Rapid controllable catalytic polymerization method of polymer

Abstract

The invention provides a rapid controllable catalytic polymerization method of a polymer. Specifically, the invention provides a catalytic synthesis method for catalytically synthesizing polypeptide, polyester and polypeptide-polyester copolymer by using a quaternary ammonium salt cationic catalyst.

Description

Technical Field

[0001] The invention belongs to the field of catalytic polymerization, and specifically provides a rapid and controllable catalytic polymerization method for a polymer, and relates to a catalytic synthesis method for synthesizing a polypeptide, a polyester, and a polypeptide-polyester copolymer by using a quaternary ammonium salt cationic catalyst. Background Art

[0002] Amino acid polymers (polypeptides or polypeptides) have been widely studied and applied in various bioengineering fields such as protein / peptide simulation, antimicrobial agent development, tissue engineering, and drug / gene delivery due to their good biocompatibility and unique biological activity. Polyesters are widely used in the manufacture of engineering materials such as leather, fiber, and food packaging films. They will not cause environmental pollution after retirement and are sustainable green polymer materials. They have been widely studied and applied. Therefore, the synthesis of amino acid polymers and polyesters has important research significance.

[0003] However, the most commonly used initiators (primary amines, organic bases) for α-amino acid N-carboxyl carbonyl cyclic anhydride monomers (NCA) are affected by the decarboxylation rate limit or fear of water. The NCA ring-opening polymerization system still has a lot of room for improvement in terms of polymerization speed and polymerization controllability. For example, it usually takes several days for NCA polymerization initiated by primary amines to complete polymerization, or even no polymerization; NCA polymerization initiated by strong organic bases has poor controllability and a wide molecular weight distribution. For the polymerization of monomers such as cyclic esters, the polymerization conversion rate is low without the addition of a catalyst, and the molecular weight of the obtained polymer is small, so there is still a lot of room for improvement.

[0004] Catalytic polymerization strategies can accelerate polymerization or improve controllability under mild conditions and have been widely studied in recent years. Existing catalytic strategies are usually limited to improving the polymerization reaction rate, and fail to simultaneously solve the key problem of poor polymerization controllability; or they only focus on improving polymerization controllability, sacrificing polymerization rate, resulting in difficulties such as long polymerization reaction time, harsh conditions, and high operating difficulty. For primary amine and base initiation systems, the inability to balance rapid polymerization and polymerization controllability is a core challenge that has not been solved. Therefore, it is urgent to establish an original and universal catalytic strategy, discover new efficient catalysts, and completely solve the core problems of slow speed and poor controllability of NCA polymerization and cyclic ester polymerization systems, so as to achieve a fast and controllable catalytic polymerization method. Summary of the invention

[0005] The purpose of the present invention is to provide an original and groundbreaking catalytic polymerization method, which uses a quaternary ammonium salt cationic catalyst to catalyze the rapid and controllable ring-opening polymerization of cyclic monomers (including NCA, NNCA, NTA, NNTA and cyclic ester monomers) initiated by an organic base, alcohol or carboxylate to prepare a polymer.

[0006] In a first aspect of the present invention, there is provided a method for catalytic polymerization of a polymer, comprising the steps of:

[0007] (a) polymerizing one or more cyclic monomers in the presence of a catalyst and an initiator to form a polymer;

[0008] Wherein, the catalyst is selected from the group consisting of a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV, or a combination thereof;

[0009]

[0010] in,

[0011] X1 is N or P;

[0012] Z1, Z2, Z3, and Z4 are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4alkyl-3-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, C0-C4alkylC6-C 12 Aryl, C0-C4 alkyl-5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-, or any two of Z1, Z2, Z3 and Z4 together with the X1 atom to which they are connected constitute a substituted or unsubstituted 3-12 heterocyclic group (including a monocyclic, spirocyclic, bridged or cyclic group); wherein the substitution refers to the replacement of one or more H on the group by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl; or 1, 2 or 3 of Z1, Z2, Z3 and Z4 are connected to the corresponding number of groups of Z1, Z2, Z3 and Z4 in another formula I to form a compound having two X1 centers, wherein the connection is connected by forming 1, 2 or 3 groups independently selected from C1-C6 alkylene;

[0013] Z1', Z2', Z3', Z4', Z5' and Z6' are each independently selected from the group consisting of substituted or unsubstituted hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C 12 Alkyl, C1-C 12 Haloalkyl, -N(C1-C6 alkyl) 1-2 、C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C0-C4 alkyl, C3-C 12Cycloalkyl, C0-C4 alkyl having 3-12 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O, C0-C4 alkyl C6-C 12 Aryl, C0-C4 alkyl having 5-12 membered heteroaryl with 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl ester group, C1-C6 alkyl CO-, or two adjacent carbon atoms of Z1', Z2', Z3' and Z4' together with the carbon atoms to which they are connected constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered or heterocyclic group (including monocyclic, spirocyclic, bridged or fused rings); wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0014] R1 and R2 are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, -C0-C4 alkyl, C3-C 12 Cycloalkyl, -C0-C4alkyl-3-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, -C0-C4alkylC6-C 12 Aryl, -C0-C4 alkyl, 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-; wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0015] X2 is N or CH;

[0016] R, R1', R2', R3', R4', R5' are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C3-C 12 Cycloalkyl, C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4 alkyl having 3-12 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O, C0-C4 alkyl C6-C 12 Aryl, C0-C4 alkyl having 5-12 membered heteroaryl with 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-; any two of R1', R2', R3', R4', R5' and the atoms to which they are connected together constitute a substituted or unsubstituted 3-12 membered heterocyclic group (including a monocyclic, spirocyclic, bridged or cyclic group); wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0017] Wherein, the monomer is selected from the following group: N-carboxyl carbonyl cyclic anhydride, N-substituted N-carboxyl carbonyl cyclic anhydride, N-carboxyl thiocarbonyl cyclic anhydride, N-substituted N-carboxyl thiocarbonyl cyclic anhydride, cyclic ester monomer, lactide, or a combination thereof.

[0018] In another preferred embodiment, the monomer is selected from formula (V), (VI), (VII), or a combination thereof;

[0019]

[0020] Wherein, Y is S or O;

[0021] m is independently 0, 1, 2, 3 or 4;

[0022] R", R1", R2", R1"', R2"', R3"' and R4"' are each independently selected from the group consisting of substituted or unsubstituted hydrogen, amino, C1-C 12 Alkyl, C1-C 12 Haloalkyl, -CH3(O-CH2-CH2) 1-6 , amino-substituted C1-C 12 Alkyl, -C1-C 12 Alkyl-N3, hydroxy substituted C1-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkylthio, 2-12 membered heteroalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C 12 Alkylsulfonyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C6-C 12 Aryl, 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, 3-12 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of N, S and O, -C1-C6 alkylguanidinyl, -(C0-C8 alkylene)-LR a or R1" and R2" on the same or adjacent carbon atoms together with the carbon atoms to which they are attached constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; or two R1"' or R1"' and R2"' together with the carbon atom to which they are attached constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the substitution refers to the substitution independently by one or more (e.g., 2, 3, 4, etc.) R m replace;

[0023] L is independently a chemical bond, -O-, -S-, -SS-, NHCO, -CO-, -COO-, -S(=O)2-, NH, or guanidinyl;

[0024] Each R a are independently selected from the following groups: substituted or unsubstituted: hydrogen, C1-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkylamino, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -(C0-C4 alkylene)-C3-C 12 Cycloalkyl, -(C0-C4 alkylene)-C4-C 12 Cycloalkenyl, -(C0-C4 alkylene)-5-12 membered heterocyclic group, -(C0-C4 alkylene)-C6-C 12 Aryl, -(C0-C4 alkylene)-5-12 membered heteroaryl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), phthaloyl (Pht), acetyl (Ac), trifluoroacetyl (Tfa), benzyl (Bn), triphenylmethyl (Tr); wherein the substitution refers to independently replacing one or more (e.g., 2, 3, 4, etc.) R m replace;

[0025] R m independently selected from the following groups substituted or unsubstituted: halogen, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, methylsulfone, -S(=O)2NH2, oxo (=O), -CN, -N3, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C6-C 12 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, 5-10 membered heterocyclic group having 1-3 heteroatoms selected from the group consisting of N, S and O, -N(C1-C6 alkyl) 1-2 , C1-C6 amide, -COOH, -SH, benzyl, -PhOH, benzyloxycarbonyl (Cbz), trityl (Trt), trifluoromethyl, glucosyl or

[0026] Y1, Y2, Y3, and Y4 are anionic groups that counteract the positive charge.

[0027] In another preferred embodiment, Y1, Y2, Y3, and Y4 are independently selected from the following groups: F, Cl, Br, I, BF4, PF6.

[0028] In another preferred embodiment, Z1, Z2, Z3, and Z4 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C2 alkyl C3-C6 cycloalkyl, C1-C2 alkylphenyl, and C1-C2 alkyl-5-6 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.

[0029] In another preferred embodiment, Z1', Z2', Z3', Z4', Z5' and Z6' are each independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -N(C1-C6 alkyl) 1-2 , C1-C2 alkyl, C3-C6 cycloalkyl, C1-C2 alkylphenyl, C1-C2 alkyl-5-6 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; wherein the substitution means that one or more H on the group is replaced by a substituent selected from the group consisting of halogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0030] In another preferred embodiment, R1 and R2 are each independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C1-C6 haloalkyl, C1-C2 alkyl C3-C6 cycloalkyl, C1-C2 alkylphenyl, C1-C2 alkyl-5-6 membered heteroaryl having 1-3 heteroatoms selected from the following group N, S and O; wherein the substitution means that one or more H on the group is replaced by a substituent selected from the following group: halogen, C1-C3 alkyl and C1-C3 haloalkyl.

[0031] In another preferred embodiment, R, R1', R2', R3', R4', and R5' are each independently selected from the following substituted or unsubstituted group: C1-C6 alkyl, C1-C6 haloalkyl; or wherein R4' and R5' together with the atoms to which they are connected constitute a substituted or unsubstituted 3-8 membered heterocyclic group, R2' and R3' together with the atoms to which they are connected constitute a substituted or unsubstituted 3-8 membered heterocyclic group, and the other groups are each independently selected from the following substituted or unsubstituted group: C1-C6 alkyl, C1-C6 haloalkyl.

[0032] In another preferred embodiment, the catalyst is selected from the following group and its salt:

[0033]

[0034] Preferably, the anionic group that counteracts the positive charge is selected from the group consisting of F, Cl, Br, I, BF4, PF6.

[0035] In another preferred embodiment, the catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylphosphine chloride, triethylbenzylammonium chloride, tetramethylammonium chloride, triethylbenzylammonium chloride,

[0036]

[0037] or a combination thereof.

[0038] In another preferred embodiment, the initiator is an organic base or a nucleophilic reagent.

[0039] In another preferred embodiment, the initiator is selected from the group consisting of primary amines, secondary amines, tertiary amines, alcohols, thiols, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, carboxylates, phosphazene bases, alkoxides, thiolates,

[0040]

[0041] or a combination thereof.

[0042] In another preferred embodiment, the initiator is selected from the group consisting of n-butylamine, p-tert-butylbenzylamine, adamantane amine, propargylamine, 3-azidopropylamine, cyclohexylamine, polyethylene glycol amine, four-arm polyethylene glycol amine, tetrabutylammonium acetate, tetramethylammonium acetate, tetrabutylammonium benzoate, methanol, p-tert-butylbenzyl alcohol, benzyl alcohol, ethanol, tert-butanol, ethylene glycol, glycerol, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide,

[0043]

[0044] or a combination thereof.

[0045] In another preferred embodiment, the monomer is selected from the following group: N-carboxyl carbonyl cyclic anhydride, cyclic ester monomer, or a combination thereof.

[0046] In another preferred embodiment, the monomer is selected from the following group: amino acid N-carboxyl carbonyl ring anhydride, N-methyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride, or a combination thereof.

[0047] In another preferred embodiment, the monomer is selected from the following group: β-propiolactone, valerolactone, glycolide, lactide, or a combination thereof.

[0048] In another preferred embodiment, the monomer is selected from the following group: L-type amino acid N-carboxyl carbonyl ring anhydride, D-type amino acid N-carboxyl carbonyl ring anhydride, D, L-type amino acid N-carboxyl carbonyl ring anhydride, or a combination thereof.

[0049] In another preferred embodiment, the amino acid is a natural amino acid or a non-natural amino acid.

[0050] In another preferred embodiment, the amino acid is selected from the following group: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, asparagine, glutamic acid, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, or a combination thereof.

[0051] In another preferred embodiment, the R", R1", R2", R1"', R2"', R3"' and R4"' are each independently selected from the following groups: H,

[0052]

[0053] In another preferred embodiment, one of R″ and R1″ is a non-H group, and the other is H.

[0054] In another preferred embodiment, the monomer is selected from the following group:

[0055]

[0056] In another preferred embodiment, the monomer is purified or unpurified.

[0057] In another preferred embodiment, the molecular weight of the polymer is determined by the activity of the monomer and the feed ratio of the monomer to the initiator, preferably 200,000 ≥ M n ≥1000(g / mol), such as 100,000≥M n ≥2000, 50,000 ≥M n ≥3000 or 20,000 ≥M n ≥4000.

[0058] In another preferred embodiment, the equivalent ratio of the monomer to the initiator is 20-1000:1, such as 50:1, 100:1 or 200:1.

[0059] In another preferred embodiment, the equivalent ratio of the monomer to the initiator is 1-1000:1, such as 50:1, 100:1 or 200:1.

[0060] In another preferred embodiment, the polymerization reaction is carried out in the presence of an organic base initiator (such as n-butylamine, lithium bis(trimethylsilyl)amide, 1,8-diazacyclo[5,4,0]undecene-7).

[0061] In another preferred embodiment, the polymerization reaction is carried out in the presence of a carboxylate initiator (such as tetrabutylammonium acetate, tetrabutylammonium benzoate, tetramethylammonium acetate).

[0062] In another preferred embodiment, one or more (such as two, three, four or more) monomers are polymerized to obtain a polymer.

[0063] In another preferred embodiment, one or more (such as two, three, four or more) monomers of the compound of formula V are polymerized to obtain a polymer.

[0064] In another preferred embodiment, one or more (such as two, three, four or more) monomers of the compound of formula VI are polymerized to obtain a polymer.

[0065] In another preferred embodiment, the polymer is a homopolymer or a copolymer.

[0066] In another preferred embodiment, the copolymer is a random copolymer or a block copolymer.

[0067] In another preferred embodiment, the polymer is a multi-segment block polymer.

[0068] In another preferred embodiment, when the monomers are two or more (such as three, four or more), the method comprises the steps of:

[0069] In the presence of a catalyst and an initiator, two or more (such as three, four or more) monomers are mixed and then polymerized to form a random copolymer;

[0070] or (a) subjecting a first monomer to a polymerization reaction in the presence of a catalyst and an initiator;

[0071] (b) after the above polymerization reaction is completed, adding a second monomer to carry out polymerization reaction;

[0072] and optionally (c) repeating (b) 0-p times, with the proviso that the monomers in each step of step (c) are different from the monomers in the previous step, thereby forming a block copolymer;

[0073] Among them, p≥1.

[0074] In another preferred embodiment, the monomers are each independently an N-carboxyl carbonyl intracyclic anhydride.

[0075] In another preferred embodiment, in the step (c), p≥1, preferably p≥5, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0076] In another preferred embodiment, the molecular weight of the block copolymer can reach more than 20,000.

[0077] In another preferred embodiment, the first monomer is N-carboxyl carbonyl cyclic anhydride, and the second monomer is a cyclic ester (such as propiolactone, valerolactone, lactide).

[0078] In another preferred embodiment, the monomer of the compound of formula V is selected from the following group:

[0079]

[0080] In another preferred embodiment, the monomer of the compound of formula VI is selected from the following group:

[0081]

[0082] In another preferred embodiment, the reaction is carried out in an inert solvent or in a solvent-free environment;

[0083] Preferably, the inert solvent is selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dioxane, dimethyl sulfoxide, dichloromethane, chloroform, acetone, N-methylpyrrolidone, esters, aromatic hydrocarbons, alkanes, water, or a combination thereof.

[0084] In another preferred embodiment, the inert solvent is tetrahydrofuran.

[0085] In another preferred embodiment, the inert solvent is dichloromethane.

[0086] In another preferred embodiment, the reaction is carried out in an inert solvent, and the method comprises the following steps:

[0087] (i) providing a monomer solution, an initiator solution, and a catalyst solution;

[0088] (ii) adding the initiator solution described in step (i) to the stirred monomer solution to carry out a polymerization reaction, thereby obtaining a polymer;

[0089] The solvent of the monomer solution and the solvent of the initiator solution are the same or different.

[0090] In another preferred embodiment, the kinetic constant k of the polymerization reaction is p [I] More than 2 hours -1 .

[0091] In another preferred embodiment, the polymerization reaction (each step independently) is carried out at 0-120°C, preferably at 10-100°C, preferably at 15-60°C, preferably at 20-40°C.

[0092] In another preferred embodiment, the polymerization reaction time is ≤30h, ≤24h, ≤18h, ≤12h, ≤10h, ≤9h, ≤8h, ≤7h, ≤6h, ≤5h, ≤4h, ≤3h, ≤2h, ≤1h, ≤30min, ≤10min, ≤5min, ≤1min, ≤30s, ≤20s or ≤10s.

[0093] In another preferred embodiment, the concentration of the monomer solution is 0.02-5 mol / L, preferably 0.1-0.5 mol / L, more preferably 0.1-0.25 mol / L, for example 0.1 mol / L, 0.125 mol / L, 0.2 mol / L, 0.25 mol / L.

[0094] In another preferred embodiment, the concentration of the initiator solution is 0.01-1.5 mol / L, preferably 0.1-0.5 mol / L, and more preferably 0.1 mol / L.

[0095] In another preferred embodiment, the concentration of the catalyst solution is 0.01-4 mol / L, preferably 0.01-0.5 mol / L, and more preferably 1 mol / L.

[0096] In another preferred embodiment, the volume ratio of the initiator solution to the monomer solution is 1:3-100, preferably 1:4-1:1000, for example 1:50, 1:100, 1:500.

[0097] In another preferred embodiment, the solvents of the initiator solution and the monomer solution are each independently an organic solvent selected from the following group: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dioxane, dimethyl sulfoxide, dichloromethane, chloroform, acetone, N-methylpyrrolidone, esters, aromatic hydrocarbons, alkanes, or a combination thereof.

[0098] In another preferred embodiment, the added equivalent amount of the catalyst is 0.1%-20% compared to the added equivalent amount of the monomer, such as 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 8%, 10%, 15%.

[0099] In another preferred embodiment, the equivalent ratio of the initiator to the monomer is 5-10,000:1, such as 10:1, 50:1, 100:1, 200:1, 500:1, 1000:1, 5000:1 or 10000:1.

[0100] In another preferred embodiment, the reaction time of the preparation method is shortened to less than 50% of that without adding a catalyst (to achieve the same reaction rate), such as 1%, 5%, 10%, 15%, 20%, 30% or less than 40%.

[0101] In a second aspect of the present invention, a polymer is provided, wherein the polymer comprises one or more polymer units represented by formula VIII, formula IX and formula X,

[0102]

[0103] R", R1", R2", R1"', R2"' are as defined above, m, m1, m2 are independently selected from 0, 1, 2, 3 or 4; n, n1, n2 are independently positive integers ≥ 2 (eg, 3-10,000).

[0104] In another preferred embodiment, n, n1, and n2 are independently positive integers of 5-100, such as 10, 15, 20, 25, 30, 40, 50, 60, 70, 80 or 90.

[0105] In another preferred embodiment, the polymer contains one or more of the following polymer units:

[0106]

[0107]

[0108] wherein each n2 is independently an integer ≥2 (e.g., 3-20,000), preferably 3-10,000, more preferably 3-5000, and preferably a positive integer of 5-100, such as 10, 15, 20, 25, 30, 40, 50, 60, 70, 80 or 90.

[0109] In another preferred embodiment, the polymer contains one or more of the following polymer units:

[0110]

[0111] Among them, 0%<x1≤100%; 0%≤y1<100%; n3 is an integer of 3-20,000, preferably 3-10,000, more preferably 3-5000, preferably a positive integer of 5-100, such as 10, 15, 20, 25, 30, 40, 50, 60, 70, 80 or 90.

[0112] In another preferred example, x1+y1=1.

[0113] In another preferred example, x1 is 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0114] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1The gel permeation chromatogram of polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride to obtain polymers of different chain lengths is shown;

[0116] Figure 2 The gel permeation chromatograms of polymers with different chain lengths obtained by polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by n-butylamine catalyzed by different types of quaternary ammonium salt cationic catalysts are shown;

[0117] Figure 3 . Shows the gel permeation chromatograms of polymers of different chain lengths obtained by polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by n-butylamine catalyzed by different anionic quaternary ammonium salt catalysts;

[0118] Figure 4 The gel permeation chromatograms of the polymerization of Nε-tert-butyloxycarbonyl-L-lysine intracyclic anhydride (monomer 2) with different chain lengths catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride and initiated by n-butylamine are shown;

[0119] Figure 5 shows the gel permeation chromatogram of the polymerization of Nε-benzyloxycarbonyl-L-lysine intracyclic anhydride (monomer 3) initiated by n-butylamine catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride;

[0120] Figure 6 shows the gel permeation chromatogram of the homopolymerization of Nδ-tert-butyloxycarbonyl-L-ornithine catalyzed by n-butylamine;

[0121] Figure 7 shows the gel permeation chromatogram of γ-tert-butyl-L-glutamic acid homopolymerization catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride;

[0122] Figure 8 shows the gel permeation chromatogram of the copolymerization of L-glutamic acid-γ-benzyl ester and L-norleucine initiated by n-butylamine catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride;

[0123] Fig. 9 shows the gel permeation chromatogram of N-ε-tert-butyloxycarbonyl-L-lysine and L-norleucine catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride;

[0124] Fig.10 shows the gel permeation chromatogram of N-ε-tert-butyloxycarbonyl-L-lysine and L-valine catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride;

[0125] Fig.11 The graphs showing the change of monomer conversion rate and ln(M0 / M) over time for the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) initiated by n-butylamine catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride;

[0126] Fig.12 The graph showing the change of ln(M0 / M) over time for the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxycarbonyl (monomer 1) initiated by n-butylamine;

[0127] Table 1 shows the molecular weight and distribution of the homopolymers of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) polymerized in different solvents catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride and initiated by n-butylamine;

[0128] Fig.13 The GPC of the polymer of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) in different solvents catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride is shown;

[0129] Table 2 shows the molecular weight and distribution of each block of the five-block copolymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) and N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride (monomer 2) catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride

[0130] Fig.14 The GPC of each polymer of the five-block copolymer of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) and N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride (monomer 2) catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride is shown;

[0131] Fig.15 shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by 3-methyl-1-n-butylpyridinium chloride;

[0132] Fig.16 shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by tetrabutylammonium chloride;

[0133] Fig.17shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by tetramethylammonium chloride;

[0134] Fig.18 The gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by triethylbenzylammonium chloride is shown;

[0135] Fig.19 shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by 1,3-dimethylimidazole chloride;

[0136] Fig. 20 . shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride;

[0137] Fig.21 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by catalyst 2 catalyzing 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene;

[0138] Fig. 22 . shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by 1,8-diazobispiro[5.4.0]undec-7-ene catalyzed by 3-methyl-1-n-butylpyridinium chloride;

[0139] Fig.23 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride;

[0140] Fig.24 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and lithium bistrimethylsilylamide;

[0141] Fig.25 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and initiated by tetrabutylammonium acetate;

[0142] Fig.26 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and initiated by tetrabutylbenzoate;

[0143] Fig. 27 . Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by tetramethylammonium benzoate catalyzed by 3-methyl-1-n-butylpyridinium chloride;

[0144] Fig.28 .Shows the gel permeation chromatogram of the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl cyclic anhydride (monomer 1) initiated by different primary amines catalyzed by 1.4-dimethylamino-1-neopentylpyridinium chloride. DETAILED DESCRIPTION

[0145] After extensive and in-depth research, the inventors unexpectedly developed a method for preparing polymers by rapid and controllable ring-opening polymerization of cyclic monomers initiated by organic bases, alcohols or carboxylates using quaternary ammonium salt cationic catalysts. The method used in the invention can significantly improve the polymerization reaction rate and polymerization controllability of cyclic monomers such as NCA, NNCA, NTA, and NNTA, and can prepare amino acid homopolymers and copolymers (including random copolymers and multi-segment block copolymers) with rich structures, and the preparation method is simple and the synthesis scenarios are rich (including various inert organic solvent systems). For cyclic ester monomers, such as β-propiolactone, valerolactone, and lactide monomers, the polymerization rate is super slow or even non-polymerized under the conditions of traditional polymerization methods. The method of the invention can achieve rapid polymerization to prepare polyester. The catalyst also exhibits excellent recyclability, and the recovered catalyst still exhibits the function of efficiently catalyzing the polymerization of cyclic monomers.

[0146] Based on this method, not only amino acid polymers can be prepared quickly and conveniently, but also polyesters with various structures can be prepared. On this basis, the present invention was completed.

[0147] the term

[0148] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0149] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0150] As used herein, the terms "N-carboxycarbonyl intracyclic anhydride," "NCA," are used interchangeably.

[0151] As used herein, the terms "N-substituted N-carboxycarbonyl intracyclic anhydride," "NNCA," are used interchangeably.

[0152] As used herein, the terms "N-carboxythiocarbonyl intracyclic anhydride," "NTA," are used interchangeably.

[0153] As used herein, the terms "N-substituted N-carboxythiocarbonyl intracyclic anhydride," "NNTA," are used interchangeably.

[0154] definition

[0155] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- includes -OCH2-.

[0156] The prefix "Cu-Cv" indicates that the following group has from u to v carbon atoms. For example, "C 1-12 "Alkyl" means that the alkyl group has 1 to 12 carbon atoms. "Cu-Cv" includes all positive integers of C atoms between u and v, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. "C0-C8" includes 0, 1, 2, 3, 4, 5, 6, 7 or 8 C atoms; "C0-C4" and "C0-C4" etc. have similar meanings.

[0157] As used herein, the term "alkyl" includes straight chain or branched chain alkyl. 12 Alkyl represents a straight or branched alkyl group having 1 to 12 carbon atoms, including, for example, 1 to 9 carbon atoms (i.e., C1-C9 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 4 carbon atoms (i.e., C1-C4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0158] As used herein, the term "alkenyl" includes straight chain or branched chain alkenyl. 12 Alkenyl refers to a straight or branched alkenyl having 2 to 12 carbon atoms, including, for example, 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), 2 to 6 carbon atoms (i.e., C2-C6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). For example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0159] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group including at least one carbon-carbon triple bond. 12 Alkynyl refers to a straight or branched alkynyl group having 2-12 carbon atoms, including, for example, 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), 2 to 6 carbon atoms (i.e., C2-C6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). For example, ethynyl, propynyl, butynyl, or the like.

[0160] As used herein, the term "2-12 membered heteroalkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a straight or branched chain alkyl group having 2-12 carbon atoms, wherein 1-3 carbon atoms are replaced by heteroatoms selected from the group consisting of N, S and O.

[0161] As used herein, the term "cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl. The term "cycloalkyl" includes cycloalkenyl (that is, the cyclic group has at least one double bond). The cycloalkyl used herein has 3 to 12 ring carbon atoms (that is, C3-C12 cycloalkyl), 3 to 8 ring carbon atoms (that is, C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (that is, C3-6 cycloalkyl). It can be a monocycle, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups. It can also be a bicyclic form, such as a bridged ring or a spirocyclic form.

[0162] As used herein, the term "C1-C 12 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 12 carbon atoms, and the alkyl portion is as defined above. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0163] As used herein, the term "alkylene" refers to a divalent alkyl group, the alkyl group being as defined above.

[0164] "Haloalkoxy" means an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0165] "Alkylthio" refers to the group "alkyl-S-."

[0166] "Guanidyl" refers to -NHC(NH)(NH2).

[0167] "Hydrazino" refers to -NHNH2.

[0168] As used herein, the term "3-12 membered heterocyclic group" refers to a saturated or partially saturated cyclic group having 3-12 atoms, wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic or bicyclic form, such as a bridged ring or a spirocyclic form. Specific examples may include oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl.

[0169] As used herein, the term "C6-C 12 The term "aryl" refers to an aromatic group having 6 to 12 carbon atoms, for example, phenyl or naphthyl and the like.

[0170] As used herein, the term "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms, wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or a condensed ring. Specific examples may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

[0171] Unless otherwise specified, the groups of the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0172] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br and I.

[0173] As used herein, "plurality" refers to 2 or more, such as 2, 3, 4, 5, 6.

[0174] Catalyst of the present invention

[0175] The present invention provides a special application of quaternary ammonium salt cationic catalysts in catalyzing the ring-opening polymerization of the cyclic monomers of the present invention, thereby providing a fast and controllable catalytic synthesis method for synthesizing polypeptides, polyesters, and polypeptide-polyester copolymers.

[0176] The present invention provides a compound as shown in formula I or II or III or IV as a catalyst for the rapid ring-opening polymerization method of the present invention:

[0177]

[0178] wherein X1, X2, Y1, Y2, Y3, Y4, Z1, Z2, Z3, Z4, Z1′, Z2′, Z3′, Z4′, Z5′, Z6′, R1, R2, R, R1′, R2′, R3′, R4′, and R5′ are as defined above.

[0179] The compound of formula I or II or III or IV is selected from the following group of cationic salts:

[0180]

[0181] Monomers of the present invention

[0182] In particular, the catalyst of the present invention is particularly suitable for (but not limited to) catalyzing the polymerization reaction between the following monomers: N-carboxylcarbonyl cyclic anhydride, N-substituted N-carboxylcarbonyl cyclic anhydride, N-carboxylthiocarbonyl cyclic anhydride, N-substituted N-carboxylthiocarbonyl cyclic anhydride, cyclic ester monomer, lactide, or a combination thereof.

[0183] Preferably, the monomer of the present invention is one or more of the compounds represented by formula V, formula VI and formula VI:

[0184]

[0185] wherein Y, R", R1", R2", R1'", R2'", R3'", R4'", m and n are as defined above.

[0186] More preferably, the monomer can be selected from the following group:

[0187]

[0188] The monomer is selected from the following group: N-carboxyl carbonyl intracyclic anhydride, N-substituted-N-carboxyl carbonyl intracyclic anhydride, or a combination thereof.

[0189] The monomer is selected from the following group: amino acid N-carboxyl carbonyl ring anhydride, amino acid N-carboxyl thiocarbonyl ring anhydride, or a combination thereof.

[0190] The amino acids are natural amino acids or unnatural amino acids.

[0191] The amino acid is selected from the following group: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, asparagine, glutamic acid, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, and derivatives derived from the above amino acids, or a combination thereof.

[0192] The monomer is selected from the following group: L-type amino acid N-carboxyl carbonyl ring anhydride, D-type amino acid N-carboxyl carbonyl ring anhydride, D,L-type amino acid N-carboxyl carbonyl ring anhydride, L-type amino acid N-carboxyl thiocarbonyl ring anhydride, D-type amino acid N-carboxyl thiocarbonyl ring anhydride, D,L-type amino acid N-carboxyl thiocarbonyl ring anhydride, or a combination thereof.

[0193] The structural formula or name of a monomer given by the inventor may only exemplify one specific configuration or may not give a specific configuration. The monomer may also include all other configurations corresponding to the given configuration.

[0194] The monomer is selected from the following group: α-amino acid N-carboxyl carbonyl ring anhydride, α-amino acid N-carboxyl thiocarbonyl ring anhydride, or a combination thereof.

[0195] The monomer is selected from the following group: L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride, N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride, L-glutamic acid-5-ethyl ester-N-carboxyl carbonyl ring anhydride, Nε-benzyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride, Nδ-tert-butyloxycarbonyl-L-ornithine-N-carboxyl carbonyl ring anhydride, γ-tert-butyl-L-glutamic acid The invention relates to an amino acid-N-carboxyl carbonyl ring anhydride, an L-norleucine-N-carboxyl carbonyl ring anhydride, an L-norvaline-N-carboxyl carbonyl ring anhydride, an N-methyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride, β-propiolactone, valerolactone, lactide, L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl ring anhydride, an N-methyl substituted α-amino acid-N-carboxylthiocarbonyl ring anhydride, or a combination thereof.

[0196] Polymer preparation method of the present invention

[0197] The present invention provides a catalytic polymerization method for a polymer, characterized in that it comprises the steps of:

[0198] (a) polymerizing one or more cyclic monomers in the presence of a catalyst and an initiator to form a polymer, wherein the catalyst is as described above.

[0199] The present invention has no special requirements for the initiator, and conventional polymerization initiators in the art can be used. For a certain type of monomer, it is easy for a person skilled in the art to select a corresponding initiator. Generally, the initiator can be a nucleophilic reagent such as an organic base, an alcohol or a carboxylate.

[0200] Usually, the reaction is carried out in an apparatus or device without any protection (eg, an open beaker, flask or various open reactors commonly used in industry).

[0201] The reaction is carried out in an apparatus or device (eg, a glove box) protected by nitrogen.

[0202] In the reaction, one monomer of the compound of formula V, formula VI or formula VII may be polymerized, or two, three or four different monomers of the compound of formula V, formula VI or formula VII may be polymerized.

[0203] In the above reaction, the obtained polymer is a homopolymer or a copolymer.

[0204] In the reaction, the copolymer obtained is a random copolymer or a block copolymer.

[0205] In the above reaction, the type of copolymer obtained depends on the kind of monomers and the order of addition.

[0206] When the monomers are two or more (such as three, four or more), the method comprises the steps of:

[0207] In the presence of a catalyst and an initiator, two or more (such as three, four or more) monomers are mixed and then polymerized to form a random copolymer;

[0208] or (a) subjecting a first monomer to a polymerization reaction in the presence of a catalyst and an initiator;

[0209] (b) after the above polymerization reaction is completed, adding a second monomer to carry out polymerization reaction;

[0210] and optionally (c) repeating (b) 0-p times, with the proviso that the monomers in each step of step (c) are different from the monomers in the previous step, thereby forming a block copolymer;

[0211] Among them, p≥1.

[0212] Preferably, when the reaction is carried out in an inert solvent, the method comprises the steps of:

[0213] (i) providing a monomer solution, an initiator solution, and a catalyst solution;

[0214] (ii) adding the initiator solution described in step (i) to the stirred monomer solution to carry out a polymerization reaction, thereby obtaining a polymer;

[0215] The solvent of the monomer solution and the solvent of the initiator solution are the same or different.

[0216] The reaction is carried out in the presence of a solvent, wherein the solvent is selected from the following group: tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dioxane, dimethyl sulfoxide, dichloromethane, chloroform, acetone, N-methylpyrrolidone, esters, aromatic hydrocarbons, alkanes, water, or a combination thereof.

[0217] The solvent of the reaction is determined according to the monomer properties and chain length of the polymer to be prepared.

[0218] The reaction is carried out at 0-120°C, preferably at 20-50°C.

[0219] The main advantages of the present invention include:

[0220] 1) Compared with the traditional ring-opening polymerization method, the method described in the present invention greatly improves the polymerization speed and significantly improves the polymerization controllability, and the reaction can be completed within 20 seconds at the fastest;

[0221] 2) The catalyst used in the method of the present invention has a very rich structural type, including quaternary ammonium salts, quaternary phosphonium salts, pyridinium salts, imidazolium salts, etc., all of which have excellent catalytic polymerization performance for the ring-opening polymerization of cyclic monomers;

[0222] 3) The method of the present invention is applicable to a variety of monomers (including NCA monomers, NNCA, NTA, NNTA, cyclic esters and lactide monomers), and can achieve rapid and controllable polymerization to prepare molecular weight adjustable (M n =2000-100,000 g / mol), polymers with narrow molecular weight distribution;

[0223] 4) The method of the present invention can be applied to a variety of initiator systems, including traditional primary amines, alcohols, organic bases (such as 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, lithium bistrimethylsilylamide, etc.), carboxylates (such as tetrabutylammonium acetate, tetrabutylammonium benzoate, tetramethylammonium acetate, etc.);

[0224] 5) The method of the present invention can prepare polymers (including homopolymers and copolymers) with rich structures, thus broadening the application field of the method of the present invention;

[0225] 6) The method of the present invention is applicable to a variety of solvent systems, from low-polarity solvents (such as toluene) to high-polarity solvents (such as N,N-dimethylacetamide), and can achieve rapid and controllable polymerization to prepare polymers;

[0226] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0227] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0228] Catalyst synthesis:

[0229] 1. Synthesis of Catalyst 1.8-Butyl-1,8-diazabicyclo[5.4.0]undec-7-ene chloride (Catalyst 1)

[0230]

[0231] In a dry round-bottom flask equipped with a magnetic stir bar, 1,8-diazabicyclo[5.4.0]undecane-7-ene (5.0 g, 32.8 mmol) was dissolved in 50 mL of MeCN. Then a solution of 1-chlorobutane (6.0 g, 65.7 mmol) in acetonitrile (10 mL) was added dropwise to the reaction flask. The reaction was heated to 50°C and stirred in the dark for 24 h to obtain a crude product, which was purified by silica gel column chromatography to obtain butter (3.4 g, yield 43%), namely DBUCl.

[0232] 2. Synthesis of Catalyst 5-Butyl-7-methylguanosine-1,5,7-triazabicyclo[4.4.0]dec-5-ene chloride (Catalyst 2)

[0233]

[0234] The experimental method is the same as step 1, except that 1-methyl-1,3,4,6,7,8-hexahydro-2H-pyrimidin-[1,2-a]pyrimidine is used to replace 1,8-diazabicyclo[5.4.0]undec-7-ene, the solvent is changed to toluene, and the reaction time is extended to 2 days.

[0235] 3. Synthesis of catalyst 4-dimethylamino-butylpyridinium chloride (catalyst 3)

[0236]

[0237] The experimental method is the same as step 1, except that 4-dimethylaminopyridine is used to replace 1,8-diazabicyclo[5.4.0]undec-7-ene, and the reaction time is shortened to 12 h.

[0238] 4. Synthesis of catalyst tetrabutylammonium trifluoromethanesulfonate (catalyst 4)

[0239]

[0240] In a dry round-bottom flask equipped with a magnetic stirring bar, tetrabutylammonium chloride (2.8 g, 10 mmol) was dissolved in 40 mL MeOH. Then, a solution of silver trifluoromethanesulfonate (2.6 g, 10 mmol) in MeOH (10 mL) was added dropwise to the reaction flask. Stir for 24 h in the dark, filter out the white precipitate, and spin dry the mixed solution to obtain the product (3.8 g, yield 98%).

[0241] Synthesis of monomers

[0242] 1. Preparation of L-glutamic acid γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1)

[0243]

[0244] In a dry round-bottom flask equipped with a magnetic stirring bar, L-glutamic acid γ-benzyl ester (5.0 g, 21.1 mmol) was suspended in 50 ml of anhydrous tetrahydrofuran. Then, under nitrogen protection, a solution of triphosgene (2.8 g, 9.3 mmol) in anhydrous THF (20 ml) was added dropwise to the reaction flask in an ice bath. The reaction was heated to 50 ° C and stirred for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was redissolved in EtOAc (50 mL). The mixture was quickly washed with cold deionized water (50 mL) and cold brine (50 mL), and then dried over anhydrous MgSO4. The crude NCA was recrystallized three times with dry EtOAc / hexane to obtain white crystals (3.4 g, conversion rate 61%).

[0245] 2. Preparation of N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxylcarbonyl ring anhydride (monomer 2)

[0246]

[0247] The experimental method is the same as step 1, except that N-ε-tert-butyloxycarbonyl-L-lysine is used to replace L-glutamic acid γ-benzyl ester, the reaction temperature is 50°C and α-pinene (7.3 g, 53.6 mmol) is added as an acidifying agent.

[0248] 3. Preparation of Nε-benzyloxycarbonyl-L-lysine-N-carboxylcarbonyl ring anhydride (monomer 3)

[0249]

[0250] The experimental method is the same as step 1, except that Nε-benzyloxycarbonyl-L-lysine is used to replace L-glutamic acid-5-benzyl ester.

[0251] 4. Preparation of Nδ-tert-butyloxycarbonyl-L-ornithine-N-carboxylcarbonyl intracyclic anhydride (monomer 4)

[0252]

[0253] The experimental method is the same as step 1, except that Nδ-tert-butyloxycarbonyl-L-ornithine is used to replace L-glutamic acid-5-benzyl ester, the reaction temperature is 50°C and α-pinene (7.7 g, 56.8 mmol) is added as an acidifying agent.

[0254] 5. Preparation of γ-tert-butyl-L-glutamic acid-N-carboxylcarbonyl ring anhydride (monomer 5)

[0255]

[0256] The experimental method is the same as step 1, except that γ-tert-butyl-L-glutamic acid is used to replace L-glutamic acid-5-benzyl ester, the reaction temperature is 50°C and α-pinene (8.8 g, 64.9 mmol) is added as an acidifying agent.

[0257] 6. Preparation of L-norleucine-N-carboxylcarbonyl intracyclic anhydride (monomer 6)

[0258]

[0259] The experimental method is the same as step 1, except that L-norleucine is used to replace L-glutamic acid-5-benzyl ester, and the reaction temperature is 50°C.

[0260] 7. Preparation of L-norvaline-N-carboxylcarbonyl intracyclic anhydride (monomer 7)

[0261]

[0262] The experimental method is the same as step 1, except that L-norvaline is used to replace L-glutamic acid-5-benzyl ester, and the reaction temperature is 50°C.

[0263] 8. Preparation of N-ε-tert-butyloxycarbonyl-D,L-lysine-N-carboxylcarbonyl ring anhydride (monomer 8)

[0264]

[0265] The experimental method is the same as step 1, except that N-ε-tert-butyloxycarbonyl-D,L-lysine is used to replace L-glutamic acid γ-benzyl ester, the reaction temperature is 50°C and α-pinene (7.3 g, 53.6 mmol) is added as an acidifying agent.

[0266] 9. Preparation of N-methyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride (monomer 9)

[0267]

[0268] Sarcosine (5.0 g, 56.1 mmol) is dissolved in 375 mL deionized water, then triethylamine (23.5 mL, 168.3 mmol) and di-tert-butyl dicarbonate (12.9 mL, 56.1 mmol) are added successively, and the reaction mixture is stirred for 6 hours. The HCl aqueous solution (4 M, 320 mL) is added, then extracted three times with ethyl acetate and dried, then concentrated under vacuum. Dry ethyl acetate / normal hexane is used to recrystallize the crude product to obtain a white intermediate.

[0269] The white intermediate is dissolved in 150mL anhydrous dichloromethane, then under ice-water bath and nitrogen protection, phosphorus trichloride (7.2g, 26.4mmol) is added dropwise in a reaction round-bottom flask, and the reaction mixture is stirred for 2 hours. Organic solvent is removed in vacuo, then extracted three times with anhydrous dichloromethane. Use dry dichloromethane / hexane recrystallization to obtain product crystals (yield 53.0%).

[0270] 10. Preparation of L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl ring anhydride (monomer 10)

[0271]

[0272] S-ethoxythiocarbonylthioacetic acid (XAA, 9.0 g, 50.0 mmol) and solid sodium bicarbonate (16.8 g, 200.0 mmol) were dissolved in a flask containing 500 mL of deionized water, mixed and stirred, and L-glutamic acid-5-benzyl ester (11.8 g, 50.0 mmol) was added after dissolution, and the mixture was stirred and reacted at 50° C. for about 2 days; then 1 M hydrochloric acid solution was slowly added dropwise, the pH was adjusted to about 3, and the organic matter in the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were quenched with saturated brine and dried over anhydrous magnesium sulfate; the crude product was purified by recrystallization with ethyl acetate and n-hexane to obtain 12 g of a white solid intermediate.

[0273] Under nitrogen protection, the white intermediate (1.6 g, 5.0 mmol) was dissolved in 50 mL of dry dichloromethane solution, mixed and stirred under ice bath conditions, and then phosphorus tribromide (1.4 g, 5.0 mmol) solution was added dropwise. After the addition was completed, the temperature was raised to 25°C and the reaction was continued for 6 hours. After the reaction was completed, the organic phase was washed three times with 0°C deionized water, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent to obtain a crude product. Under nitrogen protection, the product was purified by recrystallization with ethyl acetate and n-hexane to obtain 1.0 g of a white solid product.

[0274] 11. Preparation of N-methyl substituted α-amino acid-N-carboxylthiocarbonyl ring anhydride (monomer 11)

[0275]

[0276] S-ethoxythiocarbonylthioacetic acid (XAA, 1.8 g, 10.1 mmol) and sodium hydroxide (3.0 g, 30.3 mmol) were dissolved in a flask containing 50 mL of water, mixed and stirred, and then sarcosine (10.1 mmol) was added after dissolution, mixed and stirred for reaction, and the reaction was stirred at room temperature for about 48 hours; then 1 M hydrochloric acid solution was slowly added dropwise to adjust the pH to about 3, and the organic matter in the aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, and the organic phases were quenched with saturated brine and dried over anhydrous magnesium sulfate; the crude product was quickly separated and purified using a petroleum ether and ethyl acetate system to obtain a white intermediate.

[0277] Under nitrogen protection, the white intermediate (5.0 mmol) was dissolved in 120 mL of dry dichloromethane solution, mixed and stirred in an ice bath, and then phosphorus tribromide (1.3 g, 5.0 mmol) solution was added dropwise. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for 3 hours. After the reaction was completed, the organic phase was washed three times with 0°C deionized water, dried over anhydrous magnesium sulfate, filtered, and concentrated to remove the solvent to obtain a crude product. Under nitrogen protection, it was purified by recrystallization with ethyl acetate and n-hexane to obtain 1.1 g of a liquid product.

[0278] 12. Preparation of N-ε-tert-butyloxycarbonyl-D,L-lysine-N-carboxylcarbonyl ring anhydride (monomer 12)

[0279]

[0280] The experimental method is the same as step 1, except that L-glutamic acid γ-benzyl ester is replaced by Trt-protected L-histidine, the reaction temperature is 50°C and α-pinene (7.3 g, 53.6 mmol) is added as an acidifying agent.

[0281] Example 1. 4-Dimethylamino-1-neopentylpyridinium chloride catalyzes n-butylamine to initiate polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) to obtain polymers of different chain lengths

[0282]

[0283] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0284] n-Butylamine (9.6 μL, 0.1 mmol) was dissolved in dry tetrahydrofuran (990 μL) to prepare a 0.1 M solution for later use.

[0285] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.3 mL). 0.32 mL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction bottle, followed by 40 μL of 0.1 M n-butylamine solution. The mixture was stirred for 40 minutes, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =11800g / mol and molecular weight distribution M w / M n =1.14.

[0286] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.8 mL). 0.16 mL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction bottle, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 70 minutes, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =22200g / mol and molecular weight distribution M w / M n =1.06.

[0287] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (110 μL). In the stirred reaction bottle, 80 μL of 0.05M 4-dimethylamino-1-neopentylpyridinium chloride solution was added, followed by 10 μL of 0.1M n-butylamine solution. The mixture was stirred for 5 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =47400g / mol and molecular weight distribution M w / M n =1.04.

[0288] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (164 μL). In the stirred reaction bottle, 32 μL of 0.05M 4-dimethylamino-1-neopentylpyridinium chloride solution was added, followed by 4 μL of 0.1M n-butylamine solution. The mixture was stirred for 12 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =109500g / mol and molecular weight distribution M w / M n =1.08.

[0289] Cold petroleum ether (40 mL) was poured into all the above reaction mixtures, and the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in tetrahydrofuran (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain poly(benzyl glutamate) homopolymers of different chain lengths with a yield of 90%. The gel permeation chromatograms of the obtained poly(benzyl glutamate) homopolymers of different chain lengths are shown in FIG. Figure 1 shown.

[0290] Comparative Example 1. n-Hexylamine Initiator Monomer 1

[0291]

[0292] n-Butylamine (9.6 μL, 0.1 mmol) was dissolved in dry tetrahydrofuran (990 μL) to prepare a 0.1 M solution for later use.

[0293] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.98 mL). 20 μL of 0.1 M n-butylamine solution was added to the stirred reaction bottle. The mixture was stirred for 3 days and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =28,000g / mol and molecular weight distribution M w / M n =1.16.

[0294] The reaction time is significantly longer than that of Example 1.

[0295] Example 2. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by different types of quaternary ammonium salt cationic catalysts to obtain polymers of different chain lengths

[0296]

[0297] n-Butylamine (9.6 μL, 0.1 mmol) was dissolved in dry tetrahydrofuran (990 μL) to prepare a 0.1 M solution for later use.

[0298] Catalyst 1 (24.5 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0299] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). 80 μL of 0.1 M catalyst 1 solution was added to the stirred reaction bottle, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 6 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =33600g / mol and molecular weight distribution M w / M n =1.29.

[0300] Catalyst 2 (23.5 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0301] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M catalyst 2 solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 5 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =32100 g / mol and molecular weight distribution M w / M n =1.27.

[0302] Catalyst 3 (21.4 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0303] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of a 0.1 M solution of catalyst 3 was added, followed by 20 μL of a 0.1 M solution of n-butylamine. The mixture was stirred for 1.5 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n=22500g / mol and molecular weight distribution M w / M n =1.10.

[0304] 1,3-Dimethylimidazole chloride (13.2 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0305] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M 1,3-dimethyl imidazole chloride solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 1.5 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =30,000g / mol and molecular weight distribution M w / M n =1.08.

[0306] 1,3-Bis(2,4,6-trimethylphenyl)imidazole chloride (29.2 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0307] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M 1,3-dimethyl imidazole chloride solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 1.5 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =32,100 g / mol and molecular weight distribution M w / M n =1.18.

[0308] Accurately weigh N,N,N,N',N',N'-hexamethylethane-1,2-diamine dichloride (21.7 mg, 0.1 mmol) and prepare a 0.1 M solution with dichloromethane (1 mL) for later use.

[0309] L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1M N, N, N, N', N', N'-hexamethylethane-1,2-dichlorodiamine solution was added, followed by 20 μL of 0.1M n-butylamine solution. The mixture was stirred for 3 hours, and the TLC spot plate showed that the monomer spot disappeared, indicating that the monomer was completely converted into a polymer. The reaction solution was precipitated with petroleum ether to obtain a white flocculent, which was the corresponding amino acid polymer product.

[0310] Tetrabutylammonium chloride (27.7 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0311] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M tetrabutylammonium chloride solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 1.5 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =36,000g / mol and molecular weight distribution M w / M n =1.14.

[0312] 1,4-Dimethyl-1,4-diazabicyclo[2.2.2]octane dichloride (21.3 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0313] Accurately weigh L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) and dissolve it in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). Add 80 μL of 0.1M 1,4-dimethyl-1,4-diazabicyclo[2.2.2]octane dichloride solution to the stirred reaction bottle, followed by 20 μL of 0.1M n-butylamine solution. Stir the mixture for 3 hours, and the TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent, which is the corresponding amino acid polymer product.

[0314] Tetrabutylammonium bromide (32.2 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0315] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M tetrabutylammonium bromide solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 1.5 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =38300g / mol and molecular weight distribution M w / M n =1.18.

[0316] Tetrabutylphosphine chloride (29.4 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0317] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (52.6 mg, 0.2 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.9 mL). In the stirred reaction bottle, 80 μL of 0.1 M tetrabutylphosphine chloride solution was added, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 7 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =37,000g / mol and molecular weight distribution M w / M n =1.10.

[0318] All the above reaction mixtures were poured into cold petroleum ether (40 mL), the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in tetrahydrofuran (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. This dissolution-precipitation process was repeated three times to obtain polyglutamic acid benzyl ester homopolymer. The gel permeation chromatogram of the obtained polyglutamic acid benzyl ester homopolymer is shown in FIG. Figure 2 shown.

[0319] Comparative Example 2. Polymerization of Monomer 1 Initiated by n-Hexylamine Catalyzed by Other Hydrogen Bond Catalysts and Metal Catalysts

[0320] The experimental method is the same as that of Example 2, except that 1,3-bis(2-hydroxyhexafluoroisopropyl)benzene is used to replace catalyst 1. The reaction takes 2 days and the molecular weight of the obtained polymer is M n =21700g / mol and molecular weight distribution M w / M n =1.10; 1,3-bis(3,5-bis(trifluoroethyl)phenyl)thioureabenzene was used to replace catalyst 1, and the reaction took 3 days. The molecular weight of the obtained polymer was Mn =14500g / mol and molecular weight distribution M w / M n =1.09, the polymer molecular weight is significantly lower than the theoretical value; zinc acetate replaces catalyst 1, the reaction takes 36 hours, and the molecular weight of the obtained polymer is M n =24,000g / mol and molecular weight distribution M w / M n =1.13, there is a concern about metal residue in the polymerization reaction;

[0321] The polymerization reaction time of the currently widely used catalyst shown in the above comparative example is significantly longer than that of Example 1 and Example 2, indicating the high catalytic activity of the quaternary ammonium salt cationic catalyst.

[0322] Example 3. The polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl cyclic anhydride (monomer 1) was initiated by n-butylamine using different anionic quaternary ammonium salt catalysts.

[0323]

[0324] The experimental method is the same as that of Example 1, except that tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium trifluoromethanesulfonate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium hexafluorophosphate are used instead of tetrabutylammonium chloride to initiate the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1). The polymerization reaction time is completed within 2-10 hours. The gel permeation chromatogram of the obtained polyglutamic acid benzyl ester homopolymer is as follows: Figure 3 shown.

[0325] Example 4.1. Polymerization of Nε-tert-butyloxycarbonyl-L-lysine intracyclic anhydride (monomer 2) with different chain lengths catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and initiated by n-butylamine

[0326]

[0327] The experimental method is the same as that of Example 1, except that monomer 2 (54.4 mg, 0.2 mmol) is used instead of monomer 1. The reaction time is about 35 minutes to 5 hours. The obtained polymer is identified by gel permeation chromatography (GPC). n =12800-43500g / mol, M w / M n =1.10-1.22. The gel permeation chromatogram of the obtained Nε-tert-butyloxycarbonyl-L-lysine homopolymer is as follows: Figure 4 shown.

[0328] Example 5.1. Polymerization of Nε-benzyloxycarbonyl-L-lysine intracyclic anhydride (monomer 3) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride with n-butylamine

[0329]

[0330] The experimental method was the same as in Example 1, except that monomer 3 (61.2 mg, 0.2 mmol) was used instead of monomer 1. The reaction time was about 4 hours. The obtained polymer was identified by gel permeation chromatography (GPC). n =12400 g / mol, M w / M n =1.02. The gel permeation chromatogram of the obtained Nε-benzyloxycarbonyl-L-lysine homopolymer is as follows: Figure 5 shown.

[0331] Example 6.1. Polymerization of Nδ-tert-butyloxycarbonyl-L-ornithine cyclic anhydride (monomer 4) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and n-butylamine

[0332]

[0333] The experimental method was the same as in Example 1, except that monomer 3 (51.6 mg, 0.2 mmol) was used instead of monomer 1. The reaction time was about 2 hours. The obtained polymer was identified by gel permeation chromatography (GPC). n =11300 g / mol, M w / M n =1.21. The gel permeation chromatogram of the obtained Nδ-tert-butyloxycarbonyl-L-ornithine homopolymer is as follows: Figure 6 shown.

[0334] Example 7.1. Polymerization of γ-tert-butyl-L-glutamic acid anhydride (monomer 5) initiated by n-butylamine catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0335]

[0336] The experimental method is the same as that of Example 1, except that monomer 3 (45.8 mg, 0.2 mmol) is used instead of monomer 1. The reaction time is about 1.5 hours. The obtained polymer is identified by gel permeation chromatography (GPC). n =8700 g / mol, M w / M n =1.08. The gel permeation chromatogram of the obtained γ-tert-butyl-L-glutamic acid homopolymer is as follows: Figure 7 shown.

[0337] Example 8 1.4-Dimethylamino-1-neopentylpyridinium chloride catalyzes the polymerization of Nε-tert-butyloxycarbonyl-D,L-lysine intracyclic anhydride (monomer 8) initiated by n-butylamine

[0338]

[0339] The experimental method was the same as in Example 1, except that monomer 8 (54.4 mg, 0.2 mmol) was used instead of monomer 1. The reaction time was about 8 hours. The obtained polymer was identified by gel permeation chromatography (GPC). n =10,000 g / mol, M w / M n =1.07.

[0340] Examples 1-8 show that the polymerization method of the present invention is applicable to the preparation of homopolymers of various structures, and the preparation method is simple, the molecular weight is adjustable, and the molecular weight distribution is narrow.

[0341] Example 9.1. Copolymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) and L-norleucine-N-carboxylcarbonyl cyclic anhydride (monomer 6) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0342]

[0343] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0344] n-Butylamine (9.6 μL, 0.1 mmol) was dissolved in dry tetrahydrofuran (990 μL) to prepare a 0.1 M solution for later use.

[0345] L-Glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (26.3 mg, 0.1 mmol) and monomer 3 (15.7 mg, 0.1 mmol) were accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (0.72 mL). 0.16 mL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction bottle, followed by 20 μL of 0.1 M n-butylamine solution. The mixture was stirred for 3 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =16800g / mol and molecular weight distribution M w / M n =1.06. The gel permeation chromatogram of the copolymer is obtained as follows: Figure 8 shown.

[0346] Example 10.1. Copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine (monomer 2) and L-norleucine-N-carboxylcarbonyl intracyclic anhydride (monomer 6) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0347]

[0348] The experimental method was the same as in Example 9, except that monomer 2 (27.2 mg, 0.1 mmol) was used instead of monomer 1. The reaction time was about 3 hours. The obtained polymer was identified by gel permeation chromatography (GPC). n =16700 g / mol, M w / M n =1.04. The gel permeation chromatogram of the obtained N-ε-tert-butyloxycarbonyl-L-lysine and L-norleucine copolymer is as follows: Fig. 9 shown.

[0349] Example 11.1. Copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine (monomer 2) and L-valine-N-carboxylcarbonyl intracyclic anhydride (monomer 7) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0350]

[0351] The experimental method was the same as in Example 9, except that monomer 7 (14.3 mg, 0.1 mmol) was used instead of monomer 6. The reaction time was about 4 hours. The obtained polymer was identified by gel permeation chromatography (GPC). n =17,000 g / mol, M w / M n =1.15. The gel permeation chromatogram of the obtained N-ε-tert-butyloxycarbonyl-L-lysine and L-valine copolymer is as follows: Fig.10 shown.

[0352] Examples 9-11 show that the polymerization method of the present invention is applicable to the preparation of various copolymers, and the preparation method is simple, the molecular weight is large, and the molecular weight distribution is narrow.

[0353] Example 12. Kinetics of polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride and n-butylamine

[0354] BLGNCA (26.3 mg, 0.1 mmol) and internal standard triphenylmethane (1.3 mg, 0.005 mmol) were dissolved in anhydrous THF, and then a solution of 4-dimethylamino-1-neopentylpyridinium chloride in anhydrous dichloromethane (0.02 mmol, 0.05 M) was added. A solution of n-butylamine in THF ([M]: [I]: [Cat] = 100: 1: 4, [M] 0 = 0.2 M) was then added to the reactant, and the reaction mixture was stirred at room temperature. HPLC was used to quantify unreacted BLGNCA in real time by calculating the relative peak area ratio between BLGNCA and the internal standard. Reverse phase high performance liquid chromatography analysis used a combination of water (eluent A) and acetonitrile (eluent B) as the mobile phase. At a flow rate of 1 mL / min, the proportion of eluent B increased from 45% to 100% in 5 minutes, then remained at 100% in 5 minutes, and then dropped to 45% in 5 minutes. BLGNCA was analyzed by integrating the absorbance peak at 210 nm or 254 nm. The rate constant for chain transfer was then calculated as follows:

[0355]

[0356] [M]0 is the initial concentration of the monomer, [M] is the residual concentration of the monomer, (A BLG / A TPM ) t is the real-time integrated area ratio of the HPLC peaks of BLGNCA and TPM, (A BLG / A TPM )0_0 is the initial integrated area ratio of the HPLC peaks of BLGNCA and TPM. [I] is the concentration of the initiator, and kp is the rate constant of chain propagation.

[0357] The polymerization kinetics and time conversion rate curves of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl (monomer 1) initiated by n-butylamine and catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride are shown in Figure 2. Fig.11 The results show that the kinetic constant k of tetrabutylammonium benzoate is p [I] is 2.9h -1

[0358] Comparative Example 3. Kinetics of polymerization of monomer 1 initiated by n-butylamine

[0359] The experimental method is the same as that of Example 12, except that no catalyst is added during the polymerization process. The results show that the kinetic constant k p [I] is 0.08h -1 The polymerization time takes about 3 days, which reflects that the polymerization rate is very slow. The polymerization kinetic curve is as follows Fig.12 The polymerization in Example 12 only takes 70 minutes, and the kinetic constant is 36 times that of Example 12.

[0360] Example 13. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl (monomer 1) catalyzed by 1,4-dimethylamino-1-neopentylpyridinium chloride in different solvents

[0361] The experimental method is the same as that of Example 1, except that the polymerization solvent system used is different. The polymerization solvent used in Example 1 is tetrahydrofuran, and the solvents used in this experiment mainly include dichloromethane, toluene, ethyl acetate, dioxane, N,N-dimethylformamide and non-ultra-dry tetrahydrofuran. The reaction time is 50 minutes to 4 hours. The obtained polymer is identified by gel permeation chromatography (GPC). M n =18100-23600g / mol, M w / M n =1.05-1.18, the data are shown in label 1, and the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is shown in Fig.13 shown.

[0362] The results show that the catalytic polymerization method of the present invention can be carried out in a variety of organic solvents, including strong polar solvents (N,N-dimethylformamide) and non-polar solvents (toluene). This shows that the catalytic polymerization method of the present invention is widely applicable to solvents.

[0363] Table 1: Molecular weight and distribution of L-glutamic acid-γ-benzyl ester homopolymer in different solvents

[0364]

[0365] Example 14. 1,4-Dimethylamino-1-neopentylpyridinium chloride catalyzed n-butylamine-initiated 5-block copolymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) and N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride (monomer 2)

[0366]

[0367] Monomer 1 (263 mg, 1 mmol) and monomer 2 (272 mg, 1 mmol) were accurately weighed and prepared into 1 mmol / mL mother liquors for addition to each polymerization stage. First, monomer 1 (26.3 mg, 0.1 mmol) was dissolved in a reaction bottle equipped with a stirrer with dry tetrahydrofuran (100 μL), 400 μL of 4-dimethylamino-1-neopentylpyridinium chloride (0.05 M) was added to the reaction system, and 50 μL of 0.1 M n-butylamine solution was added to the stirred reaction bottle. The mixture was stirred for 10 minutes, and 10 μL of the reaction solution was taken and identified by gel permeation chromatography (GPC) to obtain the molecular weight and molecular weight distribution of the polymer of the first stage. Monomer 2 (0.1 mmol, 100 μL) was added to the remaining reactants and the reaction was continued for 10 minutes. After the reaction was completed, 10 μL of the reaction solution was taken and identified by gel permeation chromatography (GPC) to obtain the molecular weight and molecular weight distribution of the polymer of the second stage. After repeating this process 5 times by alternately adding the reactant liquid and taking away a portion of the mixture for GPC monitoring, a 5-block copolymer of N-ε-tert-butyloxycarbonyl-L-lysine and L-glutamic acid-5-benzyl ester was obtained. Table 2 shows the molecular weight and distribution of each block of the 5-block copolymer. Fig.14 The GPC spectrum of each segment of the multi-segment block copolymer is shown.

[0368] The number of the block copolymers reaches 5, and the reaction time of the catalytic polymerization method is short, with each polymerization time being about 10 minutes, and the method has high application value for synthesizing functional copolymers.

[0369] Table 2: Molecular weight and distribution of each segment of 5-block copolymer

[0370]

[0371] Example 15. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene using 3-methyl-1-n-butylpyridinium chloride

[0372]

[0373] 3-Methyl-1-n-butylpyridinium chloride (17.3 mg, 0.1 mmol) was accurately weighed and prepared into a 0.1 M solution with dichloromethane (1 mL) for later use.

[0374] 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (15.3 mg, 0.1 mmol) was accurately weighed

[0375] n-Butylamine (9.6 μL, 0.1 mmol) was dissolved in dry tetrahydrofuran (990 μL) to prepare a 0.1 M solution for later use.

[0376] L-Glutamic acid-γ-benzyl ester-N-carboxylcarbonyl cyclic anhydride (52.6 mg, 0.2 mmol) was accurately weighed and prepared into a 0.1 M solution with tetrahydrofuran (1 mL) for later use.

[0377] Dissolve in dry tetrahydrofuran (0.9 mL) in a reaction flask equipped with a stirrer. Add 80 μL of 0.1M 4-dimethylamino-1-neopentylpyridinium chloride solution to the stirred reaction flask, followed by 20 μL of 0.1M 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene solution. Stir the mixture for 30 seconds, add 20 μL of 0.1M n-butylamine solution, stir overnight, and identify the molecular weight of the polymer obtained by gel permeation chromatography (GPC). n =21700g / mol and molecular weight distribution M w / M n =1.23.

[0378] Cold petroleum ether (40 mL) was poured into the above reaction mixtures respectively, and the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in tetrahydrofuran (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain poly(benzyl glutamate) homopolymers of different chain lengths with a yield of 90%. The gel permeation chromatogram of the obtained poly(benzyl glutamate) homopolymer is shown in FIG. Fig.15 shown.

[0379] Comparative Example 4. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) initiated by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0380] The experimental method is the same as that of Example 15, except that no quaternary ammonium salt cationic catalyst is used. The obtained polymer is identified by gel permeation chromatography (GPC). n =78300 g / mol, M w / M n =1.37.

[0381] The results of Comparative Example 4 show that after using the quaternary ammonium salt cationic catalyst, the controllability of the polymerization is significantly improved, and the molecular weight dispersion is significantly smaller, indicating that the catalytic polymerization method of the present invention has the effect of significantly improving the controllability of the polymerization.

[0382] Example 16. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by tetrabutylammonium chloride with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0383]

[0384] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and tetrabutylammonium chloride is used instead of 3-methyl-1-n-butylpyridinium chloride. The obtained polymer is identified by gel permeation chromatography (GPC). n =26200 g / mol, M w / M n =1.27, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.16 shown.

[0385] Example 17. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by tetramethylammonium chloride with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0386]

[0387] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and tetramethylammonium chloride is used instead of 3-methyl-1-n-butylpyridinium chloride. The obtained polymer is identified by gel permeation chromatography (GPC). n =47,000 g / mol, M w / M n =1.25, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.17 shown.

[0388] Example 18. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by triethylbenzylammonium chloride with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0389]

[0390] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and triethylbenzylammonium chloride is used instead of 3-methyl-1-n-butylpyridinium chloride. The obtained polymer is identified by gel permeation chromatography (GPC). n =27800 g / mol, M w / M n =1.29, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.18 shown.

[0391] Example 19. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 1,3-dimethylimidazole chloride with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0392]

[0393] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and 1,3-dimethylimidazole chloride is used to replace 3-methyl-1-n-butylpyridinium chloride. The obtained polymer is identified by gel permeation chromatography (GPC). n =40,000 g / mol, M w / M n =1.31, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.19 shown.

[0394] Example 20. Catalyst 1 catalyzes the polymerization of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene-induced L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1)

[0395]

[0396] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and 3-methyl-1-n-butylpyridinium chloride is replaced by catalyst 1. The obtained polymer is identified by gel permeation chromatography (GPC). n =29200 g / mol, M w / M n =1.18, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig. 20 shown.

[0397] Example 21. Catalyst 2 catalyzes 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene to initiate polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1)

[0398]

[0399] The experimental method is the same as that of Example 15, except that the quaternary ammonium salt cationic catalyst used is different, and 3-methyl-1-n-butylpyridinium chloride is replaced by catalyst 2. The obtained polymer is identified by gel permeation chromatography (GPC). n =30700 g / mol, M w / Mn =1.30, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.21 shown.

[0400] The results of Examples 15-21 and Comparative Example 4 show that different types of quaternary ammonium salt cationic catalysts can effectively regulate the molecular weight of the polymer, achieve ultra-fast controllable polymerization, and the polymer has a narrow dispersity. These results prove that the catalytic polymerization method of the present invention can effectively control the molecular weight of the polymerization initiated by a strong base.

[0401] Example 22. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and 1,8-diazobispiro[5.4.0]undec-7-ene

[0402]

[0403] The experimental method is the same as that of Example 15, except that the initiator used is different, and 1,8-diazobispiro[5.4.0]undec-7-ene is used to replace 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. The obtained polymer is identified by gel permeation chromatography (GPC). n =23700 g / mol, M w / M n =1.22, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig. 22 shown.

[0404] Example 23. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and initiated by tetramethylguanidine

[0405]

[0406] The experimental method is the same as that of Example 15, except that the initiator used is different, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene is replaced by tetramethylguanidine. The obtained polymer is identified by gel permeation chromatography (GPC). n =25,000 g / mol, M w / M n =1.25, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.23 shown.

[0407] Example 24. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and lithium bis(trimethylsilyl)amide

[0408]

[0409] The experimental method is the same as that of Example 15, except that the initiator used is different, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene is replaced by lithium bistrimethylsilylamide. The obtained polymer is identified by gel permeation chromatography (GPC). n =22600 g / mol, M w / M n =1.25, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.24 shown.

[0410] Example 25. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and initiated by tetrabutylammonium acetate

[0411]

[0412] The experimental method is the same as that of Example 15, except that the initiator used is different, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene is replaced by tetrabutylammonium acetate. The obtained polymer is identified by gel permeation chromatography (GPC). n =24300 g / mol, M w / M n =1.21, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.25 shown.

[0413] Example 26. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and tetrabutylammonium benzoate

[0414] The experimental method is the same as that of Example 15, except that the initiator used is different, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene is replaced by tetrabutylammonium acetate. The obtained polymer is identified by gel permeation chromatography (GPC). n =25400 g / mol, M w / M n =1.27, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig.26 shown.

[0415] Example 27. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride and tetramethylammonium benzoate

[0416]

[0417] The experimental method is the same as that of Example 15, except that the initiator used is different, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene is replaced by tetramethylammonium acetate. The obtained polymer is identified by gel permeation chromatography (GPC). n =23700 g / mol, M w / M n =1.21, the gel permeation chromatogram of the obtained L-glutamic acid-γ-benzyl ester homopolymer is as follows Fig. 27 shown.

[0418] The results of Examples 22-27 show that the quaternary ammonium salt cationic catalyst used in the catalytic polymerization method of the present invention can be used to catalyze different types of organic bases and carboxylates to achieve ultra-fast and controllable polymerization to prepare polymers.

[0419] Example 28. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) catalyzed by 3-methyl-1-n-butylpyridinium chloride in different solvents

[0420] The experimental method is the same as that of Example 15, except that the polymerization solvent system used is different. The polymerization solvent used in Example 1 is tetrahydrofuran, and the solvents used in this experiment mainly include dichloromethane, toluene, dioxane, N,N-dimethylformamide and N,N-dimethylacetamide. The reaction time is 15 seconds to three hours. The obtained polymer is identified by gel permeation chromatography (GPC). M n =20300-31900g / mol, M w / M n =1.26-1.30, the data are shown in Table 3.

[0421] Table 3: Molecular weight and distribution of L-glutamic acid-γ-benzyl ester homopolymer in different solvents

[0422]

[0423] The results show that the catalytic polymerization method of the present invention can be carried out in a variety of organic solvents, including a strong polar solvent (N,N-dimethylformamide) and a non-polar solvent (toluene), etc. This shows that the catalytic polymerization method of the present invention is widely applicable to solvents.

[0424] Example 29. Polymerization of Nε-tert-butyloxycarbonyl-L-lysine intracyclic anhydride (monomer 2) catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene using 3-methyl-1-n-butylpyridinium chloride

[0425]

[0426] The experimental method is the same as that of Example 15, except that the polymerization monomers used are different, and monomer 1 is replaced by monomer 2. The obtained polymer is identified by gel permeation chromatography (GPC). n =21,000 g / mol, M w / M n =1.20, and Nε-tert-butyloxycarbonyl-L-lysine homopolymer was obtained.

[0427] Example 30. Polymerization of 5-ethyl L-glutamate catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by 3-methyl-1-n-butylpyridinium chloride

[0428]

[0429] The experimental method is the same as that of Example 15, except that the polymerization monomers used are different, and L-glutamic acid-5-ethyl ester replaces monomer 1. The obtained polymer is identified by gel permeation chromatography (GPC). n =14100 g / mol, M w / M n =1.24, the obtained L-glutamic acid-5-ethyl ester homopolymer.

[0430] Example 31. Polymerization of 5-ethyl L-glutamate catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene catalyzed by 3-methyl-1-n-butylpyridinium chloride

[0431]

[0432] The experimental method was the same as that of Example 15, except that the polymerization monomers used were different, and Trt-L-histidine monomer replaced monomer 1. The polymerization time was 5 minutes, and the TLC spot plate showed that the monomer spot disappeared, indicating that the monomer was completely converted into a polymer. The reaction solution was precipitated with petroleum ether to obtain a white flocculent, which was Trt-L-histidine homopolymer.

[0433] Examples 29-31 show that the catalytic polymerization method of the present invention uses a quaternary ammonium salt cationic catalyst to catalyze the polymerization initiated by an organic base for different types of monomers.

[0434] Example 32. Copolymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl ring anhydride (monomer 1) and N-ε-tert-butyloxycarbonyl-L-lysine (monomer 2) catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene using 3-methyl-1-n-butylpyridinium chloride

[0435]

[0436] The experimental method is the same as that of Example 9, except that monomer 1 and monomer 2 are used for copolymerization. The reaction time is about 5 minutes, and a copolymer of L-glutamic acid-γ-benzyl ester and N-ε-tert-butyloxycarbonyl-L-lysine is obtained. The obtained polymer is identified by gel permeation chromatography (GPC). n =21300 g / mol, M w / M n =1.23.

[0437] Example 33. Copolymerization of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) and L-norleucine-N-carboxyl carbonyl ring anhydride (monomer 6) catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene using 3-methyl-1-n-butylpyridinium chloride

[0438]

[0439] The experimental method is the same as that of Example 9, except that monomer 1 and monomer 6 are used for copolymerization. The reaction time is about 30 minutes, and a copolymer of L-glutamic acid-γ-benzyl ester and L-norleucine is obtained. The obtained polymer is identified by gel permeation chromatography (GPC). n =19300 g / mol, M w / M n =1.28.

[0440] Example 34. Copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine (monomer 2) and L-norleucine-N-carboxylcarbonyl ring anhydride (monomer 6) catalyzed by 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene

[0441]

[0442] The experimental method is the same as that of Example 9, except that monomer 2 and monomer 6 are used for copolymerization. The reaction time is about 25 minutes, and a copolymer of L-glutamic acid-γ-benzyl ester and L-norleucine is obtained. The obtained polymer is identified by gel permeation chromatography (GPC). n =16,000 g / mol, M w / M n =1.15.

[0443] Examples 32-34 show that the catalytic polymerization method of the present invention uses a quaternary ammonium salt cationic catalyst to catalyze the polymerization initiated by an organic base for copolymerization of different types of monomers.

[0444] Example 35. Block Copolymerization of L-Glutamic Acid-γ-Benzyl Ester-N-Carboxyl Carbonyl Ring Anhydride (Monomer 1) and N-ε-tert-Butyloxycarbonyl-L-Lysine-N-Carboxyl Carbonyl Ring Anhydride (Monomer 2) Initiated by 7-Methyl-1,5,7-Triazabicyclo[4.4.0]Decan-5-ene Catalyzed by 1,4-3-Methyl-1-n-Butylpyridinium Chloride

[0445]

[0446] The experimental method is the same as that of Example 14, except that the block copolymerization is performed once with monomer 1 and monomer 2. The reaction time is about 2 minutes, and a block copolymer of L-glutamic acid-γ-benzyl ester-N-carboxyl carbonyl ring anhydride (monomer 1) and N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxyl carbonyl ring anhydride (monomer 2) is obtained. The obtained polymer is identified by gel permeation chromatography (GPC). The first polymer M n =4800 g / mol, M w / M n =1.21, the second block polymer M n =11100 g / mol, M w / M n =1.29.

[0447] Example 35 shows that the catalytic polymerization method of the present invention uses a quaternary ammonium salt cationic catalyst to catalyze the organic base to initiate polymerization and is used for block copolymerization of different types of monomers.

[0448] Example 36. Polyester obtained by polymerization of β-propiolactone catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and initiated by methanol

[0449]

[0450] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0451] Methanol (3.2 mg, 0.1 mmol) was dissolved in dry dichloromethane (1 mL) to prepare a 0.1 M solution for later use.

[0452] β-propiolactone (72.0 mg, 1 mmol) was accurately weighed and dissolved in a reaction flask equipped with a stirrer using dry dichloromethane (0.5 mL). 400 μL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction flask, followed by 100 μL of 0.1 M methanol solution. The mixture was stirred at 50°C for 3 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC).n =6100g / mol and molecular weight distribution M w / M n =1.14.

[0453] All the above reaction mixtures were poured into cold petroleum ether (40 mL), the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in dichloromethane (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain a homopolymer.

[0454] Comparative Example 5. Polyester obtained by polymerization of β-propiolactone initiated by methanol

[0455] The experimental method is the same as that of Example 36, except that no quaternary ammonium salt cationic catalyst is added. The reaction time is 3 hours, and no corresponding polyester product is obtained. This indicates that without the addition of a catalyst, the methanol initiator will not initiate the polymerization of β-propiolactone to prepare polyester.

[0456] The results of Comparative Example 5 show that the catalytic polymerization method of the present invention using a quaternary ammonium salt cationic catalyst can effectively catalyze alcohol-initiated cyclic ester polymerization to prepare polyester.

[0457] Example 37. Polyester obtained by polymerization of β-phenyl substituted propiolactone catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and initiated by methanol

[0458]

[0459] The experimental method is the same as that of Example 36, except that β-phenyl substituted propiolactone is used instead of β-propiolactone. The reaction time is about 3 hours, and TLC spot plate monitoring shows that the monomer disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, thereby obtaining a β-phenyl substituted propiolactone polymer.

[0460] Example 38. Polyester obtained by polymerization of β-methyl substituted propiolactone catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and initiated by methanol

[0461]

[0462] The experimental method is the same as that of Example 36, except that β-methyl substituted propiolactone is used instead of β-propiolactone. The reaction time is about 3 hours, and HPLC monitoring shows that the monomer disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, thereby obtaining a β-methyl substituted propiolactone polymer.

[0463] Example 39. Polyester obtained by polymerization of β-Boc-methylamino substituted propiolactone catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride and initiated by methanol

[0464]

[0465] The experimental method is the same as that of Example 36, except that β-propiolactone is replaced by β-Boc-methylamino-substituted propiolactone. The reaction time is about 3 hours, and TLC spot plate monitoring shows that the monomer disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, thereby obtaining a β-Boc-methylamino-substituted propiolactone polymer.

[0466] Example 40. Polyester obtained by catalyzing methanol-induced polymerization of cyclopentyl ester with 4-dimethylamino-1-neopentylpyridinium chloride

[0467]

[0468] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0469] Methanol (3.2 mg, 0.1 mmol) was dissolved in dry dichloromethane (1 mL) to prepare a 0.1 M solution for later use.

[0470] β-propiolactone (100.0 mg, 1 mmol) was accurately weighed and dissolved in a reaction flask equipped with a stirrer using dry dichloromethane (0.5 mL). 400 μL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction flask, followed by 100 μL of 0.1 M methanol solution. The mixture was stirred at 50 °C for 24 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =1100g / mol and molecular weight distribution M w / M n =1.17.

[0471] All the above reaction mixtures were poured into cold petroleum ether (40 mL), the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in dichloromethane (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain a homopolymer.

[0472] Comparative Example 6. Polyester obtained by polymerization of cyclopentyl ester initiated by methanol

[0473] The experimental method is the same as that of Example 40, except that no quaternary ammonium salt cationic catalyst is added. The reaction time is 3 hours, and no corresponding polyester product is obtained. This indicates that without the addition of a catalyst, the methanol initiator will not initiate the polymerization of cyclopentyl ester to prepare polyester.

[0474] The results of Comparative Example 6 show that the catalytic polymerization method of the present invention using a quaternary ammonium salt cationic catalyst can effectively catalyze alcohol-initiated cyclopentyl ester polymerization to prepare polyester.

[0475] Example 41. Polyester obtained by catalyzing the polymerization of lactide initiated by methanol using 4-dimethylamino-1-neopentylpyridinium chloride

[0476]

[0477] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0478] Methanol (3.2 mg, 0.1 mmol) was dissolved in dry dichloromethane (1 mL) to prepare a 0.1 M solution for later use.

[0479] Lactide (144.0 mg, 1 mmol) was accurately weighed and dissolved in a reaction flask equipped with a stirrer using dry dichloromethane (0.5 mL). 400 μL of 0.05 M 4-dimethylamino-1-neopentylpyridinium chloride solution was added to the stirred reaction flask, followed by 100 μL of 0.1 M methanol solution. The mixture was stirred at 50°C for 24 hours, and the molecular weight of the obtained polymer was determined by gel permeation chromatography (GPC). n =1400g / mol and molecular weight distribution M w / M n =1.23.

[0480] All the above reaction mixtures were poured into cold petroleum ether (40 mL), the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in dichloromethane (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain a homopolymer.

[0481] Comparative Example 7. Polyester obtained by polymerization of lactide initiated by methanol

[0482] The experimental method is the same as that of Example 41, except that no quaternary ammonium salt cationic catalyst is added. The reaction time is 3 hours, and no corresponding polyester product is obtained. This indicates that without the addition of a catalyst, the methanol initiator will not initiate the polymerization of lactide to prepare polyester.

[0483] The results of Comparative Example 7 show that the catalytic polymerization method of the present invention can catalyze alcohol-initiated lactide polymerization to prepare polyester using a quaternary ammonium salt cationic catalyst.

[0484] Example 42 Polymerization of N-methyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride (Sar-NNCA, monomer 9) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0485]

[0486] 4-Dimethylamino-1-neopentylpyridinium chloride (22.8 mg, 0.05 mmol) was accurately weighed and prepared into a 0.05 M solution with dichloromethane (2 mL) for later use.

[0487] n-Butylamine (9.8 μg, 0.1 mmol) was dissolved in dry dichloromethane (1 mL) to prepare a 0.1 M solution for later use.

[0488] The N-methyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride (115.0 mg, 1 mmol) was accurately weighed and dissolved in a reaction bottle equipped with a stirrer with dry dichloromethane (0.5 mL). In the stirred reaction bottle, 400 μL of 0.05M 4-dimethylamino-1-neopentylpyridinium chloride solution was added, followed by 100 μL of 0.1M n-butylamine solution. The mixture was stirred for 8 hours, and the molecular weight M of the obtained polymer was determined by gel permeation chromatography (GPC). n =1600g / mol and molecular weight distribution M w / M n =1.15.

[0489] All the above reaction mixtures were poured into cold petroleum ether (40 mL) respectively, the precipitated white flocs were collected by centrifugation, dried in a gas stream, and redissolved in tetrahydrofuran (1.5 mL), and then a large amount of cold petroleum ether was added for precipitation. The dissolution-precipitation process was repeated three times to obtain a homopolymer.

[0490] Example 43 Polymerization of L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl cyclic anhydride (monomer 10) catalyzed by 3-methyl-1-n-butylpyridinium chloride and initiated by tetrabutylammonium acetate

[0491]

[0492] The experimental method was the same as that of Example 42, except that tetrabutylammonium acetate was used to replace methanol, and monomer 9 was polymerized by replacing monomer 10. The reaction time was 24 hours, and the TLC spot plate showed that the monomer spot disappeared, indicating that the monomer was completely converted into a polymer. The reaction solution was precipitated with petroleum ether to obtain a white flocculent, which was the corresponding amino acid polymer product.

[0493] Example 44 Polymerization of N-ε-tert-butyloxycarbonyl-L-lysine thiocarbonyl ring anhydride initiated by tetrabutylammonium acetate catalyzed by 3-methyl-1-n-butylpyridinium chloride

[0494]

[0495] The experimental method was the same as that of Example 43, except that N-ε-tert-butyloxycarbonyl-L-lysine thiocarbonyl ring anhydride was substituted for L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl ring anhydride for polymerization. The reaction time was 24 hours, and the TLC spot plate showed that the monomer spot disappeared, indicating that the monomer was completely converted into a polymer. The reaction solution was precipitated with petroleum ether to obtain a white flocculent substance, and the corresponding amino acid polymer product was obtained.

[0496] Example 45 Polymerization of N-cyclohexyl-substituted α-amino acid-N-carboxylcarbonyl intracyclic anhydride initiated by tetrabutylammonium acetate catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride

[0497]

[0498] The experimental method is the same as that of Example 43, except that the N-cyclohexyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride is substituted for L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl ring anhydride for polymerization. The reaction time is 24 hours. The TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, and the corresponding amino acid polymer product is obtained. Example 46 4-Dimethylamino-1-neopentylpyridinium chloride catalyzes tetrabutylammonium acetate to initiate polymerization of N-methoxyethyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride The experimental method is the same as that of Example 43, except that the N-methoxyethyl substituted α-amino acid-N-carboxyl carbonyl ring anhydride is substituted for L-glutamic acid-5-benzyl ester-N-carboxylthiocarbonyl ring anhydride for polymerization. The reaction time is 24 hours. The TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, and the corresponding amino acid polymer product is obtained. Example 47 3-Methyl-1-n-butylpyridinium chloride catalyzes tetrabutylammonium acetate to initiate polymerization of N-methyl substituted α-amino acid-N-carboxylthiocarbonyl ring anhydride (monomer 11) The experimental method is the same as that of Example 43, except that monomer 11 is substituted for monomer 10 for polymerization. The reaction time is 24 hours. The TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, and the corresponding amino acid polymer product is obtained. Example 483-Methyl-1-n-butylpyridinium chloride catalyzes tetrabutylammonium acetate to initiate polymerization of N-benzyl substituted α-amino acid-N-carboxylthiocarbonyl ring anhydride The experimental method is the same as that of Example 43, except that the N-benzyl substituted α-amino acid-N-carboxylthiocarbonyl ring anhydride is used to replace monomer 10 for polymerization. The reaction time is 24 hours. The TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, and the corresponding amino acid polymer product is obtained. Example 49. 3-Methyl-1-n-butylpyridinium chloride catalyzes tetrabutylammonium acetate to initiate copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxylcarbonyl ring anhydride (monomer 2) and N-methyl substituted α-amino acid-N-carboxylcarbonyl ring anhydride (monomer 9)

[0499]

[0500] The experimental method was the same as that of Example 9, except that monomer 2 and monomer 9 were used for copolymerization. The reaction time was about 24 hours, and the TLC spot plate showed that the monomer spot disappeared, indicating that the monomer was completely converted into a polymer. The reaction solution was precipitated with petroleum ether to obtain a white flocculent, and a copolymer of N-ε-tert-butyloxycarbonyl-L-lysine and N-methyl-substituted amino acid was obtained.

[0501] Example 50. Copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxylcarbonyl cyclic anhydride (monomer 2) and β-propiolactone catalyzed by 3-methyl-1-n-butylpyridinium chloride and tetrabutylammonium acetate

[0502]

[0503] The experimental method is the same as that of Example 9, except that monomer 2 and β-propiolactone are used for copolymerization. The reaction time is about 24 hours, and the TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent, and a copolymer of N-ε-tert-butyloxycarbonyl-L-lysine and β-propiolactone is obtained.

[0504] Example 51. Copolymerization of N-ε-tert-butyloxycarbonyl-L-lysine-N-carboxylcarbonyl intracyclic anhydride (monomer 2) and lactide catalyzed by 3-methyl-1-n-butylpyridinium chloride and tetrabutylammonium acetate

[0505]

[0506] The experimental method is the same as that of Example 9, except that monomer 2 and lactide are used for copolymerization. The reaction time is about 24 hours, and the TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent, and a copolymer of N-ε-tert-butyloxycarbonyl-L-lysine and lactide is obtained.

[0507] Example 52. 3-Methyl-1-n-butylpyridinium chloride catalyzes tetrabutylammonium acetate to initiate copolymerization of β-propiolactone and lactide

[0508]

[0509] The experimental method is the same as that of Example 9, except that β-propiolactone and lactide are used for copolymerization. The reaction time is about 24 hours, and the TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent, thereby obtaining a copolymer of β-propiolactone and lactide.

[0510] Example 53. Recovery of 4-dimethylamino-1-neopentylpyridinium chloride catalyst

[0511] After the NCA polymerization reaction initiated by the primary amine is completed, the reaction mixture is centrifuged and the precipitate is collected as part of the recovered 4-dimethylamino-1-neopentylpyridinium chloride catalyst. The supernatant is then precipitated with tetrahydrofuran / n-hexane to obtain a polymer, and the collected precipitate is washed with MeOH or ml of clean water, and the residual solution is collected and vacuum dried to obtain another portion of crude 4-dimethylamino-1-neopentylpyridinium chloride catalyst. The two portions of recovered DMAPPCl are combined, washed three times with THF, and then vacuum dried to obtain a white solid, which is the recovered catalyst.

[0512] Example 54. Use of the recovered 4-dimethylamino-1-neopentylpyridinium chloride catalyst to catalyze the polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) initiated by n-butylamine

[0513] The experimental method is the same as that of Example 1, except that the catalyst used for the first time is replaced by the recovered catalyst. The reaction time is about 70 minutes, and a homopolymer of L-glutamic acid-γ-benzyl ester is obtained. The obtained polymer is identified by gel permeation chromatography (GPC). n =23400 g / mol, M w / M n =1.08. The catalyst can be recycled for 5 cycles. The recycled catalyst shows a highly efficient catalytic polymerization function. The polymerization reaction can be completed within 1.5 hours, and the molecular weight of the prepared polymer is highly controllable.

[0514] Example 55.1. Polymerization of L-glutamic acid-γ-benzyl ester-N-carboxylcarbonyl intracyclic anhydride (monomer 1) catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride with different primary amine initiators

[0515]

[0516] The experimental method is the same as that of Example 1, except that different primary amine initiators are used instead of n-butylamine. The reaction time is about 30 to 40 minutes, and the polymerization feed ratio is 50:1. The obtained polymer is identified by gel permeation chromatography (GPC). n =11200-47000g / mol, M w / M n =1.04-1.19. The obtained polymer gel permeation chromatogram is as follows Fig.28 shown.

[0517] Example 56. Polyester obtained by polymerization of β-propiolactone catalyzed by 4-dimethylamino-1-neopentylpyridinium chloride with different alcohols

[0518]

[0519] The experimental method is the same as that of Example 36, except that different alcohol initiators are used instead of methanol. The reaction time is about 3 to 6 hours. The TLC spot plate shows that the monomer spot disappears, indicating that the monomer is completely converted into a polymer. The reaction solution is precipitated with petroleum ether to obtain a white flocculent substance, which is the corresponding polymer.

[0520] discuss

[0521] 1. The catalyst of the present invention has a rich structure, and different cationic structures and different counter anion types can all achieve efficient catalytic polymerization function;

[0522] 2. The polymerization speed of the method of the present invention is fast and highly controllable. Compared with the traditional ring-opening polymerization (for example, primary amines initiate α-amino acid N-carboxyl carbonyl ring anhydride monomer NCA, which takes 3 days), the polymerization speed is significantly improved; compared with organic strong bases (for example, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene initiates α-amino acid N-carboxyl carbonyl ring anhydride monomer NCA, which is completely uncontrollable and has a wide molecular weight distribution), the controllability of the ring-opening polymerization is significantly improved;

[0523] 3. The method of the present invention can be applied to a variety of monomers (including various intracyclic anhydride monomers and cyclic ester monomers). For cyclic ester monomers, polymerization is almost impossible without the addition of a catalyst. After the use of a quaternary ammonium salt cationic catalyst, the polymerization speed is significantly increased, and polyester can be quickly prepared;

[0524] 4. The method of the present invention can be applied to a variety of organic base or carboxylate initiation systems, and can achieve rapid and controllable polymerization to prepare polymers, satisfying diverse polymerization reactions;

[0525] 5. The method of the present invention can be applied to the preparation of polymers of various structures, including random copolymers and block copolymers, and has simple operation and rapid reaction;

[0526] 6. The method of the present invention is applicable to a variety of solvent systems, which greatly improves the applicable scope of the polymerization system;

[0527] 7. The method of the present invention can conveniently realize the recovery and reuse of the catalyst, and the recovered catalyst still maintains efficient catalytic activity, realizing rapid and controllable polymerization to prepare polymers under 5 cycles;

[0528] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A catalytic polymerization method for a polymer, characterized in that: Includes steps: (a) polymerizing one or more cyclic monomers in the presence of a catalyst and an initiator to form a polymer; Wherein, the catalyst is selected from the group consisting of a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV, or a combination thereof; in, X1 is N or P; Z1, Z2, Z3, and Z4 are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4 alkyl-3-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, C0-C4 alkyl C6-C 12 Aryl, C0-C4 alkyl-5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-, or any two of Z1, Z2, Z3 and Z4 together with the X1 atom to which they are connected constitute a substituted or unsubstituted 3-12 heterocyclic group (including a monocyclic, spirocyclic, bridged or cyclic group); wherein the substitution refers to the replacement of one or more H on the group by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl; or 1, 2 or 3 of Z1, Z2, Z3 and Z4 are connected to the corresponding number of groups of Z1, Z2, Z3 and Z4 in another formula I to form a compound having two X1 centers, wherein the connection is connected by forming 1, 2 or 3 groups independently selected from C1-C6 alkylene; Z1', Z2', Z3', Z4', Z5' and Z6' are each independently selected from the group consisting of substituted or unsubstituted hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C 12 Alkyl, C1-C 12 Haloalkyl, -N(C1-C6 alkyl) 1-2 、C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4 alkyl having 3-12 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O, C0-C4 alkyl C6-C 12 Aryl, C0-C4 alkyl having 5-12 membered heteroaryl with 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl ester group, C1-C6 alkyl CO-, or two adjacent carbon atoms of Z1', Z2', Z3' and Z4' together with the carbon atoms to which they are connected constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered or heterocyclic group (including monocyclic, spirocyclic, bridged or fused rings); wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl; R1 and R2 are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, -C0-C4 alkyl, C3-C 12 Cycloalkyl, -C0-C4alkyl-3-12 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, -C0-C4alkylC6-C 12 Aryl, -C0-C4 alkyl, 5-12 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-; wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl; X2 is N or CH; R, R1', R2', R3', R4', R5' are each independently selected from the following substituted or unsubstituted groups: hydrogen, C1-C 12 Alkyl, C1-C 12 Thioalkyl, C1-C 12 Alkoxy, C3-C 12 Cycloalkyl, -C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4 alkyl having 3-12 membered heterocyclic group with 1-3 heteroatoms selected from N, S and O, C0-C4 alkyl C6-C 12 Aryl, C0-C4 alkyl having 5-12 membered heteroaryl with 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C6 alkyl-CO-; any two of R1', R2', R3', R4', R5' and the atoms to which they are connected together constitute a substituted or unsubstituted 3-12 membered heterocyclic group (including a monocyclic, spirocyclic, bridged or cyclic group); wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of halogen, C1-C6 alkyl and C1-C6 haloalkyl; Wherein, the monomer is selected from the following group: N-carboxyl carbonyl cyclic anhydride, N-substituted N-carboxyl carbonyl cyclic anhydride, N-carboxyl thiocarbonyl cyclic anhydride, N-substituted N-carboxyl thiocarbonyl cyclic anhydride, cyclic ester monomer, lactide, or a combination thereof.

2. The method according to claim 1, characterized in that The monomer is selected from formula (V), (VI), (VII), or a combination thereof; Wherein, Y is S or O; m is independently 0, 1, 2, 3 or 4; R", R1", R2", R1"', R2"', R3"' and R4"' are each independently selected from the group consisting of substituted or unsubstituted hydrogen, amino, C1-C 12 Alkyl, C1-C 12 Haloalkyl, -CH3(O-CH2-CH2) 1-6 , amino-substituted C1-C 12 Alkyl, -C1-C 12 Alkyl-N3, hydroxy substituted C1-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkylthio, 2-12 membered heteroalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, C1-C 12 Alkylsulfonyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C0-C4 alkyl, C3-C 12 Cycloalkyl, C0-C4 alkyl, C6-C 12 Aryl, C0-C4 alkyl having 5-12 membered heteroaryl with 1-3 heteroatoms selected from the group consisting of N, S and O, C0-C4 alkyl having 3-12 membered heterocyclic group with 1-3 heteroatoms selected from the group consisting of N, S and O, -C1-C6 alkylguanidinyl, -(C0-C8 alkylene)-LR a or R1" and R2" on the same or adjacent carbon atoms together with the carbon atoms to which they are attached constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; or two R1"' or R1"' and R2"' together with the carbon atom to which they are attached constitute a substituted or unsubstituted C3-C 12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the substitution refers to the substitution independently by one or more (e.g., 2, 3, 4, etc.) R m replace; L is independently a chemical bond, -O-, -S-, -SS-, NHCO, -CO-, -COO-, -S(=O)2-, NH, hydrazine or guanidinium; Each R a are independently selected from the following groups: substituted or unsubstituted: hydrogen, C1-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkylamino, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -(C0-C4 alkylene)-C3-C 12 Cycloalkyl, -(C0-C4 alkylene)-C4-C 12 Cycloalkenyl, -(C0-C4 alkylene)-5-12 membered heterocyclic group, -(C0-C4 alkylene)-C6-C 12 Aryl, -(C0-C4 alkylene)-5-12 membered heteroaryl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), phthaloyl (Pht), acetyl (Ac), trifluoroacetyl (Tfa), benzyl (Bn), triphenylmethyl (Tr); wherein the substitution refers to independently replacing one or more (e.g., 2, 3, 4, etc.) R m replace; R m independently selected from the following groups: halogen, hydroxy, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, methylsulfone, -S(=O)2NH2, oxo (=O), -CN, -N3, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C6-C 12 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, 5-10 membered heterocyclic group having 1-3 heteroatoms selected from the group consisting of N, S and O, -N(C1-C6 alkyl) 1-2 , C1-C6 amide, -COOH, -SH, benzyl, -PhOH, benzyloxycarbonyl (Cbz), trityl (Trt), trifluoromethyl, glucosyl or Y1, Y2, Y3, and Y4 are anionic groups that counteract the positive charge.

3. The method according to claim 1, characterized in that The catalyst is selected from the following group and its salt: Preferably, the anionic group that counteracts the positive charge is selected from the group consisting of F, Cl, Br, I, BF4, PF6.

4. The method according to claim 1, characterized in that The catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylphosphine chloride, triethylbenzylammonium chloride, tetramethylammonium chloride, triethylbenzylammonium chloride, ， or a combination thereof.

5. The method according to claim 1, characterized in that The initiator is selected from the group consisting of primary amines, secondary amines, tertiary amines, alcohols, thiols, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, carboxylates, phosphazene bases, alkoxides, thiolates, or a combination thereof.

6. The method according to claim 1, characterized in that The R", R1", R2", R1"', R2"', R3"' and R4"' are each independently selected from the following groups: H, 7. The method according to claim 1, characterized in that The monomer is selected from the group consisting of:

8. The method according to claim 1, characterized in that When the monomers are two or more (such as three, four or more), the method comprises the steps of: In the presence of a catalyst and an initiator, two or more (such as three, four or more) monomers are mixed and then polymerized to form a random copolymer; or (a) subjecting a first monomer to a polymerization reaction in the presence of a catalyst and an initiator; (b) after the above polymerization reaction is completed, adding a second monomer to carry out polymerization reaction; and optionally (c) repeating (b) 0-p times, with the proviso that the monomers in each step of step (c) are different from the monomers in the previous step, thereby forming a block copolymer; Among them, p≥1.

9. The method according to claim 1, characterized in that The reaction is carried out in an inert solvent, and the method comprises the following steps: (i) providing a monomer solution, an initiator solution, and a catalyst solution; (ii) adding the initiator solution described in step (i) to the stirred monomer solution to carry out a polymerization reaction, thereby obtaining a polymer; The solvent of the monomer solution and the solvent of the initiator solution are the same or different.

10. The preparation method according to claim 1, characterized in that: The added equivalent amount of the catalyst is 0.1%-20% compared to the added equivalent amount of the monomer.

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