Initiators / catalysts, processes for their preparation and use, polylactic acid-polymalic acid and processes for their preparation and use

Abstract

The application relates to the technical field of polymer synthesis, in particular to an initiation / catalyst and a preparation method and application thereof, polylactic acid-poly(malic acid) and a preparation method and application thereof. The application provides an initiation / catalyst, and the preparation raw materials include 4-hydroxymethyl benzoic acid and 1,8-diazabicyclo[5.4.0]undec-7-ene. The initiation / catalyst has the advantage of weakened biological toxicity in biological medicine compared with a metal catalyst which is traditionally adopted.

Description

Technical Field

[0001] This invention relates to the field of polymer synthesis technology, and particularly to initiators / catalysts and their preparation methods and applications, as well as polylactic acid-polymalic acid and their preparation methods and applications. Background Technology

[0002] The construction of block copolymer structures is usually achieved through the coupling of pre-fabricated end-functionalized polymer blocks or through the independent polymerization of various monomers using heterofunctional initiators. Catalysts used for the ring-opening polymerization of lactide can be broadly classified into metal catalysts and organic catalysts. The use of metal catalysts for the ring-opening polymerization of lactide remains the main research and application method. However, the small amount of residual metal catalyst in the polymerization system has a certain degree of biotoxicity, which limits the application of the polymer in biomedicine, especially in the field of drug delivery. Summary of the Invention

[0003] The purpose of this invention is to provide an initiator / catalyst, its preparation method and application, and polylactic acid-polymalic acid, its preparation method and application. The initiator / catalyst is an organic catalyst, which has the advantage of weak biotoxicity in biomedical applications compared with existing metal catalysts.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides an initiator / catalyst, which is obtained by salt formation reaction of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene;

[0006] The molar ratio of 4-hydroxymethylbenzoic acid to 1,8-diazabicycloundec-7-ene is (1-1.2):1.

[0007] The present invention also provides the application of the initiator / catalyst described in the above technical solution in the preparation of polylactic acid, polybenzyl malate, polylactic acid-polybenzyl malate, or polylactic acid-polymalic acid.

[0008] This invention also provides a method for preparing polylactic acid, comprising the following steps:

[0009] Under nitrogen purging conditions, an initiator / catalyst, lactide, and dichloromethane are mixed and subjected to a melt polymerization reaction to obtain the polylactic acid.

[0010] The initiator / catalyst is the initiator / catalyst described in the above technical solution.

[0011] Preferably, the molar ratio of the initiator / catalyst to lactide is 1:(50-83);

[0012] The temperature of the melt polymerization reaction is 100–130°C, and the time is 1–24 h.

[0013] This invention also provides a method for preparing polybenzyl malate, comprising the following steps:

[0014] Under nitrogen purging conditions, an initiator / catalyst, β-benzyloxycarbonyl-β-propiolactone, and an organic solvent are mixed and polymerized to obtain the polybenzyl malate.

[0015] The initiator / catalyst is the initiator / catalyst described in the above technical solution.

[0016] Preferably, the organic solvent is tetrahydrofuran or dichloromethane;

[0017] The molar ratio of the initiator / catalyst to β-benzyloxycarbonyl-β-propiolactone is 1:(45-55);

[0018] The polymerization reaction is carried out at a temperature of 10–60°C for a duration of 4–24 hours.

[0019] This invention also provides a method for preparing polylactic acid-polybenzyl malate, comprising the following steps:

[0020] Under nitrogen purging, polylactic acid, β-benzyloxycarbonyl-β-propiolactone and tetrahydrofuran are mixed and subjected to block polymerization to obtain polylactic acid-polybenzyl malate; the polylactic acid is the polylactic acid prepared by the preparation method described in the above technical solution.

[0021] This invention also provides a method for preparing polylactic acid-polymalic acid, comprising the following steps:

[0022] Polylactic acid-polybenzyl malate and 1,4-dioxane were mixed to obtain a copolymer solution;

[0023] The copolymer solution was mixed with a palladium on carbon catalyst and then hydrogenated to obtain the polylactic acid-polymalic acid.

[0024] The polylactic acid-polymethylene malate is the polylactic acid-polymethylene malate prepared by the preparation method described in the above technical solution.

[0025] The present invention also provides polylactic acid-polymalic acid prepared by the preparation method described in the above technical solution.

[0026] The present invention also provides the application of polylactic acid-polymalic acid as a drug carrier as described above.

[0027] This invention provides an initiator / catalyst, which is obtained by a salt-forming reaction of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene; the molar ratio of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene is (1-1.2):1. The initiator / catalyst of this invention has the advantage of reducing biotoxicity in biomedical applications compared to conventionally used metal catalysts. Simultaneously, this carboxylate containing heterofunctional groups provides a new approach for the synthesis of polylactic acid-polymalic acid block copolymers. It allows for easier control of molecular structure compared to existing technologies that simply use organic catalysts. For the ring-opening polymerization of polylactic acid, the ring-opening of the acyl-oxygen bond of lactide is activated by hydrogen bonding; for benzyl malate, it is an anionic ring-opening polymerization of β-benzyloxycarbonyl-β-propiolactone.

[0028] This invention also provides a method for preparing polylactic acid-polybenzyl malate, comprising the following steps: under nitrogen purging, mixing polylactic acid, β-benzyloxycarbonyl-β-propiolactone, and tetrahydrofuran for block polymerization to obtain the polylactic acid-polybenzyl malate; wherein the polylactic acid is the polylactic acid prepared by the method described in the above technical solution. This invention also provides a method for preparing polylactic acid-polymalic acid, comprising the following steps: mixing polylactic acid-polybenzyl malate and 1,4-dioxane to obtain a copolymer solution; mixing the copolymer solution with a palladium-on-carbon catalyst, and then purging with hydrogen to conduct a hydrogenation reaction to obtain the polylactic acid-polymalic acid; wherein the polylactic acid-polybenzyl malate is the polylactic acid-polybenzyl malate prepared by the method described in the above technical solution. This invention synthesizes polylactic acid-polymalic acid (PLA-PMA) via a two-step process of melt polymerization and solution polymerization using the initiator / catalyst described above. The preparation process is simple. Due to the hydrophobic nature of PLA, it exhibits a low diffusion rate in aqueous solution and slow degradation of its ester-containing main chain segments. In contrast, PMA, as a biodegradable hydrophilic polyester, contains numerous carboxyl groups on its side groups, which can connect with functional groups to enhance its targeting as a drug carrier or increase drug loading, while reducing the toxicity of active substances. Therefore, when PLA-PMA is obtained by block copolymerization of PLA and PMA, it can be used as a drug carrier. On the one hand, the side groups of PMA can increase the drug loading through electrostatic interactions; on the other hand, the stereocomplexing effect of PLA can improve the stability of the drug carrier, thereby increasing both the drug loading and drug loading efficiency. Attached Figure Description

[0029] Figure 1 The 1H NMR spectrum of the 4-hydroxymethylbenzoic acid / DBU salt described in Example 1;

[0030] Figure 2 The thermogravimetric curve of the 4-hydroxymethylbenzoic acid / DBU salt described in Example 1;

[0031] Figure 3 The 1H NMR spectrum of polylactic acid-polybenzyl malate described in Example 17;

[0032] Figure 4 The 1H NMR spectrum of polylactic acid-polymalic acid (PLLA-PMLA) described in Example 19;

[0033] Figure 5 The 1H NMR spectrum of polylactic acid-polymalic acid (PDLA-PMLA) described in Example 19;

[0034] Figure 6 The infrared spectrum of polylactic acid-polymalic acid described in Example 19;

[0035] Figure 7 The 1H NMR spectrum of polylactic acid-polybenzyl malate-polymalic acid described in Example 19. Detailed Implementation

[0036] This invention provides an initiator / catalyst, which is obtained by a salt formation reaction of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene (DBU);

[0037] The molar ratio of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene is (1-1.2):1.

[0038] In this invention, the molar ratio of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene is (1 to 1.2):1, preferably 1 to 1.1:1, and more preferably 1:1.

[0039] In this invention, the method for preparing the initiator / catalyst preferably includes the following steps:

[0040] A dichloromethane solution of 4-hydroxymethylbenzoic acid and a dichloromethane solution of DBU were mixed to carry out a salt formation reaction to obtain the initiator / catalyst.

[0041] In this invention, the preferred ratio of 4-hydroxymethylbenzoic acid to dichloromethane in the dichloromethane solution of 4-hydroxymethylbenzoic acid is 1.0–5.0 mmol:10 mL, more preferably 1.0–3.0 mmol:10 mL, and most preferably 2.0 mmol:10 mL; the preferred ratio of DBU to dichloromethane in the dichloromethane solution of DBU is 1.0–5.0 mmol:10 mL, more preferably 1.0–3.0 mmol:10 mL, and most preferably 2.0 mmol:10 mL.

[0042] In this invention, the molar ratio of 4-hydroxymethylbenzoic acid in the dichloromethane solution of 4-hydroxymethylbenzoic acid to DBU in the dichloromethane solution of DBU is preferably 1 to 1.2:1, more preferably 1 to 1.1:1, and most preferably 1:1.

[0043] In this invention, the salt-forming reaction is preferably carried out at room temperature, and the time is preferably 0.5 to 24 hours, more preferably 0.5 to 5 hours, and most preferably 1 hour.

[0044] After the salt-forming reaction is completed, the present invention preferably includes sequential filtration, rotary evaporation, and drying. The filtration process is not particularly limited and can be performed using a process well-known to those skilled in the art. In this invention, the rotary evaporation temperature is preferably 35°C, and the rotary evaporation time is not particularly limited; a time well-known to those skilled in the art can be used, ensuring complete removal of dichloromethane. The drying method is preferably vacuum drying; the vacuum drying temperature is preferably 20–60°C, more preferably 30–50°C, and most preferably 40°C; the vacuum drying time is preferably 12–48 h, more preferably 20–30 h, and most preferably 24 h.

[0045] The present invention also provides the application of the initiator / catalyst described in the above technical solution in the preparation of polylactic acid, polybenzyl malate, polylactic acid-polybenzyl malate, or polylactic acid-polymalic acid.

[0046] This invention also provides a method for preparing polylactic acid, comprising the following steps:

[0047] Under nitrogen purging conditions, an initiator / catalyst, lactide (LA), and dichloromethane are mixed and subjected to a melt polymerization reaction to obtain the polylactic acid.

[0048] The initiator / catalyst is the initiator / catalyst described in the above technical solution.

[0049] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0050] Before the mixing is performed, the present invention preferably includes sequentially performing vacuuming and nitrogen purging; the present invention does not impose any special limitations on the process of vacuuming and nitrogen purging, and any process known to those skilled in the art can be used.

[0051] In this invention, the molar ratio of the initiator / catalyst to lactide is preferably 1:(50-83), more preferably 1:(50-60), and most preferably 1:50.

[0052] In this invention, the preferred ratio of lactide to dichloromethane is 4.0 mmol: 0.1-1 mL, more preferably 4.0 mmol: 0.3-0.5 mL, and most preferably 4.0 mmol: 0.4 mL.

[0053] In this invention, the mixing is preferably performed by first mixing the initiator / catalyst and lactide (LA) before adding dichloromethane. This invention does not impose any special limitations on the mixing conditions; conditions well known to those skilled in the art can be used.

[0054] After the mixing is completed, the present invention preferably includes two cycles of vacuuming and nitrogen purging; the vacuuming time is preferably 30 minutes, and the nitrogen purging time is preferably 5 minutes. After repeating the vacuuming and nitrogen purging twice, the invention further preferably includes continuing to vacuum and sealing the tube; the continued vacuuming time is preferably ≥40 minutes.

[0055] In this invention, the temperature of the melt polymerization reaction is preferably 100–130°C, more preferably 105–125°C, and most preferably 110–120°C; the time is preferably 1–24 h, more preferably 5–20 h, and most preferably 10–15 h. In this invention, the melt polymerization reaction is carried out under vacuum conditions, and preferably under oil bath conditions.

[0056] After the melt polymerization reaction is completed, the present invention preferably includes post-treatment, which preferably includes dissolving the polymer obtained from the melt polymerization reaction in 10 mL of dichloromethane, depositing it in 10 times the volume of ice-cold methanol to obtain a white solid, centrifuging at 8000 r / min for 3 min, pouring out the supernatant, and drying under vacuum at 40 °C.

[0057] This invention also provides a method for preparing polybenzyl malate, comprising the following steps:

[0058] Under nitrogen purging conditions, an initiator / catalyst, β-benzyloxycarbonyl-β-propiolactone (MLABz), and an organic solvent are mixed and polymerized to obtain the polybenzyl malate.

[0059] The initiator / catalyst is the initiator / catalyst described in the above technical solution.

[0060] In this invention, the organic solvent is preferably tetrahydrofuran or dichloromethane.

[0061] In this invention, the molar ratio of the initiator / catalyst and β-benzyloxycarbonyl-β-propiolactone is preferably 1:(45-55), more preferably 1:(48-52), and most preferably 1:50.

[0062] In this invention, the preferred ratio of MLABz to organic solvent is (1.0161~1.0312) mmol: 0.75 mL.

[0063] In this invention, the mixing process is preferably as follows: after evacuating for 30 minutes, under nitrogen purging conditions, the initiator / catalyst and MLABz are mixed and then an organic solvent is added.

[0064] In this invention, the polymerization temperature is preferably 10–60°C, more preferably 21–50°C, and most preferably 21°C; the polymerization time is preferably 4–24 h, more preferably 10–20 h. In this invention, when the organic solvent is tetrahydrofuran, a milky white paste (i.e., benzyl malate is generated) can be obtained in 4 h of polymerization; when the organic solvent is dichloromethane, a milky white paste (i.e., polybenzyl malate is generated) can be obtained in 24 h of polymerization.

[0065] After the polymerization reaction is completed, the present invention preferably includes post-treatment; the post-treatment preferably involves dissolving the obtained milky white paste in 10 mL of dichloromethane, precipitating it in 10 times its volume of ice-cold methanol, removing the solvent by filtration through a 0.45 μm filtration membrane, and drying it under vacuum at 40 °C.

[0066] This invention also provides a method for preparing polylactic acid-polybenzyl malate, comprising the following steps:

[0067] Under nitrogen purging, polylactic acid, β-benzyloxycarbonyl-β-propiolactone and tetrahydrofuran are mixed and subjected to block polymerization to obtain polylactic acid-polybenzyl malate; the polylactic acid is the polylactic acid prepared by the preparation method described in the above technical solution.

[0068] In this invention, the polylactic acid-polybenzyl malate is preferably prepared by constructing the copolymer using a two-pot two-step method or a one-pot two-step method.

[0069] Specifically, the preferred process for constructing the copolymer using the "two-pot, two-step" method is as follows: The synthesized polylactic acid with terminal carboxyl groups is post-treated without adding excessive acid to remove DBU, and can be used to initiate the ring-opening polymerization of MLABz. Under vacuum in a Leck tube for 30 minutes, and under nitrogen purging, the polylactic acid (152.00 mg, DP≈190, 0.0108 mmol) and MLABz (440.64 mg, 2.16 mmol) are added to the reaction flask, and 2 mL of tetrahydrofuran is added to dissolve the polylactic acid. The reaction is then heated to 50°C and reacted for 120 hours, after which the reaction is stopped. The product is dissolved in 10 mL of dichloromethane and precipitated in 10 times its volume of ice-cold methanol. The solvent is removed by filtration through a 0.45 μm membrane, and the product is dried under vacuum at 40°C.

[0070] The preferred method for constructing the copolymer using the "one-pot, two-step" process is as follows: The Shrek flask is evacuated for 30 minutes, then 4-hydroxymethylbenzoic acid / DBU salt (12.10 mg, 0.0378 mmol) and L-lactide (L-LA) (288.50 mg, 2.0035 mmol) are added under nitrogen purging, followed by the addition of 0.2 mL of dichloromethane. The process is repeated twice with evacuation and nitrogen purging, followed by evacuation for at least 40 minutes before sealing. The other Shrek flask is treated in the same manner, with the addition of 4-hydroxymethylbenzoic acid / DBU salt (12.05 mg, 0.0396 mmol) and D-lactide (D-LA) (292.20 mg, 2.0292 mmol). The reaction was carried out in two Leck flasks at 120°C for 1 hour, and then stopped. After the reaction tubes were brought to room temperature, 2 mL of tetrahydrofuran solution was added under nitrogen purging. After the solid in the reaction tubes dissolved, MLABz (412.50 mg, 2.0024 mmol; 417.30 mg, 2.0257 mmol) was added under nitrogen purging. Finally, the tubes were sealed under nitrogen purging and the reaction was stopped at 21°C for 48 hours. An appropriate amount of dichloromethane was added to the reaction tube, and the precipitate was precipitated dropwise in 10 times its volume of ice-cold methanol. After centrifugation to remove most of the solvent, the precipitate was removed by filtration through a 0.45 μm filter membrane and dried under vacuum at 40°C.

[0071] This invention also provides a method for preparing polylactic acid-polymalic acid, comprising the following steps:

[0072] Polylactic acid-polybenzyl malate and 1,4-dioxane were mixed to obtain a copolymer solution;

[0073] The copolymer solution was mixed with a palladium on carbon catalyst and then hydrogenated to obtain the polylactic acid-polymalic acid.

[0074] The polylactic acid-polymethylene malate is the polylactic acid-polymethylene malate prepared by the preparation method described in the above technical solution.

[0075] The present invention mixes polylactic acid-polybenzyl malate and 1,4-dioxane to obtain a copolymer solution.

[0076] In this invention, the mass concentration of polylactic acid-polybenzyl malate in the copolymer solution is preferably 1 wt% to 10 wt%, more preferably 4 wt% to 6 wt%, and most preferably 5 wt%.

[0077] This invention does not impose any special limitations on the mixing process; any process well-known to those skilled in the art can be used. In this invention, since the polybenzyl malate segment is difficult to dissolve in 1,4-dioxane at room temperature, the reaction temperature can be increased or the dissolution of the block copolymer can be accelerated by blowing hot air with a blower before the reaction. The prepared solution is clear and transparent.

[0078] After obtaining the copolymer solution, the present invention mixes the copolymer solution with a palladium on carbon catalyst and then carries out a hydrogenation reaction by passing hydrogen gas to obtain the polylactic acid-polymalic acid.

[0079] In this invention, the palladium-on-carbon catalyst is preferably a palladium-on-carbon catalyst with a palladium content of 5 wt%.

[0080] In this invention, the mass ratio of the copolymer to the palladium-carbon catalyst in the copolymer solution is preferably 1:(0.1-0.5), more preferably 1:(0.2-0.4), and most preferably 1:0.4.

[0081] In this invention, the hydrogenation reaction process is preferably repeated with three vacuuming and hydrogen gas purging processes, and stirring is performed during the hydrogen gas purging process; this invention does not impose any special limitations on the stirring process, and any process well known to those skilled in the art can be used.

[0082] In this invention, the hydrogenation reaction is preferably carried out at room temperature and for 24 hours. Preferably, the hydrogenation reaction is conducted under stirring conditions, and the hydrogen sampling bag is continuously supplied with hydrogen until the hydrogen in the sampling bag no longer decreases.

[0083] After the hydrogenation reaction is completed, the present invention preferably includes a post-treatment process. The post-treatment process preferably involves filtration on a 0.45 μm organic filtration membrane to remove black palladium on carbon, obtaining a hydrogenated copolymer solution, removing the solvent by rotary evaporation at 55 °C, adding ice-cold diethyl ether to precipitate the polymer, removing the diethyl ether, and then vacuum drying at 40 °C for 24 h.

[0084] The present invention also provides polylactic acid-polymalic acid prepared by the preparation method described in the above technical solution.

[0085] In this invention, the structural formula of the polylactic acid-polymalic acid is as follows:

[0086]

[0087] The preferred values ​​for m are 20 to 100, and the preferred values ​​for n are 20 to 100.

[0088] This invention also provides the application of polylactic acid-polymalic acid as a drug carrier as described above. This invention does not impose any special limitations on the method of application; any method well-known to those skilled in the art can be used.

[0089] The following examples illustrate in detail the initiator / catalyst and its preparation method and application, as well as polylactic acid-polymalic acid and its preparation method and application, provided by the present invention. However, these examples should not be construed as limiting the scope of protection of the present invention.

[0090] Example 1

[0091] Synthesis of 4-hydroxymethylbenzoic acid / DBU salt:

[0092] 4-Hydroxymethylbenzoic acid (304.30 mg, 2.00 mmol) was dissolved in 10 mL of dichloromethane in a reaction flask. A dichloromethane solution of DBU (304.00 mg / 2.00 mmol of DBU and 10 mL of dichloromethane) was added. The mixture was reacted at room temperature for 1 h. A small amount of solid was removed by filtration. The dichloromethane was removed by rotary evaporation at 35 °C. The mixture was then dried under vacuum at 40 °C for 24 h to obtain 4-hydroxymethylbenzoic acid / DBU salt (white solid). Figure 1 The 1H NMR spectrum of the 4-hydroxymethylbenzoic acid / DBU salt is obtained by... Figure 1 It can be seen that the above preparation process generates carboxylate; Figure 2 The thermogravimetric curve of the 4-hydroxymethylbenzoic acid / DBU salt is obtained from... Figure 2 It is known that the thermal decomposition temperature of the 4-hydroxymethylbenzoic acid / DBU salt reaches 233℃.

[0093] Examples 2-13

[0094] Synthesis of polylactic acid:

[0095] After evacuating the Shrek flask for 30 minutes, 4-hydroxymethylbenzoic acid / DBU salt (24.32 mg, 0.08 mmol) and LA were added under nitrogen purging, along with 0.4 mL of solvent. The flask was evacuated for 30 minutes and purged with nitrogen twice for 5 minutes each time. Finally, it was evacuated for at least 40 minutes before sealing. The reaction was carried out in an oil bath at different high temperatures for different times (the corresponding temperature and time conditions, LA dosage, solvent type, and conversion rate for Examples 2-13 are shown in Table 1). After dissolving the polymer in 10 mL of dichloromethane, a white solid was precipitated in 10 times its volume of ice-cold methanol. The precipitate was centrifuged at 8000 rpm for 3 minutes, and the supernatant was discarded. The solid at the bottom of the centrifuge tube was dried under vacuum at 40°C to obtain polylactic acid (white solid).

[0096] Table 1. Conditions and conversion rates for the preparation of polylactic acid in Examples 2-13.

[0097]

[0098]

[0099] Example 14

[0100] Synthesis of polybenzyl malate:

[0101] The Shrek flask was evacuated for 30 min. Under nitrogen purging, 4-hydroxymethylbenzoic acid / DBU salt (6.24 mg, 0.0205 mmol), MLABz (209.31 mg, 1.0161 mmol), and 0.75 mL of tetrahydrofuran were added to a reaction flask. The mixture was reacted at 21 °C for 4 h to form a milky white paste. The milky white paste was dissolved in 10 mL of dichloromethane and precipitated in 10 times its volume of ice-cold methanol. The solvent was removed by filtration through a 0.45 μm filter membrane. The product was dried under vacuum at 40 °C to obtain polybenzyl malate (white solid).

[0102] Example 15

[0103] Referring to Example 14, the difference is that 4-hydroxymethylbenzoic acid / DBU salt (6.05 mg, 0.199 mmol), MLABz (212.42 mg, 1.0312 mmol), and 0.75 mL of dichloromethane were added to a Shrek flask and reacted at 21°C for 24 h to form a milky white paste. The milky white paste was dissolved in 10 mL of dichloromethane, precipitated in 10 times its volume of ice-cold methanol, filtered through a 0.45 μm filter membrane to remove the solvent, and dried under vacuum at 40°C to obtain polybenzyl malate (white solid).

[0104] Example 16

[0105] Synthesis of polylactic acid-polybenzyl malate:

[0106] The copolymer was constructed using a two-pot, two-step process: A Shrek tube was evacuated for 30 min. Under nitrogen purging, polylactic acid (152.00 mg, DP≈190, 0.0108 mmol) and MLABz (440.64 mg, 2.16 mmol) were added to the reaction flask, followed by the addition of 2 mL of tetrahydrofuran to dissolve the polylactic acid. The reaction was then carried out at 50 °C for 120 h, after which the reaction was stopped. The product was dissolved in 10 mL of dichloromethane and precipitated in 10 times its volume of ice-cold methanol. The solvent was removed by filtration through a 0.45 μm membrane, and the product was dried under vacuum at 40 °C to obtain a white solid (polylactic acid-polybenzyl malate).

[0107] Example 17

[0108] Synthesis of polylactic acid-polybenzyl malate:

[0109] The copolymer was constructed using a "one-pot, two-step" method: A Shrek flask was evacuated for 30 minutes. Under nitrogen purging, 4-hydroxymethylbenzoic acid / DBU salt (12.10 mg, 0.0378 mmol) and L-LA (288.50 mg, 2.0035 mmol) were added, along with 0.2 mL of dichloromethane. The evacuation and nitrogen purging were repeated twice, followed by evacuation for at least 40 minutes before sealing the flask. The reaction was stopped at 120°C for 1 hour. After the reaction tube returned to room temperature, 2 mL of tetrahydrofuran solution was added under nitrogen purging. Once the solid in the reaction tube dissolved, MLABz (412.50 mg, 2.0024 mmol) was added under nitrogen purging. Finally, the flask was sealed under nitrogen purging and the reaction was stopped at 21°C for 48 hours. Add an appropriate amount of dichloromethane to the reaction tube, then precipitate the product dropwise into 10 times its volume of ice-cold methanol. After centrifugation to remove most of the solvent, filter the product through a 0.45 μm membrane to remove the solvent, and dry under vacuum at 40 °C to obtain polylactic acid-polybenzyl malate (white solid). The 1H NMR spectrum is shown below. Figure 3 As shown, by Figure 3 It is known that polylactic acid-polybenzyl malate is obtained by polymerization initiated by 4-hydroxymethylbenzoic acid, and the monomer conversion rate of polylactic acid is higher than that of polybenzyl malate.

[0110] The copolymer construction reaction using 4-hydroxymethylbenzoic acid / DBU salt as initiator / catalyst in a "one-pot two-step" process is as follows:

[0111]

[0112] Example 18

[0113] Referring to Example 17, the difference is that the amount of 4-hydroxymethylbenzoic acid / DBU salt was replaced with 12.05 mg (0.0396 mmol), L-LA was replaced with D-LA, and the amount of D-LA was replaced with 292.20 mg (2.0292 mmol), and the amount of MLABz was 417.30 mg (2.0257 mmol).

[0114] Example 19

[0115] Hydrogenation of block copolymers (synthesis of polylactic acid-polymalic acid):

[0116] Polylactic acid-polybenzyl malate (PLLA-PBM copolymer) and 1,4-dioxane (solvent) were mixed and prepared into a 5wt% clear and transparent copolymer solution under high temperature (60°C) or by hot air blowing. The copolymer solution and 5% palladium on carbon were added to a reaction flask at a mass ratio of 1:0.4. The mixture was repeatedly evacuated and purged with hydrogen three times, with vigorous stirring during the purging process. The reaction was carried out at room temperature for 24 hours, with vigorous stirring and a constant hydrogen supply from the hydrogen sampling bag until the hydrogen level in the bag no longer decreased. The black palladium on carbon was removed by filtration through a 0.45 μm organic filtration membrane to obtain the hydrogenated copolymer solution. After removing the solvent by rotary evaporation at 55°C, the polymer was precipitated by adding ice-cold diethyl ether, and the diethyl ether was removed. The solution was then vacuum dried at 40°C for 24 hours to obtain the hydrogenated copolymer. Figure 4 The image shows the 1H NMR spectrum of a polylactic acid-polymalic acid copolymer (PLLA-PMLA). Figure 5 The image shows the 1H NMR spectrum of dextrorotatory polylactic acid-polymalic acid copolymer (PDLA-PMLA). Figure 6 The infrared spectra of polylactic acid-polymalic acid copolymers and their homopolymers are given by... Figures 4-6 It can be seen that the hydrogenation reaction was successful; Figure 7 The 1H NMR spectrum of polylactic acid-polybenzyl malate-polymalic acid copolymer (PLA-PBM-PMLA) is obtained from... Figure 7 It can be seen that partial hydrogenation reaction products can be obtained by controlling the reaction conditions.

[0117] The reaction equation for hydrogenation is as follows:

[0118]

[0119] Example 20

[0120] Refer to Example 19, except that PLLA is replaced with PDLA.

[0121] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An initiator / catalyst, characterized in that, The initiator / catalyst is obtained by salt formation reaction of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene; The molar ratio of 4-hydroxymethylbenzoic acid and 1,8-diazabicycloundec-7-ene is (1~1.2):

1.

2. The use of the initiator / catalyst according to claim 1 in the preparation of polylactic acid, polybenzyl malate, polylactic acid-polybenzyl malate, or polylactic acid-polymalic acid.

3. A method for preparing polylactic acid, characterized in that, Includes the following steps: Under nitrogen purging conditions, an initiator / catalyst, lactide, and dichloromethane are mixed and subjected to a melt polymerization reaction to obtain the polylactic acid. The initiator / catalyst is the initiator / catalyst according to claim 1.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the initiator / catalyst to lactide is 1: (50~83). The temperature of the melt polymerization reaction is 100~130℃, and the time is 1~24h.

5. A method for preparing polybenzyl malate, characterized in that, Includes the following steps: Under nitrogen purging conditions, an initiator / catalyst, β-benzyloxycarbonyl-β-propiolactone, and an organic solvent are mixed and polymerized to obtain the polybenzyl malate. The initiator / catalyst is the initiator / catalyst according to claim 1.

6. The preparation method according to claim 5, characterized in that, The organic solvent is tetrahydrofuran or dichloromethane; The molar ratio of the initiator / catalyst to β-benzyloxycarbonyl-β-propiolactone is 1:(45~55). The polymerization reaction is carried out at a temperature of 10~60℃ for 4~24h.

7. A method for preparing polylactic acid-polybenzyl malate, characterized in that, Includes the following steps: Under nitrogen purging, polylactic acid, β-benzyloxycarbonyl-β-propiolactone and tetrahydrofuran are mixed and subjected to block polymerization to obtain the polylactic acid-polybenzyl malate ester; wherein the polylactic acid is the polylactic acid prepared by the preparation method of claim 3 or 4.

8. A method for preparing polylactic acid-polymalic acid, characterized in that, Includes the following steps: Polylactic acid-polybenzyl malate and 1,4-dioxane were mixed to obtain a copolymer solution; The copolymer solution was mixed with a palladium on carbon catalyst and then hydrogenated to obtain the polylactic acid-polymalic acid. The polylactic acid-polymethylene malate is the polylactic acid-polymethylene malate prepared by the preparation method described in claim 7.

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