 2007-05-24 | 2007-10-17 | 复旦大学 | Preparation method for glycolide |
-
2016
- 2016-09-26 CN CN201610850811.XA patent/CN107868074B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223630A (en) * | 1989-10-10 | 1993-06-29 | E. I. Du Pont De Nemours And Company | Glycolide purification process |
| CN100999516A (en) * | 2006-01-12 | 2007-07-18 | 中南大学 | Purifying process of glycolide |
| CN101054371A (en) * | 2007-05-24 | 2007-10-17 | 复旦大学 | Preparation method for glycolide |
Non-Patent Citations (1)
| Title |
|---|
| 乙交酯精制的研究进展;朱煜等;《合成纤维工业》;20151231;第38卷(第5期);43-46 * |
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