A method for preparing polylactide with high stereoregularity

Abstract

The present invention provides a method for preparing polylactide with high stereoregularity, and belongs to the technical field of polymer preparation. The method for preparing polylactide with high stereoregularity provided by the present invention comprises the following steps: mixing lactide monomer, cis catalyst, co-catalyst and organic solvent, and performing ring-opening polymerization to obtain the polylactide with high stereoregularity. The present invention is based on the combination of cis catalyst and co-catalyst, and can polymerize lactide monomer under relatively mild conditions to obtain polylactide with high stereoregularity. Specifically, the co-catalyst in the present invention acts as a nucleophilic reagent and initiator to achieve the ring opening of lactide; the two (thio)urea groups in the cis catalyst are close to each other, and can cooperate with each other during the ring-opening polymerization reaction, activate the lactide monomer through multiple hydrogen bonds, and stabilize the chain end, so the catalytic conditions are mild, the selectivity is high, and polylactide with a wide range of molecular weights can be obtained, and it has a high initiation efficiency.

Description

Technical Field

[0001] The invention relates to the technical field of polymer preparation, and in particular to a method for preparing polylactide with high stereoregularity. Background Art

[0002] Polylactide (PLA) is renewable, biodegradable and biocompatible, and has important applications in the fields of medical devices and food health. In recent decades, it has been widely studied by domestic and foreign academic and industrial circles. Due to the diversity of the chiral configuration of lactide monomers, such as levorotatory lactide (LLA), dextrorotatory lactide (DLA), meso-lactide (meso-LA) and racemic lactide (rac-LA), polylactide also has a variety of stereoregularities such as isotactic, heteroisotactic, syndiotactic and atactic. The stereoregularity of the polymer determines the mechanical strength, thermal stability and degradability of the polymer, so the synthesis of stereo-controllable PLA has important research value.

[0003] The synthesis of isotactic PLA is currently the most popular. Isotactic PLA can be prepared by catalyzing LLA or DLA, which requires that diastereomerization cannot occur during the catalytic process. Isotactic PLA can also be synthesized by catalyzing the stereoselective polymerization of racemic rac-LA. There are currently two stereoselective mechanisms, namely the chain end control mechanism and the site control mechanism. Generally speaking, the stereoselective mechanism depends on the characteristics of the structure of the catalyst itself. The existing achiral catalysts, such as achiral nitrogen heterocyclic carbenes, tBu-P2, and cyclic superphosphazene bases, usually adopt the chain end control mechanism, that is, the chirality of the next monomer to be inserted is determined by the chirality of the active chain end, but this effect is weak, and the polymerization reaction needs to be carried out at a temperature of -70°C or lower to obtain PLA with high stereoregularity. The existing chiral catalysts, such as phosphoric acid based on binaphthyl structure, cinchona alkali, chiral metal organic catalysts and amino acid derivatives, generally select monomers specifically through chiral sites, thereby controlling the stereoregularity of the polymer, so it is called the site control mechanism.

[0004] Chiral monothiourea organocatalysts based on cyclohexanediamine can achieve stereoselective ring-opening polymerization of rac-LA to synthesize highly isotactic lactide under certain conditions. Qing-Gang Wang et al. (Wang, ZY; Xu, GQ; Zhou, L.; Lv, CD; Yang, RL; Dong, BZ; Wang, QG I) developed a trans-bis(thio)urea catalyst with a chiral center based on chiral 1,2-diphenylethylenediamine or cyclohexanediamine combined with a nitrogen heterocyclic olefin NHO, which can catalyze the synthesis of isotactic (P) rac-LA at -78°C and -40°C, respectively. m ) reaches 0.83 and 0.85, and the molecular weight is less than 8.0kg / mol, and its research shows that the system is a chain end control mechanism. However, in order to obtain high isotactic PLA, the above method can only be carried out under relatively low temperature conditions, which is harsh. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing polylactide with high stereoregularity. The method provided by the present invention can prepare polylactide with high stereoregularity under relatively mild conditions.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing polylactide with high stereoregularity, comprising the following steps:

[0008] Mixing lactide monomer, cis catalyst, co-catalyst and organic solvent to carry out ring-opening polymerization to obtain the highly stereoregular polylactide;

[0009] The cis catalyst has a structure shown in Formula I or Formula II:

[0010]

[0011] In the formula I and formula II, R is selected from

[0012] The X is selected from -S- or -O-;

[0013] The co-catalyst includes a first co-catalyst or a second co-catalyst;

[0014] The first co-catalyst is an alkali metal alkoxide;

[0015] The second co-catalyst includes an alkali agent and an alcohol compound; the alkali agent is KH, NaH, KN(SiMe3)2, NaN(SiMe3)2, LiN(SiMe3)2, n BuLi, MeLi, nitrogen heterocyclic carbene, nitrogen heterocyclic olefin or organic phosphine base, the nitrogen heterocyclic carbene has the structure shown in formula III, the nitrogen heterocyclic olefin has the structure shown in formula IV or formula V, and the organic phosphine base is t-Bu-P2, t-Bu-P4, TiBP, TTMPP, a compound with the structure shown in formula VI or a compound with the structure shown in formula VII:

[0016]

[0017]

[0018] In the formula III and formula IV, R1 to R4 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl;

[0019] In the formula V and formula VI, R1 to R6 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl;

[0020] In the formula VII, R1 to R3 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, n-butyl or phenyl.

[0021] Preferably, the cis catalyst is any one of the following compounds:

[0022]

[0023] Preferably, the alkali metal alkoxide includes sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.

[0024] Preferably, the alcohol compound includes methanol, ethanol, propanol, n-butanol, isobutanol, tert-butanol, isopropanol, phenol, benzyl alcohol, phenylethyl alcohol, butanediol or glycerol.

[0025] Preferably, the lactide monomer includes L-lactide, D-lactide, meso-lactide or racemic-lactide.

[0026] Preferably, the molar ratio of the lactide monomer, the cis catalyst and the alkali metal alkoxide is (10-2000):(1-100):(1-100).

[0027] Preferably, the molar ratio of the lactide monomer, the cis catalyst, the alkaline reagent and the alcohol compound is (10-2000): (1-100): (1-100): (1-100).

[0028] Preferably, the organic solvent comprises tetrahydrofuran, toluene, dichloromethane, acetonitrile or chloroform.

[0029] Preferably, the temperature of the ring-opening polymerization reaction is -80 to 100° C., and the time is 10 min to 48 h.

[0030] Preferably, the weight average molecular weight of the highly stereoregular polylactide is 1.0 to 100 kg / mol, and the isotacticity P m is 0.76~1.0, heterotacticity P r It is 0.80~0.91.

[0031] The present invention provides a method for preparing polylactide with high stereoregularity, comprising the following steps: mixing a lactide monomer, a cis catalyst, a co-catalyst and an organic solvent, and performing a ring-opening polymerization reaction to obtain the polylactide with high stereoregularity. The present invention is based on the combination of cis-bis(thio)urea of ​​cis-1,2-diphenylethylenediamine or cis-cyclohexanediamine with a co-catalyst, and can polymerize the lactide monomer under relatively mild conditions to obtain polylactide with high stereoregularity. Specifically, in the present invention, the co-catalyst acts as a nucleophilic reagent and initiator to achieve the ring opening of lactide; the two (thio)urea groups in the cis catalyst are close to each other, and can cooperate with each other during the ring-opening polymerization reaction, activate the lactide monomer through multiple hydrogen bonds, and stabilize the chain end, so the catalytic conditions are mild, the selectivity is high, and polylactide with a wide range of molecular weights can be obtained, and it has a high initiation efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 1;

[0033] Figure 2 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 2;

[0034] Figure 3 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 3;

[0035] Figure 4 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 4;

[0036] Figure 5 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 5;

[0037] Figure 6 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 6;

[0038] Figure 7 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 7;

[0039] Figure 8 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 8;

[0040] Fig. 9 The homonuclear decoupling hydrogen spectrum of the polylactide prepared in Example 23;

[0041] Fig.10 The energy barrier diagram of the initiation stage of the ring-opening polymerization reaction catalyzed by SS-DiTU catalyst;

[0042] Fig.11 The energy barrier diagram of the initiation stage of the ring-opening polymerization reaction catalyzed by RS-DiTU catalyst;

[0043] Fig.12 Schematic diagram of the insertion mode of RS-DiTU catalyst catalyzing the polymerization of different chiral monomers during chain growth;

[0044] Fig.13 Schematic diagram of the insertion mode of SS-DiTU catalyst catalyzing the polymerization of different chiral monomers during chain growth;

[0045] Fig.14 This is a schematic diagram of the ring-opening polymerization reaction catalyzed by RS-DiTU catalyst in the present invention. DETAILED DESCRIPTION

[0046] The present invention provides a method for preparing polylactide with high stereoregularity, comprising the following steps:

[0047] Mixing lactide monomer, cis catalyst, co-catalyst and organic solvent to carry out ring-opening polymerization to obtain the highly stereoregular polylactide;

[0048] The cis catalyst has a structure shown in Formula I or Formula II:

[0049]

[0050] In the formula I and formula II, R is selected from

[0051] The X is selected from -S- or -O-;

[0052] The co-catalyst includes a first co-catalyst or a second co-catalyst;

[0053] The first co-catalyst is an alkali metal alkoxide;

[0054] The second co-catalyst includes an alkali agent and an alcohol compound; the alkali agent is KH, NaH, KN(SiMe3)2, NaN(SiMe3)2, LiN(SiMe3)2, n BuLi, MeLi, nitrogen heterocyclic carbene, nitrogen heterocyclic olefin or organic phosphine base, the nitrogen heterocyclic carbene has the structure shown in formula III, the nitrogen heterocyclic olefin has the structure shown in formula IV or formula V, and the organic phosphine base is t-Bu-P2, t-Bu-P4, TiBP, TTMPP, a compound with the structure shown in formula VI or a compound with the structure shown in formula VII:

[0055]

[0056]

[0057] In the formula III and formula IV, R1 to R4 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl;

[0058] In the formula V and formula VI, R1 to R6 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl;

[0059] In the formula VII, R1 to R3 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, n-butyl or phenyl.

[0060] In the cis catalyst of the present invention, two (thio) urea groups are close to each other, and can cooperate with each other during the ring-opening polymerization process, and the lactide monomer is activated by multiple hydrogen bonds, and the chain end is stabilized, so the catalytic conditions are mild, the selectivity is high, and polylactide with a wide range of molecular weight can be obtained, with higher initiation efficiency. Other organic catalyst systems reported before this basically have only one active site, and the two (thio) urea groups in the corresponding trans catalyst are far away from each other and cannot cooperate with each other. Therefore, ring-opening polymerization is carried out under the same temperature conditions, and compared with the corresponding trans catalyst, polylactide with higher stereoregularity can be obtained by using the cis catalyst of the present invention. The technical scheme of the present invention is described in detail below. In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0061] In the present invention, the cis-catalyst is preferably any one of the following compounds:

[0062]

[0063]

[0064] In the present invention, the cis-catalyst is more preferably the following compound:

[0065]

[0066] In the present invention, the first co-catalyst is an alkali metal alkoxide, and the alkali metal alkoxide preferably includes sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide, and more preferably is potassium methoxide.

[0067] In the present invention, the second co-catalyst includes an alkali agent and an alcohol compound. In the present invention, the alkali agent is KH, NaH, KN(SiMe3)2, NaN(SiMe3)2, LiN(SiMe3)2, n BuLi, MeLi, nitrogen heterocyclic carbene, nitrogen heterocyclic olefin or organic phosphine base, preferably KH, NaH, KN(SiMe3)2, NaN(SiMe3)2, LiN(SiMe3)2, n BuLi or MeLi. In the present invention, the nitrogen heterocyclic carbene has a structure shown in formula III, the nitrogen heterocyclic olefin has a structure shown in formula IV or formula V (the dotted line in formula V represents that the position can be a single bond or a double bond), and the organic phosphine base is t-Bu-P2, t-Bu-P4, TiBP, TTMPP, a compound having a structure shown in formula VI, or a compound having a structure shown in formula VII. In the present invention, the structural formulas of t-Bu-P2, t-Bu-P4, TiBP and TTMPP are shown in order as follows:

[0068]

[0069] In the present invention, the alcohol compound preferably includes methanol, ethanol, propanol, n-butanol, isobutanol, tert-butanol, isopropanol, phenol, benzyl alcohol, phenylethyl alcohol, butanediol or glycerol, more preferably methanol.

[0070] In the present invention, the lactide monomer preferably includes L-lactide, D-lactide, meso-lactide or racemic-lactide.

[0071] In the present invention, the molar ratio of the lactide monomer, the cis catalyst and the alkali metal alkoxide is preferably (10-2000):(1-100):(1-100), more preferably (100-1000):(1-10):(1-10), further preferably (200-800):(1-5):(1-5), and even more preferably (400-600):(1-3):(1-3).

[0072] In the present invention, the molar ratio of the lactide monomer, the cis catalyst, the alkaline reagent and the alcohol compound is preferably (10-2000): (1-100): (1-100): (1-100), more preferably (10-2000): (50-1000): (1-10): (1-10), further preferably (80-500): (1-5): (1-5): (1-5), and even more preferably (100-200): (1-3): (1-3): (1-3).

[0073] In the present invention, the organic solvent preferably includes tetrahydrofuran, toluene, dichloromethane, acetonitrile or chloroform, and more preferably tetrahydrofuran.

[0074] When the first co-catalyst is used, the present invention preferably dissolves the cis catalyst in an organic solvent, mixes the obtained cis catalyst solution with the first co-catalyst, then adds lactide monomer and supplements the organic solvent to obtain a mixed reaction liquid, and performs a ring-opening polymerization reaction. In the present invention, the concentration of the cis catalyst solution is preferably 0.0001-0.1 mol / L, more preferably 0.001-0.1 mol / L; the concentration of the lactide monomer solution in the mixed reaction liquid is preferably 0.1-1.0 mol / L, more preferably 0.3-0.5 mol / L. In the present invention, the temperature of the ring-opening polymerization reaction is preferably -80-100°C, more preferably -40-50°C, further preferably 0-35°C, and further preferably 15-25°C; the time is preferably 10min-48h, more preferably 20min-36h, further preferably 30min-32h, further preferably 1-20h, and further preferably 1.5-5h. In the present invention, the ring-opening polymerization reaction can be carried out in a dry Shrek bottle connected to a double Schlenk line to perform low-temperature ring-opening polymerization using an external temperature low-temperature bath, or in a glass reactor inside a glove box to perform room temperature ring-opening polymerization.

[0075] The present invention preferably takes out 0.1 mL of the reaction solution from the reaction system by a syringe or a pipette during the ring-opening polymerization reaction, and quickly quenches it into a vial containing 0.6 mL of undried CDCl3 (containing 250 ppm of BHT), and then 1H NMR analysis of the quenched sample is used to determine the conversion rate of the lactide monomer. After the ring-opening polymerization reaction is completed, the present invention preferably immediately adds hexane to the resulting product system, stirs to fully precipitate the polymer, and then filters it, washes the filter cake with hexane, and then dries it in a vacuum oven at 50°C overnight to constant weight to obtain the highly stereoregular polylactide. In the present invention, for polymer samples that need to be tested for homonuclear decoupling nuclear magnetic hydrogen spectrum, it is preferred to add dichloromethane for dissolution and then add hexane for precipitation, and repeat the dissolution-precipitation process three times to ensure that all lactide monomers and cis catalysts are removed.

[0076] When the second co-catalyst is used, the present invention preferably dissolves the cis catalyst in an organic solvent, mixes the obtained cis catalyst solution with an alkaline reagent, sequentially adds an alcohol compound and a lactide monomer to the obtained mixture, and further adds an organic solvent to obtain a mixed reaction liquid, and performs a ring-opening polymerization reaction. In the present invention, the concentration of the cis catalyst solution, the concentration of the lactide monomer in the mixed reaction liquid, the ring-opening polymerization reaction conditions, and the post-treatment method when the second co-catalyst is used are preferably the same as the concentration of the cis catalyst solution, the concentration of the lactide monomer in the mixed reaction liquid, the ring-opening polymerization reaction conditions, and the post-treatment method when the first co-catalyst is used, and will not be repeated here.

[0077] In the present invention, the weight average molecular weight of the polylactide is preferably 1.0 to 100 kg / mol, more preferably 10.0 to 50.0 kg / mol, and further preferably 14.0 to 35.0 kg / mol; the isotacticity P m (the lactide monomer is L-lactide, D-lactide or racemic lactide) is preferably 0.76 to 1.0, more preferably 0.85 to 0.96; heteroisotacticity P r (the lactide monomer is meso-lactide) is preferably 0.80 to 0.91, and more preferably 0.90 to 0.91. The lactide monomer provided by the present invention has a wide range of applications. As shown in the results of the embodiments, the polymerization of left-handed lactide or right-handed lactide can be achieved. During the polymerization process, the lactide monomer does not undergo diastereoisomerization, and P can be obtained by polymerization under room temperature. m The polylactide with a molecular weight of 17.0 to 18.4 kg / mol can be prepared by stereoselective ring-opening polymerization of racemic lactide to synthesize highly isotactic lactide. Polymerization at room temperature (25°C) can obtain P m Polylactide with a molecular weight of 0.85 to 0.92 and a weight average molecular weight of 14.7 to 93.5 kg / mol can even be obtained by polymerization at -40 °C. m The polylactide with a molecular weight of 0.96 and a weight average molecular weight of 30.1 kg / mol can be obtained; in addition, the polymerization of meso-lactide can be achieved at room temperature to finally obtain heterotactic polylactide, Pr The molecular weight is 0.90-0.91 and the weight average molecular weight is 16.2-16.5 kg / mol.

[0078] The cis catalyst of the present invention can be a commercially available product well known to those skilled in the art. Some of the cis catalysts can be prepared by methods well known to those skilled in the art. The preparation method of the cis catalyst of the present invention is described below using the catalyst RS-DiTU as an example. Specifically, the structural formula of the catalyst RS-DiTU is as follows:

[0079]

[0080] (R, S)-1,2-cyclohexanediamine (2.28 g, 20 mmol) was dissolved in 60 mL of dichloromethane, and then the resulting solution was cooled to 0°C using an ice-salt bath, 3,5-bis(trifluoromethyl)phenylisothiocyanate (11.1 g, 41 mmol) was slowly added dropwise thereto, and the ice bath was stopped after the addition was complete. The reaction was carried out at room temperature (25°C) for 30 min. The resulting product system was filtered, and the resulting solid material was washed with dichloromethane to obtain a white solid product, which was the catalyst RS-DiTU, and its English name was 1,1'-((1R, 2S)-cyclohexane-1,2-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea). The white solid product was placed in a vacuum oven, vacuum dried at 70°C overnight to remove residual solvent and water, and then transferred to a glove box for standby use. 1 H NMR(500MHz,DMSO-d6)δ1.32(m,4H,CH2CH2CH2CH2),1.72(m,2H,CHCH2),2.20(m,2H,CHCH2),4.3 4(m,2H,NCH),7.71(s,2H,p-Ar-H),8.15(s,2H,CHNH),8.18(s,4H,o-Ar-H),10.13(s,2H,ArNH). 13 C NMR (126MHz, DMSO-d6) δ22.3, 28.3, 53.1, 116.6, 122.2, 124.8, 130.5, 130.7, 142.3, 180.8.

[0081] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0082] Examples 1 to 8

[0083] The ring-opening polymerization reactions involved in Examples 1 to 8 were specifically carried out in a 25 mL dry Shrek bottle connected to a double Schlenk line to use an external temperature low temperature bath for low temperature ring-opening polymerization, or in a 20 mL glass reactor inside a glove box for room temperature ring-opening polymerization, and the specific steps are as follows:

[0084] The catalyst RS-DiTU was dissolved in tetrahydrofuran (THF) to obtain a catalyst RS-DiTU solution with a concentration of 0.1M, and the catalyst RS-DiTU solution was mixed with an equivalent amount of an organic base KOMe, and after stirring for 2 minutes, the obtained mixed solution was added to a vial containing a lactide monomer, and then THF was added to make the concentration of the lactide monomer 0.5 mol / L, and a ring-opening polymerization reaction was carried out, and the molar ratio of the lactide monomer to the organic base KOMe met the ratio in Table 1; wherein, during the ring-opening polymerization reaction, 0.1 mL of the reaction solution was taken out from the reaction system by a pipette, and quickly quenched into a vial containing 0.6 mL of undried CDCl3 (containing 250 ppm of BHT), and then 1 H NMR analysis of the quenched samples was used to determine the conversion of lactide monomer;

[0085] After the ring-opening polymerization reaction was completed, hexane was immediately added to the obtained product system for precipitation, and the product was filtered after stirring for 1 hour, and the filter cake was washed with hexane and then dried in a vacuum oven at 50°C overnight to constant weight;

[0086] For polymer samples that need to be tested by homonuclear decoupling H-NMR, three dissolution and precipitation steps are required using dichloromethane and hexane to ensure that all lactide monomers and the catalyst RS-DiTU are removed;

[0087] The structural formula of the catalyst RS-DiTU is as follows:

[0088]

[0089] The types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reactions in Examples 1 to 8 are shown in Table 1. Figures 1 to 8 The homonuclear decoupling hydrogen spectra (CDCl3, 500 MHz) of the polylactides prepared in Examples 1 to 8 are shown in Table 1 and Figures 1 to 8 It can be seen that the cis-catalyst provided by the present invention and KOMe as a co-catalyst can catalyze the polymerization of lactide to obtain highly isotactic polylactide.

[0090] Table 1 Conditions and results of the polymerization of lactide catalyzed by chiral dithiourea and organic base in Examples 1 to 8

[0091]

[0092] Note: a The reaction conditions were: initial molar ratio of RS-DiTU to KOMe was [RS-DiTU]0 / [KOMe]0=1 / 1, THF, and room temperature (25°C). b pass 1 H NMR was measured in CDCl3 using characteristic signal integration. c M was measured in THF at 35 °C by laser light scattering detection. w and d Using Same-core Decoupling 1 H NMR spectroscopy was measured in conjunction with the methine tetrad (δ 5.25-5.18 ppm). e The ring-opening polymerization (ROP) reaction was carried out at -40 °C.

[0093] Embodiments 9 to 15

[0094] The ring-opening polymerization reaction involved in Examples 9 to 15 is specifically carried out at room temperature in a 20 mL glass reactor inside a glove box, and the specific steps are as follows:

[0095] The catalyst RS-DiTU was dissolved in THF to obtain a catalyst RS-DiTU solution with a concentration of 0.1M, the catalyst RS-DiTU solution was mixed with a base, and after stirring for 2 minutes, methanol was added, and then the obtained mixed solution was added to a vial containing a lactide monomer, and then THF was added to make the concentration of the lactide monomer 0.5 mol / L, and a ring-opening polymerization reaction was carried out, and the initial molar ratio of the lactide monomer, the catalyst RS-DiTU, the base and the methanol was 100:1:1:1; wherein, during the ring-opening polymerization reaction, 0.1 mL of the reaction solution was taken out from the reaction system by a pipette, and quickly quenched into a vial containing 0.6 mL of undried CDCl3 (containing 250 ppm of BHT), and then 1 H NMR analysis of the quenched samples was used to determine the conversion of lactide monomer;

[0096] After the ring-opening polymerization reaction was completed, hexane was immediately added to the obtained product system for precipitation, and the product was filtered after stirring for 1 hour, and the filter cake was washed with hexane and then dried in a vacuum oven at 50°C overnight to constant weight;

[0097] For polymer samples that need to be tested by homonuclear decoupling H-NMR, three dissolution and precipitation steps are required using dichloromethane and hexane to ensure that all lactide monomers and the catalyst RS-DiTU are removed.

[0098] The types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reaction in Examples 9 to 15 are shown in Table 2. As can be seen from Table 2, the cis-catalyst provided by the present invention and other organic bases and alcohols as co-catalysts can also catalyze the polymerization of lactide to obtain highly isotactic polylactide. Table 2 Conditions and results of chiral dithiourea combined with base and alcohol to catalyze the polymerization of racemic lactide in Examples 9 to 15

[0099]

[0100] Note: a The reaction conditions were as follows: initial molar ratio of rac-LA, RS-DiTU, base and methanol was [rac-LA]0 / [RS-DiTU]0 / [base]0 / [methanol]0=100 / 1 / 1 / 1, THF, room temperature. b pass 1 H NMR was measured in CDCl3 using characteristic signal integration. c M was measured in THF at 35 °C by laser light scattering detection. w and d Using Same-core Decoupling 1 H NMR spectroscopy was determined in conjunction with the methine tetrad (δ 5.25-5.18 ppm).

[0101] Examples 16 to 23

[0102] Polylactide was prepared by referring to the method of Example 9. The types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reactions in Examples 16 to 23 are shown in Table 3. Fig. 9 The homonuclear decoupling hydrogen spectrum (CDCl3, 500MHz) of the polylactide prepared in Example 23 is shown in Table 3 and Fig. 9 It can be seen that the cis-catalyst provided by the present invention and other organic bases and alcohols as co-catalysts can catalyze the polymerization of meso-lactide to obtain highly heteroisotactic polylactide.

[0103] Table 3 Conditions and results of chiral dithiourea-catalyzed meso-lactide polymerization in Examples 16 to 23

[0104]

[0105] Note: a The reaction conditions were as follows: the initial molar ratio of rac-LA, RS-DiTU, base reagent and methanol was [rac-LA]0 / [RS-DiTU]0 / [base]0 / [methanol]0=100 / 1 / 1 / 1, THF, room temperature. b pass 1 H NMR was measured in CDCl3 using characteristic signal integration. cM was measured in THF at 35 °C by laser light scattering detection. w and d Using Same-core Decoupling 1 H NMR spectroscopy was determined in conjunction with the methine tetrad (δ 5.25-5.18 ppm). e Only MeOK was used without MeOH.

[0106] Embodiments 24 to 28

[0107] The ring-opening polymerization reaction was carried out according to the methods of Examples 3 to 7, except that the catalyst RS-DiTU was replaced by the catalyst RS-DiTU1, and the reaction time of each example was specifically shown in Table 4; the structural formula of the catalyst RS-DiTU1 is shown below:

[0108]

[0109] The types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reactions in Examples 24 to 28 are shown in Table 4. As can be seen from Table 4, the cis-catalyst provided by the present invention and KOMe as a co-catalyst can catalyze the polymerization of lactide to obtain highly isotactic polylactide.

[0110] Table 4 Conditions and results of the polymerization of lactide catalyzed by chiral dithiourea and organic base in Examples 24 to 28

[0111]

[0112] Note: a The reaction conditions were: the initial molar ratio of RS-DiTU1 to KOMe was [RS-DiTU1]0 / [KOMe]0=1 / 1, THF, and room temperature (25°C). b pass 1 H NMR was measured in CDCl3 using characteristic signal integration. c M was measured in THF at 35 °C by laser light scattering detection. w and d Using Same-core Decoupling 1 H NMR spectroscopy was measured in conjunction with the methine tetrad (δ 5.25-5.18 ppm).

[0113] Embodiment 29

[0114] The KOMe in Example 3 was replaced by benzyl alcohol (BnOH) and NHO, and the relevant reaction conditions were specifically shown in Table 5; the structural formula of the NHO is shown below:

[0115]

[0116] Table 5 shows the types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reaction in Example 29. It can be seen from Table 5 that the cis-catalyst provided by the present invention and BnOH and NHO as co-catalysts can catalyze the polymerization of lactide to obtain highly isotactic polylactide, P m is 0.91, while if the trans catalyst is used, P m Only 0.70 (Wang, ZY; Xu, GQ; Zhou, L.; Lv, CD; Yang, RL; Dong, BZ; Wang, QGIsoselective ring-opening polymerization of racemic lactide catalyzed by N-heterocyclic olefin / (thio)urea organocatalysts.ChineseJ.Polym.Sci.2021,39,709-715.).

[0117] Table 5 Types of raw materials, ratios, reaction conditions and test results involved in the ring-opening polymerization reaction in Example 29

[0118]

[0119] Note: a The reaction conditions were: initial molar ratio of RS-DiTU to KOMe was [RS-DiTU]0 / [KOMe]0=1 / 1, THF, and room temperature (25°C). b pass 1 H NMR was measured in CDCl3 using characteristic signal integration. c M was measured in THF at 35 °C by laser light scattering detection. w and d Using Same-core Decoupling 1 H NMR spectroscopy was measured in conjunction with the methine tetrad (δ 5.25-5.18 ppm).

[0120] Qing-Gang Wang et al. (Wang, ZY; Xu, GQ; Zhou, L.; Lv, CD; Yang, RL; Dong, BZ; Wang, QG Isoselective ring-opening polymerization of racemic lactide catalyzed by N-heterocyclic olefin / (thio)urea organocatalysts. Chinese J. Polym. Sci. 2021, 39, 709-715.) disclosed a trans-bis(thio)urea catalyst (denoted as SS-DiTU) having a chiral center. In the present invention, the SS-DiTU catalyst is used as a comparison, and is compared with the cis catalyst, i.e., the RS-DiTU catalyst, in the present invention based on theoretical calculations. The structural formulas of the SS-DiTU catalyst and the RS-DiTU catalyst are shown below:

[0121]

[0122] Fig.10 This is the energy barrier diagram of the initiation stage of the ring-opening polymerization reaction catalyzed by SS-DiTU catalyst. The results show that in the catalytic process, only one thiourea group of SS-DiTU catalyst is involved, and the rate-limiting energy barrier is 20.1 kcal / mol. Fig.11 This is the energy barrier diagram of the initiation stage of the ring-opening polymerization reaction catalyzed by RS-DiTU catalyst. The results show that in the catalytic process, the two thiourea groups of the RS-DiTU catalyst participate synergistically, and the rate-limiting energy barrier is lower, which is 14.2 kcal / mol, so the catalytic activity is high.

[0123] In the process of catalytic chain growth using a cis catalyst, if the chiral structure of the next monomer is the same as that of the chain end, the monomer will be inserted from the right side with large steric hindrance but matching chiral environment for chain growth, and the energy barrier is 15.2 kcal / mol. If the chiral structure of the next monomer is different from that of the chain end, the monomer will be inserted from the left side with smaller steric hindrance for chain growth, and the energy barrier is 18.8 kcal / mol. The two insertion modes are as follows: Fig.12 As shown. When using a trans-catalyst to catalyze chain growth, regardless of whether the chiral structure of the next monomer is the same as the chiral structure of the chain end, the monomer will be inserted from the cyclohexyl side to grow the chain. The energy barriers of the two methods are not much different. The two insertion methods are shown in Fig.13 As shown. Fig.12 and Fig.13It can be seen that the cis catalyst has site selectivity for monomers of different chirality during chain growth, and monomers of different chirality are inserted from different positions; while the trans catalyst has no site selectivity for monomers of different chirality, and monomers of different chirality are inserted from the same position.

[0124] Fig.14 Schematic diagram of the ring-opening polymerization reaction catalyzed by RS-DiTU catalyst in the present invention, Fig.14 It can be seen that different types of lactide monomers can be subjected to stereoselective ring-opening polymerization under the multi-site synergistic catalysis of RS-DiTU catalyst to finally obtain highly stereoregular polylactide with full isotacticity P m (Lactide monomer is L-lactide, D-lactide or racemic lactide) can reach 1.0, heteroisotacticity P r (the lactide monomer is meso-lactide) can reach 0.91, and the molecular weight and molecular weight distribution of polylactide are controllable.

[0125] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a highly stereoregular polylactide, comprising the following steps: Mixing lactide monomer, cis catalyst, co-catalyst and organic solvent to carry out ring-opening polymerization to obtain the highly stereoregular polylactide; The cis catalyst is the following compound: ； ； The co-catalyst includes a first co-catalyst or a second co-catalyst; The first co-catalyst is an alkali metal alkoxide; The second co-catalyst includes an alkali agent and an alcohol compound; the alkali agent is KH, NaH, KN(SiMe3)2, NaN(SiMe3)2, LiN(SiMe3)2, n BuLi, MeLi, nitrogen heterocyclic carbene, nitrogen heterocyclic olefin or organic phosphine base, the nitrogen heterocyclic carbene has the structure shown in formula III, the nitrogen heterocyclic olefin has the structure shown in formula IV or formula V, and the organic phosphine base is t -Bu-P2, t -Bu-P4, TiBP, TTMPP, a compound having a structure shown in Formula VI or a compound having a structure shown in Formula VII: Formula III; Formula IV; Formula V; Formula VI; Formula VII; In the formula III and formula IV, R1 to R4 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl; In the formula V and formula VI, R1 to R6 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, phenyl or 2,4,6-trimethylphenyl; In the formula VII, R1 to R3 are independently selected from hydrogen, pentafluorophenyl, methyl, isopropyl, tert-butyl, n-butyl or phenyl; The molar ratio of the lactide monomer, the cis catalyst and the alkali metal alkoxide is (10-2000): (1-100): (1-100); The molar ratio of the lactide monomer, the cis catalyst, the alkaline reagent and the alcohol compound is (10-2000): (1-100): (1-100): (1-100); The ring-opening polymerization reaction is carried out at a temperature of -40 to 100°C and a time of 10 minutes to 48 hours; The weight average molecular weight of the highly stereoregular polylactide is 1.0 to 100 kg / mol, and the isotacticity is P m 0.76~1.0, heterotacticity P r It is 0.80~0.

91.

2. The preparation method according to claim 1, characterized in that: The alkali metal alkoxide includes sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.

3. The preparation method according to claim 1, characterized in that: The alcohol compound includes methanol, ethanol, propanol, n-butanol, isobutanol, tert-butanol, phenol, benzyl alcohol, phenylethyl alcohol, butanediol or glycerol.

4. The preparation method according to claim 1, characterized in that: The lactide monomer includes L-lactide, D-lactide, meso-lactide or racemic-lactide.

5. The preparation method according to claim 1, characterized in that: The organic solvent includes tetrahydrofuran, toluene, acetonitrile or chloroform.

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