Abstract
The present invention provides a method for the synthesis of metal-free residual molecular weight controllable poly(lactic acid). Under the protection of inert gas, the reaction solvent is added to the propanediol ester to form a propanediol ester solution with a molar concentration of 0.5~1.5 M. The initiator and catalyst are added sequentially in the ratio of 6~350:1:0.06~0.35 of propanediol ester, initiator and catalyst, and the polymerization reaction is carried out for 0.25~2h; the initiator is added in the molar ratio of 1:1~5 of initiator and terminator, and the reaction is terminated for 10~20min. The reaction was terminated by adding the terminating agent for 10-20 min. Prepare methanol according to the volume ratio of reaction solution to methanol of 1:10～20, drop the reaction solution into methanol, form polylactic acid precipitate precipitation, filter, methanol washing 2～3 times, vacuum drying at 20～40℃ for 24～48h to get the product. The synthesis method can be carried out at room temperature and atmospheric pressure, the product yield is high, the process is simple, no heating and decompression conditions, easy to operate, can effectively control the molecular weight of the product PLA, the product is free of metal residues can be used as medical materials.

Description
Method for the synthesis of metal-free residual molecular weight controlled polylactic acid
(I) Technical Field
The present invention relates to a method for synthesizing organic polymer materials, specifically a method for synthesizing non-toxic polylactic acid (PLA) that can be used as a medical material.
(II) Background technology
PLA is a kind of polymer material with good biocompatibility and biodegradability. It is widely used in drug slow-release capsules, surgical sutures, orthopedic internal fixation materials, etc. because of its advantages of non-toxicity, non-accumulation and degradation products can participate in human metabolism. It can be completely decomposed under the action of microorganisms, water, acid and alkali in nature, and the end products are C02 and H20. The intermediate product lactic acid is also a product of normal sugar metabolism in the body, and will not accumulate in vital organs and cause adverse reactions.
The synthesis and application of PLA began as early as the 1950s, and the synthesis of high molecular weight D or L type PLA with spinability began in the 1970s, and was initially used in pharmaceutical preparations and surgery. In recent years, with the product development and performance requirements of PLA and its copolymers in fracture as fixation materials, bone tissue engineering materials and drug control agents, the research on the preparation of high molecular weight PLA and the synthesis of PLA and copolymers with specific composition and structure, controlled degradation rate and no metal residues harmful to human body after degradation has shown a broad development prospect.
In practical applications, PLA with different molecular weights has different properties and applications. For general-purpose materials, PLA has a molecular weight of >100,000; for drug delivery systems, PLA has a molecular weight between 4,000 and 10,000, as this molecular weight degrades in the body in accordance with the need for drug release. Therefore, molecular weight control during PLA synthesis is of great importance.
PLA is synthesized by direct polymerization, ring-opening polymerization, copolymerization and chain-spreading polymerization. The most commonly used method is the ring-opening polymerization of propyleneglycerides, which can yield polymers with high relative molecular mass and high mechanical strength. The ring-opening polymerization includes cationic ring-opening polymerization, anionic ring-opening polymerization, and coordination polymerization, of which coordination polymerization is the most studied type. Currently, most of the catalysts used in China are tin salts such as stannous octanoate as catalysts for ring-opening polymerization of propylene glycol esters (Ruan J., Liu Y., Zhang H. Po et al. Journal of Hunan University of Science and Technology, 2007, 22(1): 81; Chen Jia, Wang Yuanliang. Chemical Research and Applications, 2007, 19:358; Lin Ji, Yan Guangtao. Beijing Biomedical Engineering, 2005, 24(6): 465), but due to their cytotoxicity and metal residues that are harmful to organisms, synthetic PLA is not suitable for medical materials. Therefore, the search for tin-free catalysts with high biosafety has become a new direction in this field.
The Chinese patent No. CN 1450097 A provides a method for the preparation of poly(L-lactic acid) by adding zinc lactate-p-toluenesulfonic acid composite catalyst to L-lactic acid and condensing it at 150~200’C and 0.06~1.96 Kpa for 6~36 h. The product poly(L-lactic acid) has a heavy average molecular weight of 10,000~80,000.
The Chinese patent No. CN 1702091 A provides a method for the preparation of non-toxic polylactic acid by direct condensation of lactic acid, in which the dried D,L-lactic acid is dehydrated under reduced pressure and condensed at a temperature of 100-200°C and a vacuum of 0.1-100 mmHg for 6-50 hours, and the condensation stage is carried out by a step-warming method, with a temperature increase of 10-30°C every 3-5 hours. The molecular weight of the product PLA is 2,000~50,000.
Although the above two preparation methods can produce PLA without residual toxic metal elements, there are technical shortcomings. The disadvantage is that the production process is complicated, the process is long, the reaction needs to be under heating and reduced pressure, the investment in equipment is large, and the technical requirements are high. (iii) Invention content
The purpose of the present invention is to provide a metal-free residual molecular weight controlled PLA synthesis method, which can effectively control the molecular weight of PLA, short reaction time and high yield of the product.
The purpose of the present invention is achieved by the following steps: 1) Adding the reaction solvent to the propyleneglycolate under normal temperature, normal pressure and inert gas protection, and preparing the reaction solvent to a molar concentration of 0.5 to 1.5 mg/kg.
0.5~1.5M, add initiator and catalyst in the ratio of 6~350: 1: 0.06~0.35, and carry out polymerization reaction for 0.25~2h.
2) Add the terminating agent in the molar ratio of initiator to terminating agent of 1:1~5 and carry out the termination reaction for 10~20min.
3) Prepare methanol according to the volume ratio of reaction solution to methanol of 1: 10~20, and drop the reaction product obtained in step 2) into methanol to form polylactic acid precipitate, filter, wash 2~3 times with methanol, and dry under vacuum at 20~40’C for 24~48h to get the product.
The invention also has some technical features such as
1. The said propyl cross-ester is any one of L-propyl cross-ester, D-propyl cross-ester or LD-propyl cross-ester.
2. The catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene.
3. Said initiator is an alcohol, any one of azido alcohol, alkyl alcohol, alkyl alcohol or alkenyl alcohol.
4. Polylactic acid with a molecular weight of 1,000 to 50,000 and a PDK of 1.3 is produced by controlling the molar ratio of propyleneglyceride to initiator in the range of 6 to 350:l. The molar ratio of propyleneglyceride to initiator is controlled. Theoretical PLA
The relationship between molecular weight and the molar ratio of propylene glycol ester and initiator is
Theoretical molecular weight of PLA ^ molecular weight of propylene glycol ester x molar ratio of propylene glycol ester to initiator + molecular weight of initiator
5, said inert gas is argon or nitrogen.
6, said reaction solvent is dichloromethane or trichloromethane.
7, said terminating agent is benzoic acid.
In the current PLA synthesis technology, most of the catalysts used are catalysts containing metal elements, and the polymerization reaction process needs to be carried out under heating and reduced pressure conditions, and the reaction time is long, and the molecular weight of the product PLA is difficult to be effectively controlled. The present invention is a metal-free and controlled molecular weight PLA synthesis method, which uses a metal-free organic catalyst (1,8-diazabicyclo[5.4.0]undec-7-ene) with high catalytic activity, and completes the ring-opening polymerization of propyleneglycolate in a short time at room temperature and pressure, and controls the molecular weight of PLA by controlling the molar ratio of propyleneglycolate and initiator to obtain PLA with narrow molecular weight distribution. The molecular weight of PLA can be effectively controlled by controlling the molar ratio of propylene-to-initiator to obtain PLA with narrow molecular weight distribution. Compared with the prior art, the present invention is simple, does not require heating and decompression conditions, short reaction time, high product yield, energy saving, easy to operate, can effectively control the molecular weight of the product PLA, the product PLA molecular weight distribution is narrow, no metal residue, non-toxic, and can be used as medical materials. The invention is suitable for the synthesis of PLA with the average molecular weight of 1,000~50,000, especially for the synthesis of PLA with the terminal group of azide, alkynyl,wanyl or alkenyl, and the synthesized PLA is white powder. (iv) Specific embodiments
The present invention is described in more detail by the following examples.
Example 1:
(1) At room temperature, under atmospheric pressure and protected by argon gas, in a reaction device equipped with a stirrer, add 10 g of L-propargyl ester and 69.4 mL of dichloromethane, stir well, and prepare L-propargyl ester solution with a molar concentration of 1M. Using 2-propargyl-l alcohol as initiator, add 2-propargyl-l alcohol and 1,8-diazabicyclo[5.4.0]^^-carb-7-ene in the molar ratio of 8:1:0.08 with stirring and react for 0.25h.
(2) Add benzoic acid in the molar ratio of 2-propyn-l alcohol to benzoic acid of l: 2 with stirring and react for 20 min.
(3) Prepare methanol according to the volume ratio of reaction solution to methanol is 1: 20, drop the reaction solution into methanol, polylactic acid formed precipitation precipitation, filtration, methanol wash paint 2 times. 3(TC vacuum drying 24h.
(4) The product is poly-L-lactic acid with propargyl group as terminal group, yield 85.6%; the average molecular weight is 1,200 (theoretical molecular weight is 1,209) and the PDI is 1.18 as measured by GPC using tetrahydrofuran as solvents.
Example 2:
(1) The experimental setup and conditions were the same as in Example 1. 10 g of D-Propyleneglyceride was added, 100 mL of dichloromethane was added, and the solution was stirred well to form a molar concentration of 0.7 M of D-Propyleneglyceride. Using 4-ethynyl benzyl alcohol as initiator, the molar ratio of D-propyleneglyceride, 4-ethynyl benzyl alcohol, 1,8-diazabicyclo[5.4.0]undec-7-ene was 28:1:0.28, and 4-ethynyl benzyl alcohol and 1,8-diazabicyclo[5.4.0]i”^-carb-7-ene were added in turn with stirring. -7-ene, and the reaction was carried out for 0.5h.
(2) Add benzoic acid under stirring in the molar ratio of 1:3 between 4 ethynylbenzyl alcohol and benzoic acid and react for 18 min.
(3) Prepare methanol according to the volume ratio of reaction solution to methanol of 1: 15, and drop the reaction solution into methanol.
The reaction solution was dried under vacuum at 2(TC) for 48h.
(4) The product is poly(D-lactic acid) with the terminal group of ethynylphenyl in 84.5% yield; the number average molecular weight is 4,180 (theoretical molecular weight is 4,167) and the PDI is 1.09 as measured by GPC using tetrahydrofuran as solvent.
Example 3:
(1) The experimental setup and conditions were the same as in Example 1. 15 g of L-propyleneglyceride was added, 150 mL of dichloromethane was added, and the solution was stirred well to form a molar concentration of 0.7 M of L-propyleneglyceride. Using 6-azido-1-hexanol as initiator, add 6-azido-l-hexanol and 1,8-diazabicyclo[5.4.0]i^-carbon-7-ene in the molar ratio of 200: 1: 2 with stirring for 1.5h.
(2) Add benzoic acid according to the molar ratio of 6-azido-l-hexanol to benzoic acid as h 2 with stirring and react for 20 min.
(3) Prepare methanol according to the volume ratio of reaction solution to methanol of 1:15, put the reaction solution into methanol drop by drop, poly(lactic acid) will be precipitated, filtered and washed with methanol three times, dried under vacuum at 25 C for 48h.
(4) The product is poly-L-lactic acid with azide terminal group, yield 90.2%; the average molecular weight is 29,800 (theoretical molecular weight is 28,969) and the PDI is 1.07 as measured by GPC using tetrahydrofuran as solvents.
Example 4:
Using isopropyl alcohol as initiator, add isopropyl alcohol and 1,8-diazabicyclo[5.4.0]H^-carb-7-ene in the molar ratio of 50: 1: 0.5 with stirring, and react for 0.75h.
(2) Add benzoic acid under stirring according to the molar ratio of isopropanol to benzoic acid of l:5 and react for 10 min.
(3) Prepare methanol according to the volume ratio of reaction solution to methanol is 1:20, put the reaction solution into methanol drop by drop, polylactic acid formed precipitate precipitation, filter, methanol washing twice. 24h vacuum drying at 4(TC).
(4) The product is poly-LD-lactic acid with alkyl terminal group, yield 82.5%; the number average molecular weight is 7,340 (theoretical molecular weight is 7,267) and PDI is 1.12 as measured by GPC using tetrahydrofuran as solvents.
Example 5:
(1) The experimental setup and conditions were the same as in Example 1. 10 g of L-propyleneglyceride was added, 57.8 mL of dichloromethane was added, and the solution was stirred well to form a molar concentration of 1.2 M of L-propyleneglyceride. Using 6-azido-1-hexanol as initiator, add 6-azido-l-hexanol and 1,8-diazabicyclo[5.4.0]undec-7-ene in the molar ratio of 70: 1: 0.7 with stirring, and react for lh.
(2) Add benzoic acid according to the molar ratio of 6-azido-l-hexanol to benzoic acid of 1: 4 with stirring and react for 15 min.
(3) Prepare methanol according to the volume ratio of reaction solution to methanol of 1: 15, and drop the reaction solution into methanol.
The reaction solution was dried under vacuum at 30’C for 24h.
(4) The product was poly-L-lactic acid with azide terminal group in 88.4% yield; the average molecular weight was 10,100 (theoretical molecular weight was 10,232) and the PDI was 1.08 as measured by GPC using tetrahydrofuran as solvents.
Example 6:
(1) The experimental setup and conditions were the same as in Example 1. 10 g of L-propyleneglyceride was added, 100 mL of dichloromethane was added, and the solution was stirred well to form a molar concentration of 0.7 M of L-propyleneglyceride. Using 4-ethynyl benzyl alcohol as initiator, add 4-ethynyl benzyl alcohol and 1,8-diazabicyclo[5.4.0]undec-7-ene in the molar ratio of 35:1:0.35 with stirring, and react for 0.75h.
(2) Add benzoic acid with stirring in the molar ratio of 1:3 between 4 ethynylbenzyl alcohol and benzoic acid and react for 18 min.(3) Prepare methanol in the volume ratio of 1:12 between reaction solution and methanol, drop the reaction solution into methanol, poly(lactic acid) will be precipitated and filtered, methanol washed three times, and dried under vacuum at 25’C for 48h.
(4) The product was poly-L-lactic acid with acetylene-phenyl terminal group in 87.1% yield; the average molecular weight was 5,120 (theoretical molecular weight was 5,177) and the PDI was 1.10 as measured by GPC using tetrahydrofuran as solvent.