WO2018045941A1 - 一种合成乙交酯的方法 - Google Patents

一种合成乙交酯的方法 Download PDF

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WO2018045941A1
WO2018045941A1 PCT/CN2017/100510 CN2017100510W WO2018045941A1 WO 2018045941 A1 WO2018045941 A1 WO 2018045941A1 CN 2017100510 W CN2017100510 W CN 2017100510W WO 2018045941 A1 WO2018045941 A1 WO 2018045941A1
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reaction
rate
temperature
pressure
torr
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French (fr)
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李弘�
张全兴
盛家业
黄伟
江伟
李爱民
潘丙才
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Nanjing University
Nanjing Tech University
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Nanjing University
Nanjing Tech University
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Priority to US16/293,595 priority patent/US20190194387A1/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/70—Oxidation reactions, e.g. epoxidation, (di)hydroxylation, dehydrogenation and analogues
    • B01J2231/76—Dehydrogenation
    • B01J2231/763—Dehydrogenation of -CH-XH (X= O, NH/N, S) to -C=X or -CX triple bond species
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0251—Guanidides (R2N-C(=NR)-NR2)

Definitions

  • the invention belongs to the field of synthesis of biodegradable material polyglycolide (ie "polyglycolic acid”) and its copolymer polymerization monomer, in particular to a method for synthesizing glycolide by using a binary organic ruthenium compound as a composite catalyst.
  • biodegradable material polyglycolide ie "polyglycolic acid”
  • copolymer polymerization monomer in particular to a method for synthesizing glycolide by using a binary organic ruthenium compound as a composite catalyst.
  • glycolide usually adopts a two-step process route of "dehydration oligomerization-catalytic depolymerization", that is, glycolic acid first undergoes dehydration oligomerization to form an oligomer, and then glycolide is prepared by depolymerization reaction.
  • the catalytic depolymerization reaction is often carried out in a high boiling solvent, but the recovery process of the high boiling polar organic solvent is complicated, the recovery rate is difficult to reach 100%, and the product glycolide is easily contaminated by the solvent.
  • the synthesis catalyst of glycolide mainly uses a metal salt or a metal oxide such as SnOct 2 , SnCl 2 , strontium oxide Sb 2 O 3 or the like. Due to the large amount of heavy metal catalyst (0.1-0.7%), the crude glycolide synthesized needs to be purified by repeated recrystallization in a solvent, which is not only complicated in process but also low in yield of high-purity glycolide. Moreover, catalysts such as SnOct 2 , SnCl 2 and Sb 2 O 3 have obvious cytotoxicity, and the synthesis of glycolide as a monomer for biomedical material synthesis may cause biosafety potential hazards.
  • the object of the present invention is to solve the problems that the existing glycolide synthesis process has the problem that the toxic metal catalyst and the high-boiling polar solvent are easy to contaminate the product, and provide a method for synthesizing the total green glycolide.
  • the method provided by the invention adopts a binary composite catalytic system composed of a non-toxic cyclic organic ruthenium compound and a non-toxic linear organic ruthenium compound, and is subjected to reactive vacuum distillation by using a 70% by mass aqueous solution of glycolic acid as a raw material.
  • the method achieves high yield ( ⁇ 98.0%) synthesis of high purity ( ⁇ 99.9%) glycolide.
  • the binary composite catalytic system specifically includes:
  • a non-toxic cyclic organic hydrazine compound is bicyclic guanidine (1,5,7-triazabicyclo[5.5.0]non-5-ene), one of guanine or benzimidazole;
  • the non-toxic linear organic bismuth compound is one of thioglycolic acid, creatine or creatine phosphate.
  • the non-toxic cyclic organic hydrazine compound and the non-toxic linear organic hydrazine compound are used in an amount of 0.05% to 0.10% by mass of the glycolic acid.
  • Step 1 dehydration and oligomerization stage, using gradient heating and gradient decompression to prevent material damage Loss, increase productivity:
  • the temperature of the reactant is first raised from room temperature to 1.0-1.5 ° C / min to 100-110 ° C, atmospheric pressure dehydration reaction 1.0-2.0 h,
  • the obtained oligoglycolic acid has a weight average molecular weight M w of 5.0-6.0 ⁇ 10 3 and a yield of 100%;
  • the catalytic depolymerization stage is carried out by first reducing the pressure of the reaction system to a controlled range, and then adopting a gradient heating reaction process:
  • the absolute pressure of the reaction system is reduced from normal pressure to 3.0-5.0 torr at a rate of 1.0-1.5 torr/min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide is washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water to neutrality, and finally dried under vacuum at 20 ° C for 24 hours to obtain glycolide.
  • the binary composite catalytic system used is a non-toxic, metal-free, non-cytotoxic organic antimony compound with high catalytic efficiency and low dosage;
  • the synthesized glycolide has high yield ( ⁇ 98.0%), high purity ( ⁇ 99.9%), and does not contain any metal or solvent;
  • the temperature of the reactant was first raised to 100 ° C at a rate of 1.0 ° C / min from room temperature, 1.0 h at atmospheric pressure, and 1.0 ° C from 100 ° C.
  • the rate of min is raised to 140 ° C
  • the atmospheric pressure dehydration reaction is 1.0 h
  • the temperature is raised to 155 ° C at a rate of 1.0 ° C / min from 140 ° C
  • the dehydration reaction at normal pressure is 1.0 h
  • the rate is increased from 155 ° C at a rate of 1.0 ° C / min.
  • oligo-glycolic acid prepared in the above step 25.0 g of bicyclic guanidine and 25.0 g of thioglycolic acid were added, and the absolute pressure of the reaction system was reduced from normal pressure to 3.0 torr at a rate of 1.0 torr/min to maintain the pressure of the system.
  • the temperature of the reaction system was raised from room temperature to 250 ° C at a rate of 10 ° C / min, catalytic depolymerization reaction for 20 min, maintaining the system pressure unchanged, and the temperature of the reaction system was increased from 250 ° C to 1.0 ° C / min to 270 ° C.
  • the catalytic depolymerization reaction was carried out for 20 min to maintain the pressure of the system.
  • the temperature of the reaction system was raised from 270 ° C to 280 ° C at a rate of 1.0 ° C / min, and the catalytic depolymerization reaction was carried out for 60 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water until neutral, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 98.5%, and the purity was 99.9%.
  • the process was the same as in Example 1, except that only 25.0 g of bicycloguanidine was added in the catalytic depolymerization stage, and the obtained glycolide yield was 41.4% and the purity was 82.5%.
  • the process was the same as in Example 1, except that only 25.0 g of thioglycolic acid was added in the catalytic depolymerization stage, and the obtained glycolide yield was 34.5% and the purity was 85.3%.
  • the temperature of the reactant was first raised to 100 ° C at a rate of 1.0 ° C / min from room temperature, 1.0 h at atmospheric pressure, and 1.0 ° C from 100 ° C.
  • the rate of min is raised to 140 ° C
  • the atmospheric pressure dehydration reaction is 1.0 h
  • the temperature is raised to 155 ° C at a rate of 1.0 ° C / min from 140 ° C
  • the dehydration reaction at normal pressure is 1.0 h
  • the rate is increased from 155 ° C at a rate of 1.0 ° C / min.
  • oligo-glycolic acid prepared in the above step 50.0 g of bicyclic guanidine and 35.0 g of creatine were added, and the absolute pressure of the reaction system was reduced from 3.0 torr at a rate of 1.0 torr/min at normal pressure to maintain the pressure of the system.
  • the temperature of the system was raised from room temperature to 250 ° C at a rate of 10 ° C / min, catalytic depolymerization reaction for 20 min, the system pressure was maintained, and the temperature of the reaction system was increased from 250 ° C to 270 ° C at a rate of 1.0 ° C / min.
  • the catalytic depolymerization reaction was carried out for 20 min, and the pressure of the system was kept constant.
  • the temperature of the reaction system was raised from 270 ° C to 280 ° C at a rate of 1.0 ° C / min, and the catalytic depolymerization reaction was carried out for 60 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water until neutral, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 98.2%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 100 ° C at a rate of 1.0 ° C / min from room temperature, 1.0 h at atmospheric pressure, and 1.0 ° C from 100 ° C.
  • the rate of min is raised to 140 ° C
  • the atmospheric pressure dehydration reaction is 1.0 h
  • the temperature is raised to 155 ° C at a rate of 1.0 ° C / min from 140 ° C
  • the dehydration reaction at normal pressure is 1.0 h
  • the rate is increased from 155 ° C at a rate of 1.0 ° C / min.
  • oligo-glycolic acid prepared in the above step 35.0 g of bicyclic guanidine and 50.0 g of creatine phosphate were added, and the absolute pressure of the reaction system was reduced from normal pressure to 3.0 torr at a rate of 1.0 torr/min to maintain the pressure of the system.
  • the temperature of the reaction system was raised from room temperature to 250 ° C at a rate of 10 ° C / min, catalytic depolymerization reaction for 20 min, maintaining the system pressure unchanged, and the temperature of the reaction system was increased from 250 ° C to 1.0 ° C / min to 270 ° C.
  • the catalytic depolymerization reaction was carried out for 20 min to maintain the pressure of the system.
  • the temperature of the reaction system was raised from 270 ° C to 280 ° C at a rate of 1.0 ° C / min, and the catalytic depolymerization reaction was carried out for 60 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide is washed with an alkali solution having a mass concentration of 0.1%, and then washed with deionized water to the middle. Finally, it was vacuum dried at 20 ° C for 24 h, the yield was 98.7%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 105 ° C at a rate of 1.2 ° C / min from room temperature, 1.2 h at normal pressure, 1.2 ° C from 105 ° C /
  • the rate of min rises to 145 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starts from 145 ° C at a rate of 1.0 ° C / min to 160 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starting from 160 ° C at a rate of 1.2 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.2 torr/min from normal pressure.
  • the reaction is continued for 1.2 h under this condition.
  • the absolute pressure of the reaction system is lowered from 92.0 torr at a rate of 1.2 torr/min.
  • the reaction was continued for 1.5 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the obtained polyglycolic acid had a weight average molecular weight M w of 5.5 ⁇ 10 3 and a yield of 100%.
  • oligo-glycolic acid prepared in the above step 100.0 g of guanine and 70.0 g of thioglycolic acid were added, and the absolute pressure of the reaction system was reduced from 4.0 torr at a rate of 1.2 torr/min under normal pressure to maintain the pressure of the system.
  • the temperature of the reaction system was raised from room temperature to 255 ° C at a rate of 12 ° C / min, catalytic depolymerization reaction for 25 min, maintaining the system pressure unchanged, and the temperature of the reaction system was increased from 255 ° C to 1.2 ° C / min to 272 ° C.
  • the catalytic depolymerization reaction was carried out for 25 min, and the pressure of the system was kept constant.
  • the temperature of the reaction system was raised from 272 ° C to 282 ° C at a rate of 1.2 ° C / min, and the catalytic depolymerization reaction was carried out for 65 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water until neutral, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 98.6%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 105 ° C at a rate of 1.2 ° C / min from room temperature, 1.2 h at normal pressure, 1.2 ° C from 105 ° C /
  • the rate of min rises to 145 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starts from 145 ° C at a rate of 1.0 ° C / min to 160 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starting from 160 ° C at a rate of 1.2 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.2 torr/min from normal pressure.
  • the reaction is continued for 1.2 h under this condition.
  • the absolute pressure of the reaction system is lowered from 92.0 torr at a rate of 1.2 torr/min.
  • the reaction was continued for 1.5 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the obtained polyglycolic acid had a weight average molecular weight M w of 5.5 ⁇ 10 3 and a yield of 100%.
  • oligo-glycolic acid prepared in the above step 50.0 g of guanine and 50.0 g of creatine were added to the reaction system.
  • the absolute pressure is reduced from 4.0 torr at a rate of 1.2 torr/min at normal pressure to maintain the system pressure.
  • the temperature of the reaction system is raised from room temperature to 12 ° C / min to 255 ° C, catalytic depolymerization reaction for 25 min, maintaining The pressure of the system is constant.
  • the temperature of the reaction system is raised from 255 °C to 272 °C at a rate of 1.2 °C/min.
  • the catalytic depolymerization reaction is carried out for 25 min to maintain the system pressure.
  • the temperature of the reaction system starts at 272 °C and is 1.2 ° C/min.
  • the rate was raised to 282 ° C and the catalytic depolymerization reaction was carried out for 65 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water until neutral, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 98.3%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 105 ° C at a rate of 1.2 ° C / min from room temperature, 1.2 h at normal pressure, 1.2 ° C from 105 ° C /
  • the rate of min rises to 145 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starts from 145 ° C at a rate of 1.0 ° C / min to 160 ° C
  • the atmospheric pressure dehydration reaction for 1.2 h starting from 160 ° C at a rate of 1.2 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.2 torr/min from normal pressure.
  • the reaction is continued for 1.2 h under this condition.
  • the absolute pressure of the reaction system is lowered from 92.0 torr at a rate of 1.2 torr/min.
  • the reaction was continued for 1.5 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the obtained polyglycolic acid had a weight average molecular weight M w of 5.5 ⁇ 10 3 and a yield of 100%.
  • oligo-glycolic acid prepared in the above step 70.0 g of guanine and 100.0 g of creatine phosphate were added, and the absolute pressure of the reaction system was reduced from normal pressure to 4.0 torr at a rate of 1.2 torr/min to maintain the pressure of the system.
  • the temperature of the reaction system was raised from room temperature to 255 ° C at a rate of 12 ° C / min, catalytic depolymerization reaction for 25 min, maintaining the system pressure unchanged, and the temperature of the reaction system was increased from 255 ° C to 1.2 ° C / min to 272 ° C.
  • the catalytic depolymerization reaction was carried out for 25 min, and the pressure of the system was kept constant.
  • the temperature of the reaction system was raised from 272 ° C to 282 ° C at a rate of 1.2 ° C / min, and the catalytic depolymerization reaction was carried out for 65 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water to neutrality, and finally vacuum dried at 20 ° C for 24 hours, the yield was 98.4%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 110 ° C at a rate of 1.5 ° C / min from room temperature, 1.5 h at a normal pressure dehydration reaction, and 1.5 ° C from 110 ° C.
  • the rate of min is raised to 150 ° C
  • the atmospheric pressure dehydration reaction is 1.5 h, starting from 150 ° C at a rate of 1.5 ° C / min to 165 ° C
  • the atmospheric pressure dehydration reaction for 1.5 h starting from 165 ° C at a rate of 1.5 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.5 torr/min from normal pressure.
  • the reaction is continued for 1.5 h under this condition.
  • the absolute pressure of the reaction system is lowered from 95.0 torr at a rate of 1.5 torr/min.
  • the reaction was continued for 2.0 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the weight average molecular weight of the obtained oligomeric glycolic acid was M w 6.0 ⁇ 10 3 , and the yield was 100%.
  • oligo-glycolic acid prepared in the above step 150.0 g of benzimidazole and 75.0 g of thioglycolic acid were added, and the absolute pressure of the reaction system was reduced from normal pressure to 1.5 torr at a rate of 1.5 torr/min to maintain the system pressure.
  • the reaction system temperature was raised from room temperature to 260 ° C at a rate of 15 ° C / min, catalytic depolymerization reaction for 30 min, maintaining the system pressure unchanged, the reaction system temperature was increased from 260 ° C at a rate of 1.5 ° C / min to 275 °C, catalytic depolymerization reaction for 30min, maintaining the system pressure unchanged, the reaction system temperature from 275 ° C at 1.5 ° C / min rate to 285 ° C, catalytic depolymerization reaction 70min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water to neutrality, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 98.1%, and the purity was 99.9%.
  • the temperature of the reactant was first raised to 110 ° C at a rate of 1.5 ° C / min from room temperature, 1.5 h at a normal pressure dehydration reaction, and 1.5 ° C from 110 ° C.
  • the rate of min is raised to 150 ° C
  • the atmospheric pressure dehydration reaction is 1.5 h, starting from 150 ° C at a rate of 1.5 ° C / min to 165 ° C
  • the atmospheric pressure dehydration reaction for 1.5 h starting from 165 ° C at a rate of 1.5 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.5 torr/min from normal pressure.
  • the reaction is continued for 1.5 h under this condition.
  • the absolute pressure of the reaction system is lowered from 95.0 torr at a rate of 1.5 torr/min.
  • the reaction was continued for 2.0 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the weight average molecular weight of the obtained oligomeric glycolic acid was M w 6.0 ⁇ 10 3 , and the yield was 100%.
  • the temperature of the reaction system was raised from 275 ° C to 285 ° C at a rate of 1.5 ° C / min, and the catalytic depolymerization reaction was carried out for 70 min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water until neutral, and finally dried under vacuum at 20 ° C for 24 hours, with a yield of 99.0% and a purity of 99.9%.
  • the temperature of the reactant was first raised to 110 ° C at a rate of 1.5 ° C / min from room temperature, 1.5 h at a normal pressure dehydration reaction, and 1.5 ° C from 110 ° C.
  • the rate of min is raised to 150 ° C
  • the atmospheric pressure dehydration reaction is 1.5 h, starting from 150 ° C at a rate of 1.5 ° C / min to 165 ° C
  • the atmospheric pressure dehydration reaction for 1.5 h starting from 165 ° C at a rate of 1.5 ° C / min
  • the absolute pressure is reduced from 9 torror at a rate of 1.5 torr/min from normal pressure.
  • the reaction is continued for 1.5 h under this condition.
  • the absolute pressure of the reaction system is lowered from 95.0 torr at a rate of 1.5 torr/min.
  • the reaction was continued for 2.0 h under the above conditions, and after the end of the dehydration oligomerization stage controlled under the above conditions, the weight average molecular weight of the obtained oligomeric glycolic acid was M w 6.0 ⁇ 10 3 , and the yield was 100%.
  • oligo-glycolic acid prepared in the above step 75.0 g of benzimidazole and 150.0 g of creatine phosphate were added, and the absolute pressure of the reaction system was reduced from normal pressure to 1.5 torr at a rate of 1.5 torr/min to maintain the system pressure.
  • the reaction system temperature was raised from room temperature to 260 ° C at a rate of 15 ° C / min, catalytic depolymerization reaction for 30 min, maintaining the system pressure unchanged, the reaction system temperature was increased from 260 ° C at a rate of 1.5 ° C / min to 275 °C, catalytic depolymerization reaction for 30min, maintaining the system pressure unchanged, the reaction system temperature from 275 ° C at 1.5 ° C / min rate to 285 ° C, catalytic depolymerization reaction 70min.
  • the distilled white or yellowish crude glycolide was collected.
  • the collected crude glycolide was washed with an alkali solution having a mass concentration of 0.1%, washed with deionized water to neutrality, and finally dried under vacuum at 20 ° C for 24 hours, the yield was 99.2%, and the purity was 99.9%.

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Abstract

一种合成乙交酯的方法，采用无毒的环状有机胍化合物与无毒的线性有机胍化合物组成二元复合催化体系，以质量含量70％的乙醇酸水溶液为原料，通过反应性减压蒸馏法实现高纯度(≥99.9％)乙交酯的高产率(≥98.0％)合成。本发明的优点为：所采用的二元复合催化体系为无毒、无金属、无细胞毒性的有机胍化合物，催化效率高、用量少；所合成的乙交酯产率高、纯度高；采用无溶剂、封闭循环工艺，无三废排放，工艺流程简化，易于工业化实施。

Description

一种合成乙交酯的方法 技术领域
本发明属于生物降解材料聚乙交酯(即“聚乙醇酸”)及其共聚物聚合用单体的合成领域，具体为一种以二元有机胍化合物为复合催化剂合成乙交酯的方法。
背景技术
乙交酯的合成通常采用“脱水寡聚—催化解聚”两步法工艺路线，即乙醇酸首先经过脱水寡聚反应生成寡聚物，然后通过解聚反应制备乙交酯。为了降低反应能耗，常采用高沸点溶剂中进行催化解聚反应，但高沸点极性有机溶剂回收工艺复杂，回收率难以达到100％，产品乙交酯容易被溶剂污染的缺点。
乙交酯的合成催化剂主要采用金属盐或金属氧化物如SnOct2、SnCl2、氧化锑Sb2O3等。由于重金属催化剂用量大(0.1-0.7％)，所合成的乙交酯粗产品需要经过多次溶剂中重结晶的方法提纯，不仅工艺复杂而且高纯度乙交酯产率低。且SnOct2、SnCl2、Sb2O3等催化剂均有明显细胞毒性，合成的乙交酯作为单体用于生物医用材料合成会造成生物安全性隐患。
发明内容
本发明的目的是解决现有乙交酯合成工艺中存在有毒金属催化剂、高沸点极性溶剂容易污染产品等问题，提供一种全绿色合成乙交酯的方法。
本发明提供的工艺方法，采用无毒的环状有机胍化合物和无毒的线性有机胍化合物组成的二元复合催化体系，以质量含量70％的乙醇酸水溶液为原料，通过反应性减压蒸馏法实现高纯度(≥99.9％)乙交酯的高产率(≥98.0％)合成。
所述的二元复合催化体系具体包括：
(1)无毒的环状有机胍化合物为双环胍(1,5,7-三氮杂双环[5.5.0]癸-5-烯)、鸟嘌呤或苯并咪唑之一；
(2)无毒的线性有机胍化合物为胍基乙酸、肌酸或磷酸肌酸之一，
无毒的环状有机胍化合物和无毒的线性有机胍化合物的用量均为乙醇酸质量的0.05％-0.10％。
本发明工艺方法具体步骤如下：
第1步，脱水寡聚阶段，采用梯度升温和梯度减压的工艺方法，以防止原料损 失、提高产率：
a.将原料乙醇酸加入反应釜后首先将反应物温度由室温下开始按1.0-1.5℃/min的速率升至100-110℃，常压脱水反应1.0-2.0h，
b.由100-110℃开始按1.0-1.5℃/min的速率升至140-150℃，常压脱水反应1.0-2.0h，
c.由140-150℃开始按1.0-1.5℃/min的速率升至155-165℃，常压脱水反应1.0-2.0h，
d.由155-165℃开始按1.0-1.5℃/min的速率升至200-210℃，同时绝对压力由常压按1.0-1.5torr/min的速率降至90.0-95.0torr，在此条件继续反应1.0-1.5h，
e.维持此温度，将反应体系绝对压力由90.0-95.0torr按1.0-1.5torr/min的速率降至10.0-20.0torr，在此条件继续反应1.0-2.0h，
按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.0-6.0×103，产率100％；
第2步，催化解聚阶段，采用先将反应体系压力降至所控制范围，然后采用梯度升温反应的工艺方法：
a.在第1步中所制备的寡聚乙醇酸中加入所述的二元复合催化体系，
b.将反应体系绝对压力由常压按1.0-1.5torr/min的速率降至3.0-5.0torr，
c.维持体系压力不变，将反应体系温度由室温下开始按10-15℃/min的速率升至250-260℃，催化解聚反应20-30min，
d.维持体系压力不变，将反应体系温度由250-260℃开始按1.0-1.5℃/min的速率升至270-275℃，催化解聚反应20-30min，
e.维持体系压力不变，将反应体系温度由270-275℃开始按1.0-1.5℃/min的速率升至280-285℃，催化解聚反应60-70min，
收集蒸出的白色或微黄色的粗乙交酯。
第3步，纯化阶段，将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，得到的乙交酯产品产率≥98.0％、纯度≥99.9％。
本发明的优点和有益效果：
1.所采用的二元复合催化体系为无毒、无金属、无细胞毒性的有机胍化合物，催化效率高、用量少；
2.所合成的乙交酯产率高(≥98.0％)、纯度高(≥99.9％)，不含任何金属、溶剂；
3.采用无溶剂、封闭循环工艺，无三废排放，工艺流程简化，易于工业化实施。
具体实施方式
实施例1
将原料70％乙醇酸水溶液50kg加入反应釜中后，首先将反应物温度由室温下开始按1.0℃/min的速率升至100℃，常压脱水反应1.0h，由100℃开始按1.0℃/min的速率升至140℃，常压脱水反应1.0h，由140℃开始按1.0℃/min的速率升至155℃，常压脱水反应1.0h，由155℃开始按1.0℃/min的速率升至200℃，同时绝对压力由常压按1.0torr/min的速率降至90.0torr，在此条件继续反应1.0h，维持此温度，将反应体系绝对压力由90.0torr按1.0torr/min的速率降至10.0torr，在此条件继续反应1.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入双环胍25.0g、胍基乙酸25.0g，将反应体系绝对压力由常压按1.0torr/min的速率降至3.0torr，维持体系压力不变，将反应体系温度由室温下开始按10℃/min的速率升至250℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由250℃开始按1.0℃/min的速率升至270℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由270℃开始按1.0℃/min的速率升至280℃，催化解聚反应60min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.5％、纯度99.9％。
对比例1
工艺方法与实施例1相同，区别在于催化解聚阶段仅加入双环胍25.0g，所得乙交酯产率41.4％、纯度82.5％。
对比例2
工艺方法与实施例1相同，区别在于催化解聚阶段仅加入胍基乙酸25.0g，所得乙交酯产率34.5％、纯度85.3％。
实施例2
将原料70％乙醇酸水溶液50kg加入反应釜中后，首先将反应物温度由室温下开 始按1.0℃/min的速率升至100℃，常压脱水反应1.0h，由100℃开始按1.0℃/min的速率升至140℃，常压脱水反应1.0h，由140℃开始按1.0℃/min的速率升至155℃，常压脱水反应1.0h，由155℃开始按1.0℃/min的速率升至200℃，同时绝对压力由常压按1.0torr/min的速率降至90.0torr，在此条件继续反应1.0h，维持此温度，将反应体系绝对压力由90.0torr按1.0torr/min的速率降至10.0torr，在此条件继续反应1.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入双环胍50.0g、肌酸35.0g，将反应体系绝对压力由常压按1.0torr/min的速率降至3.0torr，维持体系压力不变，将反应体系温度由室温下开始按10℃/min的速率升至250℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由250℃开始按1.0℃/min的速率升至270℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由270℃开始按1.0℃/min的速率升至280℃，催化解聚反应60min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.2％、纯度99.9％。
实施例3
将原料70％乙醇酸水溶液50kg加入反应釜中后，首先将反应物温度由室温下开始按1.0℃/min的速率升至100℃，常压脱水反应1.0h，由100℃开始按1.0℃/min的速率升至140℃，常压脱水反应1.0h，由140℃开始按1.0℃/min的速率升至155℃，常压脱水反应1.0h，由155℃开始按1.0℃/min的速率升至200℃，同时绝对压力由常压按1.0torr/min的速率降至90.0torr，在此条件继续反应1.0h，维持此温度，将反应体系绝对压力由90.0torr按1.0torr/min的速率降至10.0torr，在此条件继续反应1.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入双环胍35.0g、磷酸肌酸50.0g，将反应体系绝对压力由常压按1.0torr/min的速率降至3.0torr，维持体系压力不变，将反应体系温度由室温下开始按10℃/min的速率升至250℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由250℃开始按1.0℃/min的速率升至270℃，催化解聚反应20min，维持体系压力不变，将反应体系温度由270℃开始按1.0℃/min的速率升至280℃，催化解聚反应60min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中 性，最后在20℃下真空干燥24h，产率98.7％、纯度99.9％。
实施例4
将原料70％乙醇酸水溶液100kg加入反应釜中后，首先将反应物温度由室温下开始按1.2℃/min的速率升至105℃，常压脱水反应1.2h，由105℃开始按1.2℃/min的速率升至145℃，常压脱水反应1.2h，由145℃开始按1.0℃/min的速率升至160℃，常压脱水反应1.2h，由160℃开始按1.2℃/min的速率升至205℃，同时绝对压力由常压按1.2torr/min的速率降至92.0torr，在此条件继续反应1.2h，维持此温度，将反应体系绝对压力由92.0torr按1.2torr/min的速率降至15.0torr，在此条件继续反应1.5h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.5×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入鸟嘌呤100.0g、胍基乙酸70.0g，将反应体系绝对压力由常压按1.2torr/min的速率降至4.0torr，维持体系压力不变，将反应体系温度由室温下开始按12℃/min的速率升至255℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由255℃开始按1.2℃/min的速率升至272℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由272℃开始按1.2℃/min的速率升至282℃，催化解聚反应65min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.6％、纯度99.9％。
实施例5
将原料70％乙醇酸水溶液100kg加入反应釜中后，首先将反应物温度由室温下开始按1.2℃/min的速率升至105℃，常压脱水反应1.2h，由105℃开始按1.2℃/min的速率升至145℃，常压脱水反应1.2h，由145℃开始按1.0℃/min的速率升至160℃，常压脱水反应1.2h，由160℃开始按1.2℃/min的速率升至205℃，同时绝对压力由常压按1.2torr/min的速率降至92.0torr，在此条件继续反应1.2h，维持此温度，将反应体系绝对压力由92.0torr按1.2torr/min的速率降至15.0torr，在此条件继续反应1.5h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.5×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入鸟嘌呤50.0g、肌酸50.0g，将反应体系 绝对压力由常压按1.2torr/min的速率降至4.0torr，维持体系压力不变，将反应体系温度由室温下开始按12℃/min的速率升至255℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由255℃开始按1.2℃/min的速率升至272℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由272℃开始按1.2℃/min的速率升至282℃，催化解聚反应65min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.3％、纯度99.9％。
实施例6
将原料70％乙醇酸水溶液100kg加入反应釜中后，首先将反应物温度由室温下开始按1.2℃/min的速率升至105℃，常压脱水反应1.2h，由105℃开始按1.2℃/min的速率升至145℃，常压脱水反应1.2h，由145℃开始按1.0℃/min的速率升至160℃，常压脱水反应1.2h，由160℃开始按1.2℃/min的速率升至205℃，同时绝对压力由常压按1.2torr/min的速率降至92.0torr，在此条件继续反应1.2h，维持此温度，将反应体系绝对压力由92.0torr按1.2torr/min的速率降至15.0torr，在此条件继续反应1.5h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 5.5×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入鸟嘌呤70.0g、磷酸肌酸100.0g，将反应体系绝对压力由常压按1.2torr/min的速率降至4.0torr，维持体系压力不变，将反应体系温度由室温下开始按12℃/min的速率升至255℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由255℃开始按1.2℃/min的速率升至272℃，催化解聚反应25min，维持体系压力不变，将反应体系温度由272℃开始按1.2℃/min的速率升至282℃，催化解聚反应65min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.4％、纯度99.9％。
实施例7
将原料70％乙醇酸水溶液150kg加入反应釜中后，首先将反应物温度由室温下开始按1.5℃/min的速率升至110℃，常压脱水反应1.5h，由110℃开始按1.5℃/min的速率升至150℃，常压脱水反应1.5h，由150℃开始按1.5℃/min的速率升至165℃，常压脱 水反应1.5h，由165℃开始按1.5℃/min的速率升至210℃，同时绝对压力由常压按1.5torr/min的速率降至95.0torr，在此条件继续反应1.5h，维持此温度，将反应体系绝对压力由95.0torr按1.5torr/min的速率降至20.0torr，在此条件继续反应2.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 6.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入苯并咪唑150.0g、胍基乙酸75.0g，将反应体系绝对压力由常压按1.5torr/min的速率降至5.0torr，维持体系压力不变，将反应体系温度由室温下开始按15℃/min的速率升至260℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由260℃开始按1.5℃/min的速率升至275℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由275℃开始按1.5℃/min的速率升至285℃，催化解聚反应70min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率98.1％、纯度99.9％。
实施例8
将原料70％乙醇酸水溶液150kg加入反应釜中后，首先将反应物温度由室温下开始按1.5℃/min的速率升至110℃，常压脱水反应1.5h，由110℃开始按1.5℃/min的速率升至150℃，常压脱水反应1.5h，由150℃开始按1.5℃/min的速率升至165℃，常压脱水反应1.5h，由165℃开始按1.5℃/min的速率升至210℃，同时绝对压力由常压按1.5torr/min的速率降至95.0torr，在此条件继续反应1.5h，维持此温度，将反应体系绝对压力由95.0torr按1.5torr/min的速率降至20.0torr，在此条件继续反应2.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 6.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入苯并咪唑105.0g、肌酸105.0g，将反应体系绝对压力由常压按1.5torr/min的速率降至5.0torr，维持体系压力不变，将反应体系温度由室温下开始按15℃/min的速率升至260℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由260℃开始按1.5℃/min的速率升至275℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由275℃开始按1.5℃/min的速率升至285℃，催化解聚反应70min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率99.0％、纯度99.9％。
实施例9
将原料70％乙醇酸水溶液150kg加入反应釜中后，首先将反应物温度由室温下开始按1.5℃/min的速率升至110℃，常压脱水反应1.5h，由110℃开始按1.5℃/min的速率升至150℃，常压脱水反应1.5h，由150℃开始按1.5℃/min的速率升至165℃，常压脱水反应1.5h，由165℃开始按1.5℃/min的速率升至210℃，同时绝对压力由常压按1.5torr/min的速率降至95.0torr，在此条件继续反应1.5h，维持此温度，将反应体系绝对压力由95.0torr按1.5torr/min的速率降至20.0torr，在此条件继续反应2.0h，按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw 6.0×103，产率100％。
在上述步骤所制备的寡聚乙醇酸中加入苯并咪唑75.0g、磷酸肌酸150.0g，将反应体系绝对压力由常压按1.5torr/min的速率降至5.0torr，维持体系压力不变，将反应体系温度由室温下开始按15℃/min的速率升至260℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由260℃开始按1.5℃/min的速率升至275℃，催化解聚反应30min，维持体系压力不变，将反应体系温度由275℃开始按1.5℃/min的速率升至285℃，催化解聚反应70min。收集蒸出的白色或微黄色的粗乙交酯。
将收集到的粗乙交酯用质量浓度为0.1％的碱溶液洗涤，再用去离子水洗涤至中性，最后在20℃下真空干燥24h，产率99.2％、纯度99.9％。

Claims (2)

  1. 一种合成乙交酯的方法，其特征在于，包括如下步骤：
    第1步，脱水寡聚阶段：
    a.将质量含量70％的乙醇酸水溶液加入反应釜后将反应物温度由室温下开始按1.0-1.5℃/min的速率升至100-110℃，常压脱水反应1.0-2.0h，
    b.由100-110℃开始按1.0-1.5℃/min的速率升至140-150℃，常压脱水反应1.0-2.0h，
    c.由140-150℃开始按1.0-1.5℃/min的速率升至155-165℃，常压脱水反应1.0-2.0h，
    d.由155-165℃开始按1.0-1.5℃/min的速率升至200-210℃，同时绝对压力由常压按1.0-1.5torr/min的速率降至90.0-95.0torr，在此条件继续反应1.0-1.5h，
    e.维持此温度，将反应体系绝对压力由90.0-95.0torr按1.0-1.5torr/min的速率降至10.0-20.0torr，在此条件继续反应1.0-2.0h，
    按上述条件控制的脱水寡聚阶段反应结束后，所得到寡聚乙醇酸的重均分子量Mw5.0-6.0×103，产率100％；
    第2步，催化解聚阶段：
    a.在第1步中所制备的寡聚乙醇酸中加入二元复合催化体系，
    b.将反应体系绝对压力由常压按1.0-1.5torr/min的速率降至3.0-5.0torr，
    c.维持体系压力不变，将反应体系温度由室温下开始按10-15℃/min的速率升至250-260℃，催化解聚反应20-30min，
    d.维持体系压力不变，将反应体系温度由250-260℃开始按1.0-1.5℃/min的速率升至270-275℃，催化解聚反应20-30min，
    e.维持体系压力不变，将反应体系温度由270-275℃开始按1.0-1.5℃/min的速率升至280-285℃，催化解聚反应60-70min，得到白色或微黄色的粗乙交酯，纯度≥99.9％，产率≥98.0％。
  2. 根据权利要求1所述的方法，其特征在于，所述二元复合催化体系由无毒的环状有机胍化合物与无毒的线性有机胍化合物组成，无毒的环状有机胍化合物为双环胍(1,5,7-三氮杂双环[5.5.0]癸-5-烯)、鸟嘌呤或苯并咪唑之一，无毒的线性有机胍化合物为胍基乙酸、肌酸或磷酸肌酸之一，无毒的环状有机胍化合物与无毒的线性有 机胍化合物的用量均为乙醇酸质量的0.05％-0.10％。
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CN106831700B (zh) * 2017-03-28 2019-05-24 南京大学 一种全绿色封闭循环工艺生产光学纯l-/d-丙交酯的方法
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CN112250661B (zh) * 2020-11-18 2021-11-02 南京大学 一种催化合成丙交酯的方法
CN115707697A (zh) * 2021-08-20 2023-02-21 中国石油化工股份有限公司 一种粗乙交酯的提纯方法及所得乙交酯
CN114478472B (zh) * 2022-02-23 2024-02-13 中国科学院长春应用化学研究所 一种乙交酯的制备方法
CN114773310A (zh) * 2022-04-20 2022-07-22 长兴电子（苏州）有限公司 一种复合催化法合成光学纯丙交酯的方法
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