A method for preparing high-purity glycolide

Abstract

The present invention belongs to the technical field of chemical production, and specifically relates to a method for preparing high-purity glycolide. The method comprises the following steps: firstly, glycolic acid is mixed with a calcium catalyst for polymerization reaction, then thiourea and a co-catalyst are added for cracking reaction, fractions are collected after distillation, and high-purity glycolide is obtained after recrystallization from ethyl acetate. Compared with the prior art, the present invention adopts a biocompatible calcium compound as a catalyst, thereby avoiding corrosion to production equipment, and improves the catalytic activity by adding thiourea and a co-catalyst, so as to prepare high-purity glycolide. The catalytic system is simple, easy to obtain, low in price, and environmentally friendly, and has good prospects for industrial application.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical production, and particularly relates to a method for preparing high-purity glycolide. Background Art

[0002] Poly(glycolic acid) (PGA) is widely used in the biomedical field, such as absorbable sutures and drug delivery systems. As a key chemical intermediate of PGA, the optimization of its preparation process is crucial for improving the performance of biodegradable materials. However, the existing synthesis technologies still face significant process difficulties and technical barriers, especially in the core aspects such as catalyst toxicity residue, side reaction control, and product separation. The synthesis of glycolide generally undergoes two steps: dehydration polycondensation of glycolic acid and high-temperature pyrolysis. During the pyrolysis process, the intermediate is prone to thermal degradation, and complex purification steps are required to improve the purity, increasing the production cost. Moreover, the existing industrial catalytic system is mainly based on tin catalysts, but the residue of metallic tin limits its application in the medical material field. Research shows that even trace amounts of tin residue can cause cytotoxicity, leading to local inflammatory reactions after material implantation. Although zinc-based catalysts can reduce the metal residue to a relatively low level, their catalytic activity is low, increasing the production cost and it is also difficult to meet the medical-grade purity requirements.

[0003] The current core technical barriers in glycolide preparation lie in the biological toxicity of the catalyst, the efficiency of product separation, and the stability of continuous production. Based on this, developing a low-toxic and highly efficient catalytic system that can be applied to industrial production is expected to break through the bottleneck of large-scale production of medical-grade glycolide and promote the application of biodegradable materials in high-end medical fields such as tissue engineering scaffolds and drug delivery carriers. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing high-purity glycolide, which adopts a ternary composite catalytic system composed of thiourea, a calcium catalyst, and a co-catalyst to catalyze glycolic acid to prepare high-purity glycolide.

[0005] To solve the above technical problems, the technical solution provided by the present invention is: first, mix glycolic acid with a calcium catalyst and carry out a polymerization reaction at 130 °C and 20 kPa, then add thiourea and a co-catalyst and carry out a pyrolysis reaction at 250 °C and 500 Pa, distill and collect the fractions, and obtain high-purity glycolide after recrystallization with ethyl acetate.

[0006] In some embodiments, the calcium catalyst is one of calcium chloride, calcium fluoride, calcium sulfate, calcium carbonate, calcium oxide, calcium selenide, calcium acetate, and preferably calcium oxide.

[0007] In some embodiments, the dosage of the calcium catalyst is 1% to 5% of the mass of glycolic acid, preferably 3%. Using the calcium catalyst in such a dosage can fully react with the other two catalytic components to achieve the best catalytic effect.

[0008] In some embodiments, the dosage of thiourea is 3% to 7% of the mass of glycolic acid, preferably 5%.

[0009] In some embodiments, the cocatalyst is one of N-benzylsulfonamide, 4-chlorobenzenesulfonamide, pentafluorobenzenesulfonamide, dinitrobenzenesulfonamide, cresol butylsulfonamide, 6-indolesulfonamide, N-benzylmethanesulfonamide, preferably 6-indolesulfonamide. The cocatalyst contains an indole ring, and the pyrrole nitrogen and sulfonamide group therein can both coordinate with calcium ions to form a multidentate coordination structure. Moreover, the indole ring has a rigid structure and a large steric hindrance, thereby restricting the generation of side reactions.

[0010] In some embodiments, the dosage of the cocatalyst is 1% to 5% of the mass of glycolic acid, preferably 2%. Such a dosage can catalytically synthesize high-purity glycolide economically and efficiently.

[0011] Compared with the prior art, the advantages of the present invention are as follows:

[0012] In the present invention, a catalytic system for preparing glycolide from glycolic acid uses a calcium catalyst. First, calcium also has good biocompatibility, is rich in resources and low in cost, and can effectively avoid corrosion of production equipment. Second, calcium ions have excellent coordination ability and can bind to the N-H bond in thiourea and the cocatalyst, making the catalytic system stable. The cocatalyst 6-indolesulfonamide in the catalytic system can selectively carry out catalytic reactions by using its unique indole ring and steric hindrance, inhibit the generation of side reactions, and thus obtain high-purity glycolide. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 It is the gas chromatogram of the product obtained in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0014] The following examples further elaborate on the present invention rather than further limiting the present invention.

[0015] The present invention discloses that glycolic acid and a calcium catalyst are first subjected to a polymerization reaction, then thiourea and a cocatalyst are added for a cracking reaction, the distillate is collected after distillation, and high-purity glycolide is obtained after recrystallization with ethyl acetate.

[0016] Example 1

[0017] A method for preparing high-purity glycolide, comprising the following steps:

[0018] Add 100 g of glycolic acid and 3.0 g of calcium oxide to a 250 mL round-bottom flask, and perform vacuum distillation at 130 °C and 20 kPa for 6 hours, continuously removing the water generated by the reaction. Then add 5.0 g of thiourea and 2.0 g of 6-indole sulfonamide, and carry out a cracking reaction at 250 °C and 500 Pa for 4 hours. Collect the distillate components and recrystallize with ethyl acetate to obtain glycolide, with a yield of 91.3% and a purity of 99.8%. The gas chromatography is as Figure 1 shown, where the peak of glycolide appears at 10.350 min.

[0019] The detection instrument and conditions of gas chromatography are as follows:

[0020] Instrument model: Agilent GC-8890;

[0021] Chromatographic column: HP-5 capillary column 30m × 320μm × 0.25μm;

[0022] Detector: FID detector;

[0023] Carrier gas: N 2 ;

[0024] Temperature programming: The initial temperature is 50 °C, rising to 250 °C at a rate of 10 °C / min and holding for 3 min;

[0025] Injector temperature: 250 °C;

[0026] Detector temperature: 300 °C;

[0027] Injection mode: Split flow (50:1);

[0028] Injection volume: 5 μL.

[0029] In the above experiment, the sources and purities of the drugs used are as follows:

[0030] Glycolic acid (CAS No.: 79-14-1), purchased from Aladdin, purity 99.5%;

[0031] Calcium oxide (CAS No.: 1305-78-8), purchased from Aladdin, purity 98%;

[0032] Thiourea (CAS No.: 62-56-6), purchased from Aladdin, purity 98%;

[0033] 6-Indole sulfonamide (CAS No.: 145951-26-4), purchased from Aladdin, purity 95%;

[0034] Ethyl acetate (CAS No.: 141-78-6), purchased from Aladdin, purity 99.8%.

[0035] Example 2

[0036] Preparation method of glycolide. To test the catalytic effects of different calcium catalysts, only the types of calcium catalysts were changed while other conditions were the same as those in Example 1. The results are shown in Table 1.

[0037] Table 1. Comparison table of the effects of different calcium catalysts

[0038]

[0039] It can be seen from the above results that calcium oxide has the best catalytic effect on this catalytic system (No. 5, corresponding to Example 1). Calcium ions contain empty orbitals, and thiourea and indole ring can act as ligands to combine with calcium ions to form a synergistic catalytic effect. Other calcium catalysts (such as calcium chloride, calcium fluoride, calcium sulfate, calcium carbonate, calcium selenide, calcium acetate) will introduce more anions into the reaction system to participate in coordination, affecting the synergistic effect between thiourea and 6-indole sulfonamide, thus reducing the catalytic effect.

[0040] Example 3

[0041] Preparation method of glycolide. To test the catalytic effects of different dosages of calcium oxide, only the dosage of calcium oxide was changed while other conditions were the same as those in Example 1. The results are shown in Table 2.

[0042] Table 2. Comparison table of the effects of different dosages of calcium oxide

[0043]

[0044] It can be seen from the above results that when the dosage of calcium oxide is 3% (No. 3, corresponding to Example 1), the yield and purity of glycolide are the highest.

[0045] Example 4

[0046] Preparation method of glycolide. To test the catalytic effects of different dosages of thiourea, only the dosage of thiourea was changed while other conditions were the same as those in Example 1. The results are shown in Table 3.

[0047] Table 3. Comparison table of the effects of the dosage of thiourea

[0048]

[0049] It can be seen from the above results that when the dosage of thiourea is 5%, the yield and purity of glycolide are the highest (No. 3, corresponding to Example 1). The N-H in the amino group adjacent to the sulfur atom in the thiourea molecule has strong polarity and can act as a hydrogen bond donor to form a hydrogen bond with the lone pair electrons of the pyrrole nitrogen in the indole ring, providing a stable catalytic effect. When thiourea does not participate in the reaction, 6-indole sulfonamide cannot fully play its role.

[0050] Example 5

[0051] Preparation method of glycolide. To study the influence of different cocatalysts on the reaction, only the type of cocatalyst was changed, and other conditions were the same as in Example 1. The catalytic effects of different cocatalysts were studied, and the results are shown in Table 4.

[0052] Table 4. Comparison table of the effects of different cocatalysts

[0053]

[0054] It can be seen from the above results that the introduction of sulfonamide cocatalysts can improve the yield and purity of glycolide in this catalytic system. The best effect is achieved when 6-indole sulfonamide is used (No. 6, corresponding to Example 1). In 6-indole sulfonamide, both the pyrrole nitrogen of the indole ring and the sulfonamide group can further coordinate with the calcium ion center to form a multidentate coordination structure, enhancing the catalytic activity. Moreover, the rigid structure of the indole ring can provide steric hindrance, restrict the orientation of reactant molecules, and reduce the generation of side reactions.

[0055] Example 6

[0056] Preparation method of glycolide. Only the amount of 6-indole sulfonamide was changed, and other conditions were the same as in Example 1. The influence of different amounts of 6-indole sulfonamide on the catalytic effect was studied, and the results are shown in Table 5.

[0057] Table 5. Comparison table of the influence effects of the amount of 6-indole sulfonamide

[0058]

[0059] It can be seen from the above results that when the amount of 6-indole sulfonamide is 2%, the catalytic effect of this catalytic system is the best and most economical (No. 2, corresponding to Example 1). Even if the amount is continuously increased, the change in the catalytic effect is not obvious.

[0060] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Any person skilled in the relevant art, without departing from the scope of the technical solution of the present invention, based on the technical essence of the present invention, any simple modification, equivalent replacement, and improvement made to the above embodiments still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing high-purity glycolide, characterized in that: The method comprises the following steps: firstly mixing glycolic acid with a calcium catalyst, performing a polymerization reaction at 130°C and 20 kPa, then adding thiourea and a co-catalyst, performing a cracking reaction at 250°C and 500 Pa, collecting fractions by distillation, and obtaining high-purity glycolide after recrystallization with ethyl acetate; the calcium catalyst is any one of calcium chloride, calcium fluoride, calcium sulfate, calcium carbonate, calcium oxide, calcium selenide, and calcium acetate; The co-catalyst is any one of N-benzylsulfonamide, 4-chlorobenzenesulfonamide, pentafluorobenzenesulfonamide, dinitrobenzenesulfonamide, cresolbutanesulfonamide, 6-indolesulfonamide and N-benzylmethanesulfonamide.

2. The method for preparing high-purity glycolide according to claim 1, characterized in that: The calcium catalyst is calcium oxide.

3. The method for preparing high-purity glycolide according to claim 1, characterized in that: The calcium catalyst is used in an amount of 1-5% of the mass of glycolic acid.

4. The method for preparing high-purity glycolide according to claim 3, characterized in that: The calcium catalyst is used in an amount of 3% of the mass of glycolic acid.

5. The method for preparing high-purity glycolide according to claim 1, characterized in that: The amount of thiourea used is 3-7% of the mass of glycolic acid.

6. The method for preparing high-purity glycolide according to claim 5, characterized in that: The amount of thiourea used is 5% of the mass of glycolic acid.

7. The method for preparing high-purity glycolide according to claim 1, characterized in that: The co-catalyst is 6-indolesulfonamide.

8. The method for preparing high-purity glycolide according to claim 1, characterized in that: The amount of the co-catalyst used is 1-5% of the mass of glycolic acid.

9. The method for preparing high-purity glycolide according to claim 8, characterized in that: The amount of the co-catalyst used is 2% of the mass of glycolic acid.

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