Preparation method of high-purity glycolide

Abstract

The invention belongs to the technical field of chemical production, and particularly relates to a preparation method of high-purity glycolide. Comprising the following steps: firstly, mixing glycollic acid with a calcium catalyst to carry out polymerization reaction, then adding thiourea and a cocatalyst to carry out cracking reaction, collecting fractions after distillation, and recrystallizing with ethyl acetate to obtain high-purity glycolide. Compared with the prior art, the method has the advantages that the calcium compound with biocompatibility is adopted as the catalyst, corrosion to production equipment is avoided, the catalytic activity is improved by adding thiourea and a cocatalyst, the method is used for preparing high-purity glycolide, and a catalytic system is simple, easy to obtain, low in price and environmentally friendly and has a good industrial application prospect.

Description

Technical Field

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

[0002] Polyglycolide (PGA) is widely used in the biomedical field, such as absorbable sutures and drug sustained-release systems. As a key chemical intermediate of PGA, the optimization of its preparation process is crucial to improving the performance of biodegradable materials. However, the existing synthesis technology still faces significant process difficulties and technical barriers, especially in the core links such as catalyst toxicity residue, side reaction control and product separation. The synthesis of glycolide generally requires two steps of dehydration condensation and high-temperature cracking of glycolic acid. During the cracking process, the intermediate is prone to thermal degradation, and the purity needs to be improved through complex purification steps, which increases production costs. In addition, the existing industrial catalytic system is mainly based on tin catalysts, but the residue of metallic tin limits its application in the field of medical materials. Studies have shown that even trace amounts of tin residues can cause cytotoxicity and lead to local inflammatory reactions after material implantation. Although zinc-based catalysts can reduce the amount of metal residues to a minimum, their catalytic activity is low, which increases production costs and is difficult to meet medical-grade purity requirements.

[0003] The core technical barriers to the preparation of glycolide currently lie in the biological toxicity of the catalyst, the efficiency of product separation, and the stability of continuous production. Based on this, a low-toxic and high-efficiency catalytic system that can be applied to industrial production has been developed, which is expected to break through the bottleneck of large-scale production of medical-grade glycolide and promote the application of degradable materials in high-end medical fields such as tissue engineering scaffolds and drug sustained-release 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, calcium catalyst and co-catalyst to catalyze glycolic acid to prepare high-purity glycolide.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is: firstly, glycolic acid is mixed with a calcium catalyst, a polymerization reaction is carried out at 130°C and 20 kPa, thiourea and a co-catalyst are added, a cracking reaction is carried out at 250°C and 500 Pa, the fractions are collected by distillation, and high-purity glycolide is obtained after recrystallization from ethyl acetate.

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

[0007] In some embodiments, the amount of the calcium catalyst is 1-5% of the mass of the glycolic acid, preferably 3%. The calcium catalyst in this amount can fully react with the other two catalytic components to exert the best catalytic effect.

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

[0009] In some embodiments, the co-catalyst is one of N-benzylsulfonamide, 4-chlorobenzenesulfonamide, pentafluorobenzenesulfonamide, dinitrobenzenesulfonamide, cresol butylsulfonamide, 6-indolesulfonamide, and N-benzylmethanesulfonamide, among which 6-indolesulfonamide is preferred. The co-catalyst contains an indole ring, in which the pyrrole nitrogen and sulfonamide groups can coordinate with calcium ions to form a multidentate coordination structure, and the indole ring has a rigid structure and large steric hindrance, thereby limiting the generation of side reactions.

[0010] In some embodiments, the amount of the co-catalyst is 1-5% of the mass of glycolic acid, preferably 2%. The amount can catalyze the synthesis of high-purity glycolide economically and efficiently.

[0011] Compared with the prior art, the advantages of the present invention are: The catalyst system for preparing glycolide from glycolic acid in the present invention adopts a calcium catalyst. Firstly, the calcium element also has good biocompatibility, is abundant in resources, and is low in cost, and can effectively avoid corrosion to production equipment; secondly, the calcium ion has excellent coordination ability and can combine with thiourea and the NH bond in the co-catalyst to stabilize the catalyst system. The co-catalyst 6-indolesulfonamide in the catalyst system can selectively carry out the catalytic reaction 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

[0012] Figure 1 The gas chromatogram of the product obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0013] The following examples illustrate the present invention in more detail but are not intended to further limit the present invention.

[0014] The invention discloses that glycolic acid and a calcium catalyst are first subjected to polymerization reaction, thiourea and a co-catalyst are then added to carry out cracking reaction, fractions are collected after distillation, and high-purity glycolide is obtained after recrystallization with ethyl acetate.

[0015] Example 1 A method for preparing high-purity glycolide comprises the following steps: In a 250 mL round-bottom flask, 100 g of glycolic acid and 3.0 g of calcium oxide were added, and vacuum distillation was performed at 130°C and 20 kPa for 6 hours to continuously remove the water generated by the reaction. Then, 5.0 g of thiourea and 2.0 g of 6-indolesulfonamide were added, and the cracking reaction was carried out at 250°C and 500 Pa for 4 hours. The distilled components were collected and recrystallized from ethyl acetate to obtain glycolide with a yield of 91.3% and a purity of 99.8%. The gas chromatographic results were as follows: Figure 1 As shown, the glycolide peak is at 10.350 min.

[0016] The gas chromatography detection instruments and conditions are as follows: Instrument model: Agilent GC-8890; Chromatographic column: HP-5 capillary column 30m×320μm×0.25μm; Detector: FID detector; Carrier gas: N2; Heating program: starting temperature was 50 °C, increasing to 250 °C at 10 °C / min, and maintaining for 3 min; Inlet temperature: 250°C; Detector temperature: 300°C; Injection mode: split (50:1); Injection volume: 5 µL.

[0017] In the above experiments, the sources and purity of the drugs used are as follows: Glycolic acid (CAS No. 79-14-1), purchased from Anaiji, purity 99.5%; Calcium oxide (CAS No.: 1305-78-8), purchased from Anaiji, purity 98%; Thiourea (CAS No.: 62-56-6), purchased from Anaiji, purity 98%; 6-Indolesulfonamide (CAS No.: 145951-26-4), purchased from Anaiji, purity 95%; Ethyl acetate (CAS No.: 141-78-6) was purchased from Anaiji with a purity of 99.8%.

[0018] Example 2 In order to test the catalytic effect of different calcium catalysts, only the type of calcium catalyst was changed, and other conditions were the same as those in Example 1. The results are shown in Table 1.

[0019] Table 1. Comparison of the effects of different calcium catalysts

[0020] From the above results, it can be seen that calcium oxide has the best catalytic effect on this catalyst system (No. 5, corresponding to Example 1). Calcium ions contain empty orbitals, and thiourea and indole rings 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, and calcium acetate) will introduce more anions into the reaction system to participate in coordination, affecting the synergistic effect of thiourea and 6-indolesulfonamide, thereby reducing the catalytic effect.

[0021] Example 3 Preparation method of glycolide: In order to test the catalytic effect of different amounts of calcium oxide, only the amount of calcium oxide was changed, and other conditions were the same as Example 1. The results are shown in Table 2.

[0022] Table 2. Comparison of the effects of different calcium oxide dosages

[0023] It can be seen from the above results that when the amount of calcium oxide is 3% (No. 3, corresponding to Example 1), the yield and purity of glycolide are the highest.

[0024] Example 4 Preparation method of glycolide: In order to test the catalytic effect of different amounts of thiourea, only the amount of thiourea was changed, and other conditions were the same as in Example 1. The results are shown in Table 3.

[0025] Table 3. Comparison of the effects of thiourea dosage

[0026] From the above results, it can be seen that when the amount of thiourea is 5%, the yield and purity of glycolide are the highest (No. 3, corresponding to Example 1). The NH in the amino group adjacent to the sulfur atom in the thiourea molecule has a strong polarity and can act as a hydrogen bond donor to form a hydrogen bond with the lone pair of electrons of the pyrrole nitrogen in the indole ring, providing a stable catalytic effect. When thiourea is not involved in the reaction, 6-indolesulfonamide cannot fully play its role.

[0027] Example 5 Preparation method of glycolide, in order to study the effect of different co-catalysts on the reaction, only the type of co-catalyst was changed, and other conditions were the same as Example 1, and the catalytic effects of different co-catalysts were studied. The results are shown in Table 4.

[0028] Table 4. Comparison of the effects of different co-catalysts

[0029] From the above results, it can be seen that the introduction of sulfonamide co-catalysts can improve the yield and purity of glycolide in this catalytic system, and the best effect is achieved when 6-indolesulfonamide is used (No. 6, corresponding to Example 1). The pyrrole nitrogen and sulfonamide groups of the indole ring in 6-indolesulfonamide can further coordinate with the calcium ion center to form a multidentate coordination structure, thereby enhancing the catalytic activity. In addition, the rigid structure of the indole ring can provide steric hindrance, limit the orientation of the reactant molecules, and reduce the generation of side reactions.

[0030] Example 6 In the preparation method of glycolide, only the amount of 6-indolesulfonamide was changed, and other conditions were the same as those in Example 1. The effect of different amounts of 6-indolesulfonamide on the catalytic effect was studied, and the results are shown in Table 5.

[0031] Table 5. Comparison of the effects of 6-indolesulfonamide dosage

[0032] From the above results, it can be seen that when the dosage of 6-indolesulfonamide is 2%, the catalytic effect of this catalytic system is the best and most economical (No. 2, corresponding to Example 1). Even if the dosage is further increased, the catalytic effect does not change significantly.

[0033] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any technician familiar with the profession, without departing from the scope of the technical solution of the present invention, according to the technical essence of the present invention, any simple modification, equivalent replacement and improvement made to the above embodiment still falls 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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