CN102875779A - Process method for synthesizing medical biodegradable polylactic acid by performing polycondensation on lactic acid through catalysis of 1,5,7-triazabicyclo[4.4.0]decane-5-ene (TBD) - Google Patents

Abstract

The invention discloses a method for the direct condensation polymerization of lactic acid catalyzed by bicyclic guanidine to synthesize medical biodegradable polylactic acid. The present invention uses bicyclic guanidine (TBD) as a catalyst, industrial-grade lactic acid aqueous solution with a mass content of 90% as a monomer, and adopts solvent-free (bulk) and second-stage condensation polymerization to obtain a product polylactic acid with high biological safety. The invention avoids the use of cytotoxic tin catalysts, and the catalysts used are biocompatible and biosafe; the synthesized polylactic acid does not contain any metals and other toxic components, and is suitable for medical applications; green catalysts and Green process (does not use any reagents, no toxic products are produced), and synthesizes green biodegradable polylactic acid; the polymerization reaction is convenient and easy, the cost of raw materials is low, and it is easy for industrial production; the molecular weight distribution of the synthesized product is narrow, and the molecular weight is 1.0×10 ⁴ ~4.0 It can be regulated within the range of ×10 ⁴ .

Description

Process method for synthesis of medical biodegradable polylactic acid by bicyclic guanidine catalyzed polycondensation of lactic acid

Technical field:

The invention belongs to the technical field of drug degradable materials, and relates to a process method for synthesizing polylactic acid with high biological safety by using bicyclic guanidine to catalyze lactic acid.

Background technique:

In recent years, with the rapid development of medicine and biomedicine, the demand for degradable materials that can be applied to controlled release and targeted drug carriers, hard tissue repair materials, and bioactive scaffold materials in biological tissue engineering has increased dramatically. Biodegradable polylactic acid has good biocompatibility. As a drug carrier, it can improve drug efficacy, reduce dosage and drug side effects, etc., making it have many important applications in pharmaceutical science and biomedicine. At present, the production of commercialized polylactic acid is mainly synthesized by the ring-opening polycondensation method of stannous octoate and the direct polycondensation method of lactic acid catalyzed by stannous chloride. However, when used as a drug carrier, it is required that the polymer does not contain any toxic metals and other toxic components. The above two methods can meet the molecular weight (1.0×10 ⁴ ～4.0×10 ⁴ ) required by the drug carrier, but the heavy metal tin salt catalyst used is difficult to remove from the polymer. Studies have shown that stannous octoate and stannous chloride With cytotoxicity, the safety of engineering materials synthesized with tin-based catalysts has aroused widespread concern, limiting their application in the field of medicine. Therefore, the development of high-efficiency, non-toxic catalysts for the synthesis of polylactic acid is the focus of current research.

Invention content:

The purpose of the present invention is to solve the problem of potential safety hazards of polylactic acid synthesized by tin-based catalysts when used as human drug carriers, and to provide a non-toxic, metal-free bicyclic guanidine compound as a catalyst to directly catalyze the polymerization of lactic acid to generate a highly biological A safe medical biodegradable polylactic acid process.

For the first time, the present invention has developed a new process for synthesizing polylactic acid with high biological safety by bulk condensation polymerization using non-toxic, metal-free organic guanidine compound (bicyclic guanidine) as catalyst, and 90% lactic acid aqueous solution as monomer. .

The nontoxic, metal-free organic guanidine compound used in the present invention——bicyclic guanidine, its chemical name is: 1,5,7-triazabicyclo[4.4.0]dec-5-ene (1,5,7 -Triazabicyclo[4.4.0]dec-5-ene, English abbreviation: TBD), its molecular structure is as follows:

The process method of bicyclic guanidine catalyzed direct polycondensation of lactic acid to synthesize highly biosafety and degradable polylactic acid provided by the present invention is to use organic guanidine compound (bicyclic guanidine) as a catalyst, and the mass content is 90% lactic acid aqueous solution as a monomer. Polymerization and synthesis of polylactic acid with high biological safety, including:

synthetic route:

Synthetic steps:

1. Synthesis of oligomeric lactic acid OLLA

Using industrial-grade lactic acid aqueous solution with a mass content of 90% as a monomer, first synthesize oligomeric lactic acid OLLA with a number-average molecular weight Mn of 400-600. Heat to 100~120°C at 200 Torr, dehydrate for 1 hour; depressurize the reactor to 100 Torr and continue the reaction at 130~150°C for 1 hour; then reduce the pressure of the reactor to 30 Torr and continue the reaction at 150~170°C for 1 hour.

2. Synthesis of polylactic acid PLLA

Using the oligomeric lactic acid OLLA synthesized in the first step as a raw material, using commercial bicyclic guanidine as a catalyst, controlling the mass ratio of bicyclic guanidine to lactic acid at 1:300~1:6500, performing bulk melt polycondensation under reduced pressure and a certain temperature to synthesize High biosafety pharmaceutical polylactic acid was obtained. Synthesis conditions: add catalyst bicyclic guanidine to the reactor, depressurize the reactor to 10Torr, raise the temperature to 180~230℃ for 10~20h, and obtain polylactic acid PLLA.

The molecular weight of the polylactic acid synthesized by the method of the invention is 1.0×10 ⁴ to 4.0×10 ⁴ , and the molecular weight distribution index (PDI) is 1.7-2.0.

Advantages and beneficial effects of the present invention:

1. The catalyst used has high biocompatibility and biosafety;

2. The synthesized polylactic acid does not contain any metals and other toxic components, so it is suitable for the carrier of controlled release and targeted drugs;

3. Synthesize green (highly biologically safe) biodegradable polylactic acid by using green catalysts and green processes (no solvents are used, no toxic products are produced);

4. The molecular weight distribution of the synthesized product is narrow, and the molecular weight can be controlled within the range of 1.0×10 ⁴ ~4.0×10 ⁴ .

5. The reaction time is short (10~20h);

6. The polymerization process is simple, the cost of raw materials is low, and it is easy to implement industrially.

Detailed ways:

Example 1

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heating to 100°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr, and the reaction was continued at 130° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 160° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 240 mg of catalyst bicyclic guanidine to the reactor, depressurize the reactor to 10 Torr, and raise the temperature to 180° C. for 10 h. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 75.6%, polymer molecular weight 1.5×10 ⁴ , PDI 1.87.

Example 2

80 g of L-lactic acid (mass content 90%) was charged into the reaction kettle, and the vacuum pumping and argon filling operations were repeated three times. Heated to 110°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 130° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 150° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 240 mg of catalyst bicyclic guanidine to the reactor, depressurize the reactor to 10 Torr, and raise the temperature to 190° C. for 16 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 73.1%, polymer molecular weight 2.3×10 ⁴ , PDI 1.70.

Example 3

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heated to 120°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 130° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 150° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 120 mg of catalyst bicyclic guanidine to the reactor, depressurize the reactor to 10 Torr, and raise the temperature to 200° C. for 20 h. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 70.1%, polymer molecular weight 3.6×10 ⁴ , PDI 1.90.

Example 4

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heated to 110°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 140° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 150° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 120 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 210° C. for 13 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 69.2%, polymer molecular weight 4.0×10 ⁴ , PDI 1.85.

Example 5

80 g of L-lactic acid (mass content 90%) was charged into the reaction kettle, and the vacuum pumping and argon filling operations were repeated three times. Heating to 100°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 150° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 150° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 72 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 220° C. for 10 h. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 67.4%, polymer molecular weight 2.9×10 ⁴ , PDI 2.00.

Example 6

80 g of L-lactic acid (mass content 90%) was charged into the reaction kettle, and the vacuum pumping and argon filling operations were repeated three times. Heating to 120°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 140° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 160° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 136 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 220° C. for 15 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 48.5%, polymer molecular weight 3.4×10 ⁴ , PDI 1.85.

Example 7

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heating to 100°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 140° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 170° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 72 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 230° C. for 16 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 66.3%, polymer molecular weight 3.9×10 ⁴ , PDI 1.78.

Example 8

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heated to 110°C at 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 150° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 160° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 36 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 200° C. for 15 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 74.6%, polymer molecular weight 2.4×10 ⁴ , PDI 1.92.

Example 9

80 g of L-lactic acid (mass content 90%) was charged into the reaction kettle, and the vacuum pumping and argon filling operations were repeated three times. Heating to 120°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 150° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 150° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 36 mg of catalyst bicyclic guanidine to the reactor, reduce the pressure of the reactor to 10 Torr, and raise the temperature to 200° C. for 16 hours. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 71.3%, polymer molecular weight 3.2×10 ⁴ , PDI 1.75.

Example 10

80g of L-lactic acid (mass content 90%) was charged into the reactor, and the vacuuming-argon filling operation was repeated three times. Heated to 120°C under 200 Torr, dehydration reaction for 1h. Then the reactor was depressurized to 100 Torr and the reaction was continued at 150° C. for 1 h. Then the reactor was depressurized to 30 Torr and the reaction was continued at 170° C. for 1 h to obtain oligomeric lactic acid OLLA.

Add 11.1 mg of catalyst bicyclic guanidine to the reactor, depressurize the reactor to 10 Torr, and raise the temperature to 210° C. for 20 h. After stopping the reaction, cool the reactor to room temperature, dissolve the polymer with acetone, then pour it into ethanol at 0°C, filter under reduced pressure, and dry the solid at 50°C under vacuum for 36 hours to obtain a white solid, which is highly biosafety Pharmaceutical polylactic acid, yield 68.4%, polymer molecular weight 4.0×10 ⁴ , PDI 1.91.

Claims (2)

1. the method for a bicyclo guanidine catalysis acid through direct polycondensation by lactic synthesis of medical biodegradable poly(lactic acid), it is characterized in that the method utilizes the organic guanidine catalyst of biological safety, lactic acid is monomer, synthesizes through bulk polymerization to have height biological safety poly(lactic acid), specifically comprises:

Synthetic route:

Synthesis step:

1st, lactic acid oligomer OLLA's is synthetic

Take the technical grade mass content as 90% lactic acid aqueous solution as monomer, the lactic acid oligomer OLLA of composite number average molecular weight Mn 400 ~ 600 at first, synthesis condition: in reactor, add lactic acid, repeat to vacuumize applying argon gas operation three times after; Be to be heated to 100 ~ 120 ℃ under the 200Torr in vacuum, dehydration 1h; Reactor is decompressed to 100Torr continues reaction 1h at 130 ~ 150 ℃; Then reactor is decompressed to 30Torr and continues reaction 1h at 150 ~ 170 ℃;

2nd, poly(lactic acid) PLLA's is synthetic

Go on foot synthetic lactic acid oligomer OLLA as raw material, take the commercialization bicyclo guanidine as catalyzer take the 1st, control bicyclo guanidine and lactic acid mass ratio are 1:300 ~ 1:6500, under decompression and certain temperature, carry out the body melt phase polycondensation, the synthetic medicinal poly(lactic acid) of height biological safety that obtains, synthesis condition: in reactor, add the catalyzer bicyclo guanidine, reactor is decompressed to 10Torr, is warming up to 180 ~ 230 ℃ of reaction 10 ~ 20h, obtain poly(lactic acid) PLLA.

2. method according to claim 1, the polylactic acid molecule amount that it is characterized in that adopting the method for organic guanidine catalyzing and condensing polymerization to be synthesized in 10-20h is 1.0 * 10 ⁴~ 4.0 * 10 ⁴, molecular weight distributing index (PDI) is 1.7 ~ 2.0.