CN115124501A - Method and device for preparing glycolide - Google Patents
Method and device for preparing glycolide Download PDFInfo
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- CN115124501A CN115124501A CN202211045342.6A CN202211045342A CN115124501A CN 115124501 A CN115124501 A CN 115124501A CN 202211045342 A CN202211045342 A CN 202211045342A CN 115124501 A CN115124501 A CN 115124501A
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Abstract
The present disclosure provides a method for preparing glycolide, comprising: preparing a crude glycolide product; preparing a cleaning solvent, and refrigerating the cleaning solvent to ensure that the temperature of the refrigerated cleaning solvent is 0-5 ℃, wherein the cleaning solvent is isopropanol or a mixed solution of isopropanol and any one of ethyl acetate, butyl acetate, methanol, absolute ethyl alcohol and acetone, and the mass fraction of the isopropanol in the cleaning solvent is 50-100%; washing the crude glycolide product by using the refrigerated washing solvent to obtain a purified glycolide product, wherein the single washing time is 30-150 minutes; recrystallizing the purified glycolide product to obtain glycolide crystals; and drying the glycolide crystals to obtain glycolide. According to the present disclosure, a method for preparing glycolide with a short production cycle and high purity and yield can be provided.
Description
Technical Field
The disclosure relates to the field of preparation of biodegradable high polymer materials, in particular to a preparation method and a preparation device of glycolide.
Background
Polyglycolic acid, poly (glycolide-co-lactide) copolymer and the like obtained by ring-opening polymerization of glycolide have good biocompatibility, good mechanical properties and biodegradability, can be absorbed by human bodies, and are converted into water and carbon dioxide through metabolism to be discharged out of the bodies, so that the polyglycolic acid, poly (glycolide-co-lactide) copolymer and the like have wide application in the medical fields of surgical sutures, surgical staples, bone fixing materials, medical anti-adhesion membranes, drug release, tissue engineering scaffolds and the like. Wherein, the fields of surgical operation suture lines, surgical suturing nails and bone fixing materials need polymers with high molecular weight to ensure that the materials have excellent thermodynamic properties, and the high-strength high-performance materials are applied to medical treatment.
There are two main methods for synthesizing polyglycolic acid and its copolymers, the first is direct polycondensation of glycolic acid, but the polyglycolic acid obtained by this method has a low molecular weight and can be generally used only in the field of drug release. The second method is a more common preparation method in which polyglycolic acid having a low molecular weight is obtained by polycondensation of glycolic acid, followed by cracking and purification to obtain glycolide having a high purity, and then the glycolide is subjected to ring-opening homopolymerization or copolymerization to obtain a polymer having a high molecular weight, thereby satisfying the standards for absorbable bone screws, surgical sutures and other medical materials. Among these, the key factors for obtaining a polymer having a high molecular weight are the purity of glycolide, and the crude glycolide product obtained by polycondensation and cleavage of glycolic acid generally contains impurities such as water, glycolic acid, and glycolic acid oligomers, and whether or not these impurities are sufficiently removed, that is, the purity of glycolide directly affects the molecular weight of the ring-opening polymerization.
In the prior art, the crude glycolide product is usually purified by solvent recrystallization. For example, patent document No. CN110511205A discloses a method for producing high-purity glycolide, which comprises dissolving a crude glycolide product in an organic solvent, cooling and crystallizing the solution, and repeating the dissolving and crystallization at least three times to obtain glycolide with a purity of 99.85%. In the method of purifying a crude glycolide product by solvent recrystallization, the purification effect is generally not good if only a single recrystallization is performed, but if the crude glycolide product is purified by a multiple recrystallization method as disclosed in the above-mentioned CN110511205A patent document, the purification time period is relatively long (the time for performing a single recrystallization is generally 1 day), and the purification yield decreases as the number of times of recrystallization increases.
Disclosure of Invention
The present disclosure has been made in view of the above-described state of the art, and an object thereof is to provide a method for producing glycolide with a short production cycle and high purity and yield, and a production apparatus using the production method.
To this end, a first aspect of the present disclosure provides a method for preparing glycolide, comprising the steps of: preparing a crude glycolide product, and crushing the crude glycolide product; preparing a cleaning solvent, and refrigerating the cleaning solvent to enable the temperature of the refrigerated cleaning solvent to be 0-5 ℃, wherein the cleaning solvent is isopropanol or a mixed solution of isopropanol and any one of ethyl acetate, butyl acetate, methanol, absolute ethyl alcohol and acetone, and the mass fraction of the isopropanol in the cleaning solvent is 50-100%; washing the crude glycolide product by using the washing solvent after refrigeration, keeping stirring during washing, and removing the solvent after stirring for a preset time to obtain a purified glycolide product, wherein the single washing time is 30-150 min, and the mass ratio of the crude glycolide product to the washing solvent is 1: 1-1: 1.5; recrystallizing the purified glycolide product to obtain glycolide crystals; and drying the glycolide crystal to obtain the glycolide, wherein the purity of the glycolide is not less than 95%.
In the first aspect of the disclosure, by pulverizing the crude glycolide product, the crude glycolide product can be pulverized into powder, and can be in full contact with a cleaning solvent in the subsequent cleaning process, so that the impurities in the crude glycolide product can be conveniently removed; the method comprises the steps of taking isopropanol or a mixed solution of isopropanol and any one of ethyl acetate, butyl acetate, methanol, absolute ethyl alcohol and acetone as a cleaning solvent, configuring the mass fraction of the isopropanol to be 50-100%, and then cleaning a glycolide crude product by using the cleaning solvent with specific components, so that impurities such as glycolic acid and glycolic acid oligomer in the glycolide crude product can be dissolved in the cleaning solvent, and the impurities can be removed by removing the solvent containing the impurities, thereby effectively improving the purity of the prepared glycolide; the temperature of the cleaning solvent can be reduced by refrigerating the cleaning solvent, so that the temperature of the refrigerated cleaning solvent is 0-5 ℃, and when the refrigerated cleaning solvent is used for cleaning the crude glycolide product, the solubility of the glycolide in the crude glycolide product in the cleaning solvent can be reduced due to the lower temperature of the cleaning solvent, the loss of the glycolide in the cleaning process is reduced, and the yield of the prepared glycolide is improved; the mass ratio of the crude glycolide product to the cleaning solvent is set to be 1:1 to 1: 1.5, and stirring treatment is carried out in the cleaning process, so that the crude glycolide product can be favorably and fully contacted with the cleaning solvent, impurities in the crude glycolide product can be fully dissolved in the cleaning solvent, and the solvent containing the impurities is removed to remove the impurities in the crude glycolide product, so that the purity of the prepared glycolide product is improved; the time for cleaning the crude glycolide product for one time is controlled to be 30-150 min, so that the time for cleaning for multiple times is short, and the production period can be shortened; further, after the washing is performed a plurality of times, the purity of glycolide is further improved by a recrystallization method, and glycolide having a purity of not less than 95% can be produced. Compared with the purification method by multiple recrystallization, the purification method by multiple washing and single recrystallization can shorten the production period and improve the yield. Thus, a method for producing glycolide with a short production cycle and high purity and yield can be provided.
In the production method according to the first aspect of the present disclosure, optionally, the rotation speed of the stirring process is 100r/min to 300r/min, and the predetermined time is 15min to 90 min. Under the condition, the crude glycolide product can be in full contact with the cleaning solvent, so that impurities in the crude glycolide product are fully dissolved in the cleaning solvent, and the purity of the prepared glycolide is improved.
In the preparation method related to the first aspect of the present disclosure, optionally, the solvent is removed by vacuum filtration, and the time of the vacuum filtration is 15min to 60 min. In this case, the solvent containing impurities can be effectively removed by suction filtration under reduced pressure, and thus, the purity of the produced glycolide can be advantageously improved.
In the production method according to the first aspect of the present disclosure, optionally, the degree of vacuum of the reduced-pressure suction filtration is 90kPa to 100 kPa. In this case, it is possible to facilitate sufficient removal of the solvent containing impurities, thereby improving the purity of the glycolide to be produced.
In the preparation method according to the first aspect of the present disclosure, optionally, the number of times of the multiple washing is 2 to 5. In this case, by configuring the number of washing times to 2 to 5 times, impurities in the crude glycolide product can be effectively removed to increase the purity of glycolide while increasing the yield of glycolide as much as possible.
In the production method relating to the first aspect of the present disclosure, optionally, the gas-phase purity of the glycolide is not less than 99.95%. In this case, the glycolide having such a purity produced by the production method of the present disclosure can be used as an intermediate raw material that satisfies the processing requirements of medical products (for example, as an intermediate raw material for producing high-molecular-weight polyglycolic acid).
In the preparation method related to the first aspect of the present disclosure, optionally, the glycolide crystals are vacuum-dried at 40 ℃ to 60 ℃, and the vacuum-drying time is 24h to 36 h. Therefore, the water in the glycolide crystals can be conveniently removed, and the high-purity glycolide can be obtained.
In the preparation method according to the first aspect of the present disclosure, optionally, the preparing the crude glycolide product comprises the following steps: preparing a glycolic acid raw material with the purity of not less than 99%; polycondensing the glycolic acid raw material to obtain a glycolic acid oligomer; and cracking the glycolic acid oligomer to obtain the crude glycolide product. In this case, by selecting glycolic acid having a purity of not less than 99% as a raw material, a crude glycolide product having a high glycolide content can be obtained, thereby facilitating the preparation of high-purity glycolide.
In the preparation method related to one aspect of the present disclosure, optionally, recrystallizing the purified glycolide product comprises the following steps: adding the purified glycolide product into a recrystallization solvent to obtain a recrystallization mixed solution, wherein the recrystallization solvent is ethyl acetate subjected to water removal treatment; heating and stirring the recrystallization mixed solution to dissolve the purified glycolide product in the recrystallization solvent; and cooling the recrystallization mixed solution to separate out the glycolide crystals from the recrystallization mixed solution, thereby obtaining the glycolide crystals. In this case, the purity of glycolide can be further improved by the recrystallization method, and high-purity glycolide can be obtained.
A second aspect of the present disclosure provides a device for producing glycolide, which employs any one of the production methods according to the first aspect of the present disclosure. In the second aspect of the present disclosure, by producing glycolide by the apparatus and the method for producing glycolide, high-purity glycolide can be obtained.
According to the present disclosure, a method for producing glycolide with a short production cycle and high purity and yield, and a glycolide production apparatus using the production method can be provided.
Drawings
Fig. 1 is a flow diagram illustrating a method of making glycolide in accordance with an example of the present disclosure.
Fig. 2 is a flow diagram illustrating the preparation of a crude glycolide product according to an example of the disclosure.
Fig. 3 is a flow diagram illustrating cleaning of a crude glycolide product according to an example of the disclosure.
Fig. 4 is a schematic diagram illustrating a cleaning vessel according to an example of the present disclosure.
Fig. 5 is a flow diagram illustrating recrystallization of a glycolide purified product according to examples of the disclosure.
Fig. 6 is a gas chromatogram showing a glycolide standard solution.
Fig. 7 is a standard curve showing a single point external standard method of a glycolide standard solution.
Fig. 8 is a gas chromatogram showing glycolide of example 1 of the present disclosure.
Fig. 9 is a gas chromatogram showing glycolide of example 2 of the present disclosure.
Fig. 10 is a gas chromatogram showing glycolide of example 3 of the present disclosure.
Fig. 11 is a gas chromatogram showing glycolide of example 4 of the present disclosure.
Fig. 12 is a gas chromatogram showing glycolide of example 5 of the present disclosure.
Fig. 13 is a gas chromatogram showing glycolide of example 6 of the present disclosure.
Fig. 14 is a gas chromatogram showing glycolide of example 7 of the present disclosure.
Fig. 15 is a gas chromatogram showing glycolide of example 8 of the present disclosure.
Fig. 16 is a gas chromatogram showing glycolide of example 9 of the present disclosure.
Fig. 17 is a gas chromatogram showing glycolide of example 10 of the present disclosure.
Fig. 18 is a gas chromatogram showing glycolide of example 11 of the present disclosure.
Fig. 19 is a gas chromatogram showing glycolide of example 12 of the present disclosure.
Fig. 20 is a gas chromatogram showing glycolide of comparative example 1 of the disclosure.
Fig. 21 is a gas chromatogram showing glycolide of comparative example 2 of the present disclosure.
Fig. 22 is a gas chromatogram showing glycolide of comparative example 3 of the present disclosure.
Description of reference numerals:
1 … cleaning container, 10 … main body part, 20 … cover body, 30 … stirrer, 40 … chamber, 41 … solid feed inlet, 42 … liquid feed inlet, 43 … liquid discharge outlet, 50 … crude glycolide product and 60 … cleaning solvent.
Detailed Description
All references cited in this disclosure are incorporated by reference in their entirety as if fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. In the following description, the same components are denoted by the same reference numerals, and redundant description thereof is omitted. The drawings are schematic and the ratio of the dimensions of the components and the shapes of the components may be different from the actual ones.
The first aspect of the present disclosure relates to a method for producing glycolide, which has a short production cycle and a high yield, and by which high-purity glycolide can be produced. The preparation method of glycolide of the present disclosure may be simply referred to as "preparation method".
The high purity glycolide prepared by the preparation method disclosed herein can be used as an intermediate raw material for meeting the processing requirements of medical products. For example, it can be used as a raw material for producing polyglycolic acid and copolymers thereof, and can be further applied to the fields of biomedical materials such as surgical sutures, artificial tissues, drug controlled release systems, and the like. Specifically, the high-purity glycolide obtained by the production method of the present disclosure can be subjected to ring-opening homopolymerization or copolymerization to obtain polyglycolic acid having a molecular weight of several tens of thousands to several hundreds of thousands, which can satisfy the standards for absorbable medical materials such as bone nails and surgical sutures. Of course, the glycolide prepared by the preparation method disclosed by the invention can also be applied to other fields requiring high-purity glycolide as a raw material.
In the present disclosure, glycolide produced by the production method of the present disclosure may also be referred to as medical glycolide, and the production method of glycolide of the present disclosure may also be referred to as "a production method of medical glycolide".
Hereinafter, the method for producing glycolide according to the present disclosure will be described with reference to the drawings.
Fig. 1 is a flow diagram illustrating a method of making glycolide in accordance with an example of the present disclosure.
In this embodiment, the method for preparing glycolide may include: preparing a crude glycolide product (step S100); preparing a cleaning solvent, and refrigerating the cleaning solvent (step S200); washing the crude glycolide product for multiple times by using the refrigerated washing solvent to obtain a purified glycolide product (step S300); recrystallizing the purified glycolide product to obtain glycolide crystals (step S400); the glycolide crystals are dried to obtain glycolide (step S500) (see fig. 1). The sequence of step S100 and step S200 is not sequential, for example, step S100 may be performed first and then step S200 may be performed, step S200 may be performed first and then step S100 may be performed, or step S100 and step S200 may be performed simultaneously.
In this case, the crude glycolide product is washed for a plurality of times by the washing solvent, so that impurities in the crude glycolide product can be effectively removed, and the purity of the prepared glycolide can be further improved by recrystallizing the washed purified glycolide product; in addition, in step S200, the temperature of the cleaning solvent can be reduced by refrigerating the cleaning solvent, and when the crude glycolide product is cleaned by the cleaning solvent, the solubility of the crude glycolide product in the cleaning solvent can be reduced due to the low temperature of the cleaning solvent, the loss of the crude glycolide product in the cleaning process can be reduced, and the yield of glycolide can be increased.
In some examples, the gas phase purity of the produced glycolide is not less than 95%. In some examples, preferably, the gas phase purity of the glycolide produced by the production method related to the present disclosure may be not less than 99.95%. In this case, the glycolide having such a purity produced by the production method of the present disclosure can be used as an intermediate raw material that satisfies the processing requirements of medical products (for example, as an intermediate raw material for producing high-molecular-weight polyglycolic acid).
In the present disclosure, the gas purity of a sample refers to the purity of the sample measured by a gas chromatograph, and the calculation formula is:
W(%)=vc/m × 100%，
wherein W (%) is the purity of glycolide in the product, v is the volume of the test solution (in ml), c is the measured concentration of glycolide in the sample of the test solution (in mg/ml), and m is the product weighing (in mg). That is, the gas phase purity of the present disclosure may also be referred to as purity, meaning purity in the general sense.
In some examples, the melting point of glycolide made by the manufacturing process to which the present disclosure relates is greater than 81 ℃. In some examples, preferably, the melting point of the glycolide produced by the production method to which the present disclosure relates may be greater than 82 ℃. In this case, the glycolide having such a melting point produced by the production method of the present disclosure can be used as an intermediate raw material that satisfies the processing requirements of medical products (for example, as an intermediate raw material for producing high-molecular-weight polyglycolic acid).
Fig. 2 is a flow diagram illustrating the preparation of a crude glycolide product according to examples of the disclosure.
In some examples, in step S100, preparing the crude glycolide product may include the steps of: preparing a glycolic acid raw material having a purity of not less than 99% (step S11); polycondensing a glycolic acid raw material to obtain a glycolic acid oligomer (step S12); and the glycolic acid oligomer is cracked to obtain a crude glycolide product (step S13) (see fig. 2). In this case, by selecting glycolic acid having a purity of more than 99% as a raw material, a crude glycolide product having a high glycolide content can be obtained, thereby facilitating the preparation of high-purity glycolide.
In some examples, in step S100, the crude glycolide product obtained may contain glycolide and impurities. Among the impurities may be water, glycolic acid and glycolic acid oligomers.
In some examples, in step S100, the crude glycolide product may be subjected to a pulverization process. In this case, the crude glycolide product is pulverized into powder, which can facilitate sufficient contact with a cleaning solvent in a subsequent cleaning process, thereby facilitating removal of impurities in the crude glycolide product, and thus, improving the purity of the prepared glycolide.
In some examples, in step S100, the crude glycolide product may be pulverized by a pulverizer. Thereby, the crude glycolide product can be easily pulverized into particles of a predetermined size. In some examples, the crude glycolide product after being pulverized may be in the form of a powder. Therefore, the crude glycolide product can be fully contacted with the cleaning solvent when being cleaned subsequently, so that impurities can be conveniently removed.
In some examples, as described above, in step S200, a cleaning solvent may be formulated and refrigerated.
In some examples, the temperature of the washing solvent after refrigeration may be 0 to 5 ℃ in step S200. That is, in step S200, the cleaning solvent may be refrigerated such that the temperature of the refrigerated cleaning solvent is 0 to 5 ℃. In this case, the solubility of glycolide in the washing solvent can be reduced, so that the loss of glycolide during washing can be reduced, whereby the yield of glycolide can be further improved. In the present invention, the crude glycolide product is washed with the washing solvent by dissolving impurities in the washing solvent, removing the impurities from the liquid solvent containing the impurities, and keeping the solid glycolide purified product, thereby improving the yield of the glycolide produced by refrigerating the washing solvent.
In addition, it is understood that even if the solvent is in the same environment, the respective portions in the solvent may have different temperatures, for example, for a portion of the solvent stored in a refrigerator, the upper and lower layers of the solvent may have a certain temperature difference, and therefore, in the present invention, the temperature of the cleaning solvent of 0 ℃ to 5 ℃ means that the temperature of the cleaning solvent is in the range of 0 ℃ to 5 ℃, and it is not necessarily required that the cleaning solvent as a whole has a certain fixed temperature.
In some examples, in step S200, the cleaning solvent may be placed at-15 ℃ after being formulated, so that the cleaning solvent has a predetermined temperature (0 ℃ to 5 ℃). In this case, it is possible to facilitate a time for lowering the cleaning solvent to the above-mentioned predetermined temperature, thereby improving the production efficiency. In some examples, refrigerating the cleaning solvent may also be referred to as freezing the cleaning solvent, which refers to adjusting the temperature of the cleaning solvent to within a predetermined temperature range.
In some examples, in step S200, the cleaning solvent may be isopropanol, or a mixed solution of isopropanol and any one of ethyl acetate, butyl acetate, methanol, absolute ethanol, and acetone. In this case, the crude glycolide product can be washed by preparing a washing solvent having a specific composition, whereby impurities such as glycolic acid and glycolic acid oligomers in the crude glycolide product can be effectively removed.
In some examples, in step S200, the cleaning solvent may be a mixed solution of isopropyl alcohol and ethyl acetate, a mixed solution of isopropyl alcohol and butyl acetate, a mixed solution of isopropyl alcohol and methanol, a mixed solution of isopropyl alcohol and absolute ethyl alcohol, or a mixed solution of isopropyl alcohol and acetone. In this case, by preparing a washing solvent having a specific composition to wash the crude glycolide product, impurities such as glycolic acid and glycolic acid oligomers in the crude glycolide product can be effectively removed, and the yield of glycolide can be effectively ensured.
In some examples, in step S200, the mass fraction of isopropanol in the cleaning solvent is 50% to 100%. For example, the mass fraction of isopropanol in the cleaning solvent may be 50%, 60%, 70%, 80%, 90% or 100%. In this case, the solubility of the cleaning solvent for impurities (for example, glycolic acid and glycolic acid oligomer) in the crude glycolide product can be improved, and the impurities can be effectively removed during cleaning, thereby improving the purity of the glycolide produced.
In some examples, in step S200, preferably, the cleaning solvent may be a mixed solution of isopropyl alcohol and ethyl acetate. In this case, the solubility of the cleaning solvent for impurities in the crude glycolide product can be improved, so that the impurities can be effectively removed during cleaning, and the purity of the produced glycolide can be improved.
In some examples, in step S200, the mass ratio of isopropanol to ethyl acetate in the cleaning solvent may be 9:1 to 5: 5. For example, the mass ratio of isopropanol to ethyl acetate may be 9:1, 8:2, 7:3, 6:4, or 5: 5. This further improves the solubility of the cleaning solvent for impurities in the glycolide crude product.
In some examples, as described above, in step S300, the crude glycolide product may be washed a plurality of times with the washing solvent after refrigeration. This can improve the purity of the glycolide to be produced.
In some examples, the single wash time for the crude glycolide product can be from 30min to 150 min. For example, the time for a single washing of the crude glycolide product can be 30min, 45min, 60min, 75min, 90min, 105min, 120min, 135min or 150 min. In this case, the time for performing a single washing of the crude glycolide product is controlled to 30min to 150min, and even if the washing is performed for a plurality of times, the total time consumption is short, and the production cycle can be significantly shortened compared with the purification method by a plurality of recrystallization.
In some examples, the mass ratio of the crude glycolide product to the cleaning solvent in step S300 can be from 1:1 to 1: 1.5. For example, the mass ratio of crude glycolide to washing solvent can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1: 1.5. Therefore, the method is beneficial to fully contacting the crude glycolide product with the cleaning solvent, so that impurities in the crude glycolide product can be conveniently removed.
In some examples, in step S300, the number of times of the plurality of washes may be 2 to 5. For example, the number of washes may be 2, 3, 4, or 5. If the cleaning frequency is too low, the impurities can be insufficiently removed, and the purity of the glycolide is influenced; if the number of washing times is too large, the yield of glycolide may be affected, and in this case, by configuring the number of washing times to be 2 to 5, impurities in the crude glycolide product can be effectively removed to increase the purity of glycolide while increasing the yield of glycolide as much as possible.
In some examples, the crude glycolide product can be washed at a temperature of from 0 ℃ to 5 ℃. In this case, the solubility of glycolide in the washing solvent can be reduced, and the loss of glycolide during washing can be reduced, whereby the yield of glycolide produced can be improved.
In some examples, in step S300, during the washing of the crude glycolide product, the stirring process may be maintained, and the solvent is removed after stirring for a predetermined time to obtain a purified glycolide product. In this case, the crude glycolide product can be in full contact with the cleaning solvent by stirring, so that impurities in the crude glycolide product can be dissolved conveniently, the liquid solvent is removed to remove the impurities, and the remaining solid substance is a purified glycolide product, so that the purity of the prepared glycolide can be improved.
In some examples, in step S300, after a single cleaning of the crude glycolide product, a new cleaning solvent may be added to mix with the cleaned crude glycolide product, the solvent may be removed after stirring for a predetermined time, and the cleaning may be repeated for a plurality of times to perform a plurality of cleaning of the crude glycolide product. This can further improve the purity of the glycolide to be produced.
Fig. 3 is a flow diagram illustrating cleaning of a crude glycolide product according to an example of the disclosure.
In some examples, in step S300, the step of performing a single washing on the crude glycolide product may include: mixing the crude glycolide product with a cleaning solvent to obtain a mixture (step S31); stirring the mixture for a predetermined time (step S32); the solvent was removed to obtain a purified glycolide product (step S33) (see fig. 3). Wherein the "removal of the solvent" in step S33 means: the solid material (i.e., the purified glycolide product) is retained and the liquid solvent with the impurities dissolved therein is removed.
In some examples, in step S32, the rotation speed when the stirring process is performed may be 100r/min to 300 r/min. For example, the stirring treatment may be performed at a rotational speed of 100r/min, 150r/min, 200r/min, 250r/min, or 300 r/min. In some examples, in step S32, the predetermined time (stirring time) for the stirring process may be 15min to 90 min. For example, the predetermined time may be 15min, 30min, 45min, 60min, 75min, or 90 min. In this case, it is possible to facilitate sufficient mixing of the crude glycolide product with the cleaning solvent, thereby facilitating sufficient dissolution of impurities in the crude glycolide product into the cleaning solvent, and also, in view of improving the yield of glycolide, it is possible to reduce the dissolution rate of glycolide in the cleaning solvent as much as possible by controlling the stirring treatment time within a range of 15min to 90 min.
In some examples, in step S33, the solvent may be removed by suction filtration under reduced pressure. In some examples, in step S33, the time for the reduced pressure suction filtration may be 15min to 60 min. For example, the time for the vacuum filtration is 15min, 20min, 30min, 45min or 60 min. In this case, the solvent containing impurities can be effectively removed by suction filtration under reduced pressure, and thus, the purity of the produced glycolide can be advantageously improved.
In some examples, in step S33, the degree of vacuum at which the reduced pressure suction filtration is performed may be 90kPa to 100 kPa. In this case, it is possible to facilitate sufficient removal of the solvent containing impurities, thereby improving the purity of the glycolide to be produced.
In some examples, in step S300, the washing of the crude glycolide product may be performed in the washing vessel 1. Specifically, the crude glycolide product and the cleaning solvent may be added to the cleaning vessel 1 and mixed to obtain a mixture, the mixture is stirred in the cleaning vessel 1 for a predetermined time, the liquid solvent containing impurities is removed, and then a new cleaning solvent is added to the cleaning vessel 1 for repeated cleaning, and the purified glycolide product is obtained after repeated cleaning. In this case, the crude glycolide product can be easily cleaned.
Fig. 4 is a schematic view showing a cleaning vessel 1 according to an example of the present disclosure. In fig. 4, 50 schematically represents a crude glycolide product, and 60 schematically represents a cleaning solvent.
In some examples, the cleaning vessel 1 may be a cleaning kettle. In some examples, the cleaning container 1 may include a main body portion 10 having a receiving space and an opening, a cover body 20 covering the opening, and an agitator 30 disposed in the receiving space, and the cover body 20 and the main body portion 10 may cooperate to form a sealed cavity 40 (see fig. 4). The chamber 40 may have a solids feed port 41, a liquid feed port 42, and a liquid discharge port 43 (see fig. 4). The solid inlet 41 and the liquid inlet 42 may be disposed on the cover 20, and the liquid outlet 43 may be disposed at the bottom of the main body 10.
In some examples, a screen may be provided between liquid outlet 43 and chamber 40. In some examples, a double screen may be provided between liquid outlet 43 and chamber 40. This can reduce discharge of solid substances from the liquid discharge port 43.
In some examples, as shown in fig. 4, when washing the crude glycolide product 50, the crude glycolide product 50 and the washing solvent 60 can be added to the washing vessel 1 from the solid feed port 41 and the liquid feed port 42, the parameters in the chamber 40 are then adjusted to meet the cleaning environment conditions, the agitator 30 is started to agitate the mixture of crude glycolide product 60 and cleaning solvent 50, and after a predetermined period of agitation, the solvent in the cleaning container 1 is decompressed and filtered through the liquid discharge port 43 to transfer the liquid solvent containing impurities to the outside, the filter screen arranged at the liquid discharge port 43 can reduce the outflow of solid substances (purified glycolide products) in the chamber 40 along with the liquid solvent in the filtering process, thereby being beneficial to improving the productivity of the glycolide, and finishing the first cleaning of the crude glycolide product 50 after the preset time of suction filtration; then, the liquid outlet 43 may be closed, the above steps of adding the cleaning solvent 60, stirring, and suction filtration under reduced pressure may be repeated for a predetermined number of times, and finally the solid substance remaining in the cleaning container 1 is a purified glycolide product, and then the lid body 20 may be opened, and the purified glycolide product may be transferred from the opening of the main body 10 to the outside of the cleaning container 1 for the next operation. In this case, the crude glycolide product 50 can be easily washed a plurality of times by washing the vessel 1.
In some examples, in step S300, when the solvent is removed by vacuum filtration, a vacuum may be drawn on the cleaning container 1 to make the vacuum degree in the chamber 40 reach a predetermined value of the vacuum filtration.
In some examples, in step S300, the inert gas may be introduced into the cleaning container 1 to remove oxygen in the chamber 40, so as to reduce the influence of oxygen on the cleaning process. For example, argon gas may be introduced into the cleaning vessel 1.
In some examples, the volume of the chamber 40 in the cleaning vessel 1 may be not less than 20L in step S300. In this case, a large amount of crude glycolide can be washed at a time, and thus, the method is suitable for industrial batch continuous operation. For example, 25kg of crude glycolide product can be treated in a single pass. That is, by the production method of the present disclosure, glycolide can also be produced in large quantities.
In some examples, as described above, in step S400, the purified glycolide product may be recrystallized to obtain glycolide crystals. This can further improve the purity of the glycolide to be produced.
Fig. 5 is a flow diagram illustrating recrystallization of a glycolide purified product according to examples of the disclosure.
In some examples, in step S400, recrystallizing the glycolide purified product may include the steps of: adding the purified glycolide product to a recrystallization solvent to obtain a recrystallization mixed solution (step S41); heating and stirring the recrystallization mixed solution to dissolve the purified glycolide product in the recrystallization solvent (step S42); and cooling the recrystallization mixed solution to precipitate glycolide crystals from the recrystallization mixed solution, thereby obtaining glycolide crystals (step S43) (see fig. 5). This can further improve the purity of the glycolide to be produced.
In some examples, in step S41, the recrystallization solvent may be ethyl acetate. In some examples, the ethyl acetate may be subjected to a water removal treatment. In this case, the water content in ethyl acetate can be reduced by performing a water removal treatment on ethyl acetate, so that the influence of water on the purified glycolide product (for example, the purified glycolide product is hydrolyzed to generate impurities) can be reduced, and the purity of the prepared glycolide crystals can be further improved. In some examples, in step S41, water removal may be performed on ethyl acetate with calcium hydride.
In some examples, in step S42, the temperature of the recrystallization mixed solution may be raised to 80 ℃ to 90 ℃. Thereby, the purified glycolide product can be advantageously dissolved in the recrystallization mixed solution sufficiently.
In some examples, in step S42, the recrystallization mixed solution may be cooled to 0 ℃ to-15 ℃. This can facilitate precipitation of glycolide crystals.
In some examples, in step S400, the number of times the glycolide purified product is recrystallized may be one. In this case, while the purity of the produced glycolide can be further improved, the overall production time can be controlled within a certain range, and a production method having a shorter production cycle can be obtained as compared with a scheme of multiple recrystallization.
In some examples, as described above, the glycolide crystals may be dried in step S500. This enables removal of water from the glycolide crystals, thereby obtaining high-purity glycolide.
In some examples, the glycolide crystals may be dried by vacuum drying in step S500. Thus, the water in the glycolide crystals can be easily removed, and high-purity glycolide can be produced.
In some examples, the glycolide crystals may be dried under the condition of 50 ℃ to 60 ℃ in step S500. Thus, the water in the glycolide crystals can be easily removed, and high-purity glycolide can be obtained.
In some examples, the above steps in the preparation of glycolide, such as washing, recrystallization, and drying, may be performed in a clean room conforming to GMP standards. In this case, the influence of impurities in the surrounding environment on the purification process can be reduced, thereby improving the purity of the prepared glycolide and further ensuring the stability of the product.
In summary, the present disclosure can provide a method for preparing glycolide with short production cycle and high yield, wherein the gas phase purity of the prepared glycolide is greater than 95%, and the melting point is greater than 82 ℃. In a preferred embodiment, the resulting glycolide has a gas phase purity of greater than 99.95% and a melting point greater than 82 ℃ and can be used as an intermediate feedstock for processing of medical articles (e.g., as an intermediate feedstock for the production of high molecular weight polyglycolic acid).
A second aspect of the present disclosure relates to a glycolide production apparatus that employs the glycolide production method according to the first aspect of the present disclosure. In the second aspect of the present disclosure, by producing glycolide by the apparatus and the method for producing glycolide, high-purity glycolide can be obtained. The second aspect of the present disclosure relates to glycolide produced by the glycolide production apparatus and the glycolide production method, which has a gas-phase purity of greater than 95% and a melting point of greater than 81 ℃. In a preferred embodiment, the resulting glycolide has a gas phase purity of greater than 99.95% and a melting point of greater than 82%, and can be used as an intermediate feedstock for processing of medical articles (e.g., as an intermediate feedstock for the production of high molecular weight polyglycolic acid).
Hereinafter, the preparation method of glycolide provided by the present disclosure will be described in detail with reference to examples and comparative examples, but they should not be construed as limiting the scope of the present disclosure.
Fig. 6 is a gas chromatogram showing glycolide standards. Fig. 7 is a standard curve showing the glycolide standard single-site external standard method. Fig. 8 is a gas chromatogram showing glycolide of example 1 of the present disclosure. Fig. 9 is a gas chromatogram showing glycolide of example 2 of the present disclosure. Fig. 10 is a gas chromatogram showing glycolide of example 3 of the present disclosure. Fig. 11 is a gas chromatogram showing glycolide of example 4 of the present disclosure. Fig. 12 is a gas chromatogram showing glycolide of example 5 of the present disclosure. Fig. 13 is a gas chromatogram showing glycolide of example 6 of the present disclosure. Fig. 14 is a gas chromatogram showing glycolide of example 7 of the present disclosure. Fig. 15 is a gas chromatogram showing glycolide of example 8 of the present disclosure. Fig. 16 is a gas chromatogram showing glycolide of example 9 of the present disclosure. Fig. 17 is a gas chromatogram showing glycolide of example 10 of the present disclosure. Fig. 18 is a gas chromatogram showing glycolide of example 11 of the present disclosure. Fig. 19 is a gas chromatogram showing glycolide of example 12 of the present disclosure. Fig. 20 is a gas chromatogram showing glycolide of comparative example 1 of the present disclosure. Fig. 21 is a gas chromatogram showing glycolide of comparative example 2 of the present disclosure. Fig. 22 is a gas chromatogram showing glycolide of comparative example 3 of the present disclosure.
[ examples ]
First, the crude glycolide products of examples 1 to 12 were prepared by the following steps: glycolic acid having a purity of 99% was selected as a raw material, antimony trioxide was added thereto, and the mixture was reacted at 170 ℃ for 8 hours to polycondense the glycolic acid raw material into glycolic acid oligomers (white solids), and at 280 ℃ for 10 hours to cleave the glycolic acid oligomers into glycolide crude products (yellow solids), thereby obtaining glycolide crude products of examples 1 to 12.
Next, cleaning solvents of examples 1 to 12 were prepared according to table 1, and the cleaning solvents of the respective examples were refrigerated at-15 ℃.
Then, 12 parts by mass (25 kg) of the crude glycolide product was taken out and pulverized into a powder by a pulverizer in accordance with table 1, thereby obtaining crude glycolide products after pulverization of examples 1 to 12.
Then, adding the crushed glycolide crude product and the refrigerated cleaning solvent (the temperature is 0-5 ℃) into a cleaning kettle according to the proportion shown in the table 1 for mixing; vacuumizing the cleaning kettle, and introducing argon into the cleaning kettle; according to the table 1, stirring the mixture at a preset rotating speed for a preset time, and then carrying out reduced pressure suction filtration (the vacuum degree is 90 kPa-100 kPa) for a preset time to remove the solvent, thereby finishing the first cleaning; the crude glycolide product was repeatedly washed in the same procedure as the first washing according to the number of repeated washing shown in table 1 to obtain purified glycolide products of examples 1 to 12.
Then, 1-time recrystallization is carried out on the purified glycolide product, and the specific steps are as follows: mixing the purified glycolide product with the dehydrated ethyl acetate according to the mass ratio of 1:1 to obtain a recrystallization mixed solution; heating the recrystallization mixed solution to 90 ℃, and keeping stirring until the purified glycolide product is completely dissolved in the recrystallization mixed solution; and (3) cooling the recrystallization mixed solution to-15 ℃, precipitating glycolide crystals, mashing the glycolide crystals by using a glass rod, and performing suction filtration to remove the solvent to obtain the glycolide crystals of the examples 1 to 12.
Finally, the glycolide crystals were dried under vacuum at 50 ℃ for 24h to give the glycolides of examples 1 to 12.
TABLE 1
[ comparative example ]
First, crude glycolide products of comparative examples 1 to 3 were prepared by the following steps: glycolic acid having a purity of 99% was selected as a raw material, antimony trioxide was added, and the mixture was reacted at 170 ℃ for 8 hours to polycondense the glycolic acid raw material to glycolic acid oligomer (white solid), and at 280 ℃ for 10 hours to cleave the glycolic acid oligomer to glycolide crude product (yellow solid), to obtain glycolide crude products of comparative examples 1 to 3.
Comparative example 1
(1) Preparing a cleaning solvent: preparing a mixed solvent of isopropanol and absolute ethyl alcohol in a mass ratio of 1:1, and refrigerating at-15 ℃; (2) taking 25kg of crude glycolide products, and crushing the crude glycolide products into powder by using a crusher; (3) adding the crushed glycolide crude product and the refrigerated cleaning solvent into a cleaning kettle for mixing, wherein the mass ratio of the glycolide crude product to the cleaning solvent is 1:1, and the temperature of the cleaning solvent is 0-5 ℃; (4) vacuumizing the cleaning kettle, introducing argon into the cleaning kettle, stirring for 15min under the condition that the rotating speed is 100r/min, decompressing and filtering for 15min, and removing the solvent; (5) repeating the step (3) and the step (4) 3 times (i.e., washing 4 times in total) to obtain a purified glycolide product; (6) the purified glycolide product was dried under vacuum at 50 ℃ for 24h to give the glycolide of comparative example 1.
Comparative example 2
(1) Taking 25kg of crude glycolide products, and crushing the crude glycolide products into powder by using a crusher; (2) taking ethyl acetate as a recrystallization solvent, and mixing the crude glycolide product with the ethyl acetate according to the mass ratio of 1:1 to obtain a recrystallization mixed solution; (3) heating the recrystallization mixed solution to 90 ℃ to completely dissolve the crude glycolide product in the recrystallization solvent; (4) cooling the recrystallization mixed solution to-15 ℃, separating out glycolide crystals, mashing the glycolide crystals by using a glass rod, and performing suction filtration to remove the solvent; (5) repeating the steps (2) to (4) 5 times (i.e., recrystallizing 6 times in total) to obtain glycolide crystals; (6) the glycolide crystals were dried under vacuum at 50 ℃ for 24h to give the glycolide of comparative example 2.
Comparative example 3
(1) Preparing a cleaning solvent: preparing a mixed solvent of isopropanol and ethyl acetate in a mass ratio of 8:2, and refrigerating at-15 ℃; (2) taking 25kg of crude glycolide products, and crushing the crude glycolide products into powder by using a crusher; (3) adding the crushed glycolide crude product and the refrigerated cleaning solvent into a cleaning kettle for mixing, wherein the mass ratio of the glycolide crude product to the cleaning solvent is 1:1.2, and the temperature of the cleaning solvent is 0-5 ℃; (4) vacuumizing the cleaning kettle, introducing argon into the cleaning kettle, stirring for 45min under the condition that the rotating speed is 200r/min, carrying out vacuum filtration for 30min, and removing the solvent to obtain a purified glycolide product; (6) the purified glycolide product was dried under vacuum at 50 ℃ for 24h to give the glycolide of comparative example 3.
In the above-described operation, the overall time (i.e., the preparation time period, excluding the time for preparing the crude glycolide product) consumed in all the steps of each example (example 1 to example 12) and each comparative example (comparative example 1 to comparative example 3) was counted, the statistical results are shown in table 3, and the parameters of the glycolide obtained in each example and each comparative example were measured as follows:
1. the weight of glycolide obtained in each example and each comparative example was measured using an electronic scale, and the yield of glycolide was calculated from the measurement results, the results of which are shown in table 3; wherein, the calculation formula of the yield is as follows: yield = mass of glycolide/mass of crude glycolide product x 100%.
2. Melting points of the glycolides obtained in each example and each comparative example were measured by a melting point meter, and the results are shown in table 3.
3. The purity of the glycolide obtained in each example and each comparative example was measured by a gas chromatograph, specifically as follows:
instrument for measuring the position of a moving object
A gas chromatograph: shimadzu GC-2014C gas chromatograph
A detector: flame Ionization Detector (FID)
Sample preparation
Standard solution: precisely weighing 50.0mg of glycolide standard substance, placing the glycolide standard substance in a 50ml measuring flask, adding a proper amount of N, N-dimethylformamide to the scale of the measuring flask, and shaking up to obtain the glycolide standard solution with the concentration of 1 mg/ml.
Test solution: glycolide test solutions were prepared as above.
Chromatographic parameters
A chromatographic column: fused silica capillary chromatographic column (SH-Rtx-5) with specification of 30m multiplied by 0.25um multiplied by 0.25mm
Column temperature: 135 deg.C
Sample inlet temperature: 280 deg.C
Sample introduction mode: split-flow sample injection with a split-flow ratio of 20:1
Sample injection volume: 1 μ l
Flow rate of carrier gas: 0.5ml/min
Hydrogen flow rate: 40ml/min
Air flow rate: 400ml/min
Detection of
Taking 6 parts of glycolide standard solutions (glycolide standard solution 1 to glycolide standard solution 6 in the table 2 respectively), carrying out sample injection and detection according to the chromatographic parameters, and obtaining the results shown in the following table 2, fig. 6 and fig. 7.
TABLE 2
Fig. 6 is a gas chromatogram showing one of the glycolide standard solutions 1 to 6. Since the peak areas of the glycolide standard solutions are not greatly different, the gas chromatograms are similar and are not shown one by one.
Fig. 7 is a standard curve which is averaged based on the data of table 2 and plotted using a single point external standard method based on the average value, wherein the X-axis is concentration and the Y-axis is peak area, that is, fig. 7 is a standard curve showing a single point external standard method for a glycolide standard solution, and the linear regression equation of the standard curve is: y =6.4429.6x, R 2 =1。
In FIG. 7, the first peak from left to right is the chromatographic peak for N, N dimethylformamide, the second is the chromatographic peak for glycolide, "3.509/N, N dimethylformamide" means that the retention time of the N, N dimethylformamide sample is 3.509min, "5.197/glycolide" means that the retention time of the glycolide sample is 5.197 min. The chromatograms of the subsequent other samples are schematically consistent with the labels in fig. 7, and are not described herein again.
Sampling and detecting solutions to be tested made of the glycolides obtained in examples 1 to 12 and comparative examples 1 to 3 respectively according to the chromatographic parameters to obtain gas chromatograms of the examples and the comparative examples, wherein the gas chromatograms of the examples 1 to 12 and the comparative examples 1 to 3 are respectively shown in fig. 8 to 22, the peak areas of the glycolides in the chromatograms of the examples and the comparative examples are shown in the following table 3, substituting the peak areas of the glycolides in the chromatograms of the examples and the comparative examples into a linear regression equation of the standard curve to obtain the glycolide test concentrations (c) of the examples and the comparative examples, calculating according to the gas purity calculation formula W) = vc/m × 100% to obtain the glycolide purity of the examples and the comparative examples, the results are shown in Table 3.
In the examples, comparative examples, and the measurement processes described above, reagents and instruments used in the present disclosure were commercially available products unless otherwise specified.
TABLE 3
As can be seen from table 3, the glycolide obtained in each example (example 1 to example 12) had a melting point of 81.1 ℃ or more, a purity of 95.56% or more, and a yield of 74% or more, and a preparation period of 3 days or less.
In particular, in a preferred embodiment, the purity of example 8 and example 9 is above 99.96%, the melting point is above 82.3 ℃, and the yield of example 8 is greater than 80%.
Comparative example 1 although the obtained glycolide also had a high melting point and yield and the preparation period was 2 days, the purity of the glycolide was low mainly because 1 recrystallization was not performed after washing.
The melting point and purity of glycolide obtained in comparative example 2 were high, but the preparation time was 6 days, and the yield was less than 60%, mainly due to the fact that multiple recrystallization was performed, the time was long, and the loss of glycolide during the multiple recrystallization was large.
The yield of glycolide obtained in comparative example 3 was high and the preparation time was 2 days, but the purity of glycolide was significantly lower compared to that of the glycolide of comparative example 1, comparative example 2 and each example, mainly because only 1 washing was performed and the impurity removal in the crude glycolide product was insufficient.
In conclusion, the glycolide obtained in each example (example 1 to example 12) has high melting point, high purity, high yield and short preparation time. In contrast, the glycolide obtained in each of the comparative examples (comparative examples 1 to 3) could not achieve both the performance and effect of the glycolide obtained in each of the above examples.
While the present disclosure has been described in detail above with reference to the drawings and examples, it should be understood that the above description is not intended to limit the disclosure in any way. Variations and changes may be made as necessary by those skilled in the art without departing from the true spirit and scope of the disclosure, which fall within the scope of the disclosure.
Claims (10)
1. A method for preparing glycolide, which is characterized by comprising the following steps:
preparing a glycolide crude product, and crushing the glycolide crude product;
preparing a cleaning solvent, and refrigerating the cleaning solvent to enable the temperature of the refrigerated cleaning solvent to be 0-5 ℃, wherein the cleaning solvent is isopropanol or a mixed solution of isopropanol and any one of ethyl acetate, butyl acetate, methanol, absolute ethyl alcohol and acetone, and the mass fraction of the isopropanol in the cleaning solvent is 50-100%;
washing the crude glycolide product for multiple times by using the washing solvent after refrigeration, keeping stirring during the washing process, and removing the solvent after stirring for a preset time to obtain a purified glycolide product, wherein the single washing time is 30-150 min, and the mass ratio of the crude glycolide product to the washing solvent is 1: 1-1: 1.5;
recrystallizing the purified glycolide product to obtain glycolide crystals; and is provided with
And drying the glycolide crystal to obtain the glycolide, wherein the purity of the glycolide is not less than 95%.
2. The production method according to claim 1,
the rotating speed of the stirring treatment is 100r/min to 300r/min, and the preset time is 15min to 90 min.
3. The production method according to claim 1,
and removing the solvent by adopting a reduced pressure suction filtration mode, wherein the reduced pressure suction filtration time is 15min to 60 min.
4. The production method according to claim 3,
the vacuum degree of the decompression suction filtration is 90kPa to 100 kPa.
5. The production method according to claim 1,
the number of the multiple washing is 2 to 5.
6. The production method according to claim 1,
the gas-phase purity of the glycolide is not less than 99.95%.
7. The production method according to claim 1,
and (3) carrying out vacuum drying on the glycolide crystals at the temperature of 40-60 ℃, wherein the vacuum drying time is 24-36 h.
8. The production method according to claim 1,
the preparation of the crude glycolide product comprises the following steps:
preparing a glycolic acid raw material with the purity of not less than 99%;
polycondensing the glycolic acid raw material to obtain a glycolic acid oligomer; and is
And (3) cracking the glycolic acid oligomer to obtain the crude glycolide product.
9. The method according to claim 1,
the recrystallization of the purified glycolide product comprises the following steps:
adding the purified glycolide product into a recrystallization solvent to obtain a recrystallization mixed solution, wherein the recrystallization solvent is ethyl acetate subjected to water removal treatment;
heating and stirring the recrystallization mixed solution to dissolve the purified glycolide product in the recrystallization solvent; and is
And cooling the recrystallization mixed solution to separate out the glycolide crystals from the recrystallization mixed solution, thereby obtaining the glycolide crystals.
10. A glycolide preparation device is characterized in that,
the production apparatus employs the production method according to any one of claims 1 to 9.
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