A polytehnic acid polymerization monomer and a preparation method thereof, and a polytehnic acid and a preparation method thereof

Abstract

The application belongs to the technical field of polyamino acids, and provides a polytehine polymerization monomer, a preparation method of the polytehine polymerization monomer, a polytehine and a preparation method of the polytehine. N The polytehine polymerization monomer with the structure shown in formula I is tea amino acid-NTA, and the polytehine can be synthesized by an NTA ring-opening polymerization method; the polytehine polymerization monomer with the structure shown in formula II is phenoxy carbonyl tea amino acid (The-NPC), and the polytehine can be synthesized by an NPC polymerization method. N The polytehine polymerization monomer provided by the application avoids harsh conditions of the existing amino acid-NCA ring-opening polymerization method for synthesizing the polytehine, so that the preparation conditions of the polytehine are mild. N The polytehine polymerization monomer provided by the application avoids harsh conditions of the existing amino acid-NCA ring-opening polymerization method for synthesizing the polytehine, so that the preparation conditions of the polytehine are mild.

Description

Technical Field

[0001] This invention relates to the field of polyamino acid technology, and in particular to a polymer monomer of polytheanine and its preparation method, as well as polytheanine and its preparation method. Background Technology

[0002] Poly(α-amino acid)s (PAAs) are macromolecular compounds formed by repeating amino acids linked by peptide bonds, exhibiting excellent biocompatibility and biodegradability. The abundance of R-groups on the side groups of PAAs contributes to their diverse physicochemical properties. For example, polylysine (PLys) and polyglutamic acid (PGlu) are pH-responsive, polyalanine (PAla) and polyphenylalanine (PPhe) are oil-soluble, while polyserine (PSer) and polysarcosine (PSar) possess good water solubility. These unique properties give PAAs broad application prospects in biomedical fields such as drug delivery, gene transfection, biosensors, and tissue engineering.

[0003] Currently, the main chemical synthesis methods for polyamino acids include: solid-phase synthesis (primarily used for oligopeptide synthesis), amino acid- N -Ring-opening polymerization of carboxylic anhydrides (NCA), amino acids- N -Ring-opening polymerization of thiocarboxylic anhydrides (NTA) and N -Phenoxycarbonyl amino acid (NPC) polymerization method.

[0004] Theanine (N-ethyl-γ-glutamine) has the following structure:

[0005] .

[0006] Theanine, a derivative of glutamine, is a natural non-protein amino acid widely found in tea. Studies have shown that theanine possesses various physiological activities, including neuroprotection, anti-fatigue, anti-tumor, and blood pressure reduction, making it valuable in the food, pharmaceutical, and chemical industries. Polytheanine (PThe) is a class of polyamino acids with amide groups in their side chains, and research on its synthesis and applications is still in its early stages. Currently, some researchers have attempted to prepare polytheanine via electrochemical polymerization, but have failed to successfully isolate the target product for systematic characterization of its structure and properties (J. Electroanal. Chem., 2013, 709, 1-9). In the same year, researchers proposed a new method for the direct synthesis of amino acids from amino acids containing amide groups, such as theanine. N-Carboxylic anhydride (NCA) monomers were used to prepare the corresponding polyamino acids via ring-opening polymerization (Japanese Patent JP 2013-234207 A 2013.11.21). However, NCA monomers are highly reactive, and strict anhydrous and oxygen-free conditions are required in their synthesis, purification, preservation, and polymerization to form polytheanine, which greatly limits the feasibility of large-scale production. Summary of the Invention

[0007] In view of this, the object of the present invention is to provide a polymeric monomer of polytheanine and a method for preparing the same, as well as polytheanine and a method for preparing the same. The polymeric monomer provided by the present invention enables a mild preparation method for polytheanine.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] This invention provides a polymeric monomer for polytheanine, having the structure shown in Formula I or Formula II:

[0010] Formula I, Formula II.

[0011] This invention also provides a method for preparing the polymer monomer of polytheanine as described in the above technical solution, wherein the preparation method of the structure shown in Formula I includes the following steps:

[0012] Theanine, S-ethoxythiocarbonyl mercaptoacetic acid, base and water were mixed and subjected to a nucleophilic substitution reaction to obtain N-ethoxythiocarbonyl theanine intermediate;

[0013] The N-ethoxythiocarbonyl theanine intermediate under phosphorus tribromide conditions underwent a cyclization reaction to obtain the structure shown in Formula I.

[0014] The preparation method of the structure shown in Formula II includes the following steps:

[0015] Theanine, phenyl chloroformate, and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II; the two-phase mixed solvent includes water and an organic solvent.

[0016] Preferably, in the nucleophilic substitution reaction, the theanine is L-theanine; the base includes one or more of inorganic and / or organic bases;

[0017] The inorganic base includes sodium hydroxide and / or potassium hydroxide;

[0018] The organic base includes one or more of sodium alkoxide, potassium alkoxide, and tetraalkylammonium hydroxide;

[0019] The sodium alkoxide and potassium alkoxide each have 1 to 4 carbon atoms independently;

[0020] The number of carbon atoms in the alkyl group of the tetraalkylammonium hydroxide is 2 to 8;

[0021] The molar ratio of theanine to S-ethoxythiocarbonyl mercaptoacetic acid is 1~2:1, and the molar ratio of theanine to the base is 1:2~4.

[0022] The nucleophilic substitution reaction takes 12 to 120 hours.

[0023] Preferably, during the ring-closing reaction, the molar ratio of the N-ethoxythiocarbonyl theanine intermediate to phosphorus tribromide is 1:1~3, and the ring-closing reaction takes 3 hours.

[0024] Preferably, during the elimination reaction, the theanine is L-theanine, the molar ratio of theanine to phenyl chloroformate is 2:1 to 1:2, and the molar ratio of theanine to sodium bicarbonate is 1:2 to 4.

[0025] The organic solvent includes one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane, dichloroethane, and trichloromethane;

[0026] The volume ratio of water to organic solvent in the two-phase mixed solvent is 2:1 to 1:2; the elimination reaction is carried out at a temperature of 15 to 35°C for 3 to 24 hours.

[0027] The present invention also provides a polytheanine having the structure shown in Formula III:

[0028] Formula III;

[0029] In Formula III, R1 is one or more of alkyl, benzyl, silyl, polyamino acid chain, polyether chain or polyamide chain; R2 is hydrogen, silyl or C1~C8 alkyl; R3 is hydrogen.

[0030] This invention also provides a method for preparing polytheanine as described in the above technical solution, comprising the following steps:

[0031] Polytheanine monomers, initiators, and polar solvents are mixed and polymerized to obtain the polytheanine.

[0032] The polymer monomer of polytheanine is the polymer monomer of polytheanine described in the above technical solution;

[0033] The initiator is one or more of the following: aliphatic primary amine, aliphatic secondary amine, benzylamine, silylamine, polyamino acid, polyetheramine, or polyamide.

[0034] Preferably, the molar ratio of the polymerizable monomer to the initiator of the polytheanine is 5~200:1.

[0035] Preferably, the polar solvent includes one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform, toluene, acetone, methanol, ethanol, ethylene glycol, and water.

[0036] Preferably, the temperature of the first polymerization reaction is 20~100℃ and the time is 0.5~72h.

[0037] The present invention provides a polymeric monomer of polytheanine having the structures shown in Formula I and Formula II.

[0038] The monomer with the structure shown in Formula I provided by this invention is theanine- N -Thiocarboxylic anhydride (The-NTA) can be used to synthesize polythenine via NTA ring-opening polymerization; the monomer with the structure shown in Formula II is... N -Phenoxycarbonyltheanine (The-NPC) can be used to synthesize polytheanine via NPC polymerization. The monomers The-NTA and The-NPC provided by this invention exhibit superior nucleophilic reagent tolerance, higher storage stability, and better polymerization operability compared to common NCA monomers. Furthermore, the monomers of this invention are more stable under water, oxygen, and heat conditions, and the synthesis process does not require complex protective measures, allowing for direct polymerization and significantly simplifying the synthesis process. In addition, the two monomers of this invention can be further copolymerized with various types of amino acid-NTA or amino acid-NPC monomers to obtain polyamino acids with diverse structures and functions. The monomers provided by this invention avoid the harsh conditions required for the synthesis of polytheanine via existing NCA ring-opening polymerization methods, resulting in milder conditions for the preparation of polytheanine.

[0039] The present invention also provides a method for preparing the polymer monomer of polytheanine described in the above technical solution. The preparation method provided by the present invention can be formed under aqueous conditions without the need for anhydrous and oxygen-free conditions, and the reaction conditions are mild.

[0040] The present invention also provides a method for preparing polytheanine as described in the above technical solution. The preparation method of the present invention uses polymer monomers with the structures shown in Formula I and Formula II to prepare polytheanine. The polytheanine prepared by the present invention has a controllable molecular weight and a narrow molecular weight distribution; the composition of polytheanine is adjustable and the content of theanine residues is adjustable; more importantly, the polytheanine has excellent adjustable properties, such as water solubility, oil solubility, and processing performance, making it adaptable to different application scenarios and having broad application potential. Attached Figure Description

[0041] Figure 1 The-NTA in Example 11 H NMR spectrum;

[0042] Figure 2 The-NPC in Example 2 1 H NMR spectrum;

[0043] Figure 3 For example, the polytheanine in Example 3 1 H NMR spectrum;

[0044] Figure 4 An optical photograph of the polytheanine aqueous solution (150 mg / mL) in Example 4;

[0045] Figure 5 Polysarcosine in Example 9 b - Polytheanine 1 H NMR spectrum. Detailed Implementation

[0046] This invention provides a polymeric monomer for polytheanine, having the structure shown in Formula I or Formula II:

[0047] Formula I, Formula II.

[0048] In this invention, Formula I is theanine- N -Thiocarboxylic anhydride (The-NTA). In this invention, Formula II is... N -Phenoxycarbonyltheanine (The-NPC).

[0049] In this invention, The-NTA may have optical isomers, including L-type, D-type, or racemic mixtures (DL-type).

[0050] In this invention, The-NPC may have optical isomers, including L-type, D-type, or racemic mixtures (DL-type).

[0051] The polymerizable monomers The-NTA and The-NPC of this invention exhibit superior nucleophilic reagent tolerance, higher storage stability, and better polymerization operability compared to common NCA monomers. Furthermore, the polymerizable monomers of this invention are more stable under water, oxygen, and heat conditions, and the synthesis process does not require complex protective measures, allowing for direct polymerization reactions, significantly simplifying the synthesis process for polytheanine.

[0052] This invention also provides a method for preparing the polymer monomer of polytheanine as described in the above technical solution, wherein the preparation method of the structure shown in Formula I includes the following steps:

[0053] Theanine, S-ethoxythiocarbonyl mercaptoacetic acid, base and water were mixed and subjected to a nucleophilic substitution reaction to obtain N-ethoxythiocarbonyl theanine intermediate;

[0054] The N-ethoxythiocarbonyl theanine intermediate under phosphorus tribromide conditions underwent a cyclization reaction to obtain the structure shown in Formula I.

[0055] The preparation method of the structure shown in Formula II includes the following steps:

[0056] Theanine, phenyl chloroformate, and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II;

[0057] The two-phase mixed solvent includes water and an organic solvent.

[0058] Unless otherwise specified, the raw materials used in this invention are preferably commercially available products.

[0059] In this invention, the preparation method of the structure shown in Formula I includes the following steps: mixing theanine, S-ethoxythiocarbonyl mercaptoacetic acid, alkali and water, and carrying out a nucleophilic substitution reaction to obtain an N-ethoxythiocarbonyl theanine intermediate; the N-ethoxythiocarbonyl theanine intermediate undergoes a cyclization reaction under the conditions of phosphorus tribromide to obtain the structure shown in Formula I.

[0060] In this invention, the theanine is preferably L-theanine, which reduces the preparation cost. In this invention, the alkali preferably includes one or more of inorganic and / or organic alkalis. In this invention, the inorganic alkali preferably includes sodium hydroxide and / or potassium hydroxide. In this invention, the organic alkali preferably includes one or more of sodium alkoxide, potassium alkoxide, and tetraalkylammonium hydroxide. In this invention, the sodium alkoxide and potassium alkoxide preferably have 1 to 4 carbon atoms, specifically sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium n-butoxide, or potassium n-butoxide. In this invention, the tetraalkylammonium hydroxide preferably has 2 to 8 carbon atoms in the alkyl group, more preferably 2 to 4, specifically tetraethylammonium hydroxide, tetrapropylammonium hydroxide, or tetrabutylammonium hydroxide.

[0061] In this invention, the molar ratio of theanine and S-ethoxythiocarbonyl mercaptoacetic acid is preferably 1 to 2:1, and more preferably 1:1, 1.5:1 or 2:1.

[0062] In this invention, the molar ratio of theanine to alkali is preferably 1:2 to 4, and more preferably 1:2, 1:3 or 1:4.

[0063] In this invention, the mixing of theanine, S-ethoxythiocarbonyl mercaptoacetic acid, alkali, and water preferably includes the following steps: mixing theanine and...S -Ethoxythiocarbonylmercaptoacetic acid is dissolved in water, and then an alkali is added and stirred until dissolved. In this invention, the addition of the alkali is preferably carried out under ice-water bath conditions. This invention does not specifically limit the stirring speed and time, as long as the alkali is completely dissolved.

[0064] In this invention, the temperature of the nucleophilic substitution reaction is preferably room temperature, i.e., no additional heating or cooling is required; the time of the nucleophilic substitution reaction is preferably 12~120h, specifically preferably 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h or 120h.

[0065] Following the nucleophilic substitution reaction, the present invention preferably further includes: adjusting the pH of the obtained nucleophilic substitution reaction solution to acidity to obtain an acidified solution; extracting the acidified solution with ethyl acetate and combining the organic phases; and sequentially washing, drying, and concentrating the organic phases to obtain the N-ethoxythiocarbonyl theanine intermediate. In this invention, the acidic pH value is preferably 1-2, specifically preferably 1, 1.5, or 2. In this invention, the washing reagent is preferably a 5 wt% citric acid aqueous solution. In this invention, the drying is preferably done with a desiccant, preferably anhydrous sodium sulfate. In this invention, the concentration method is preferably rotary evaporation; the parameters of the rotary evaporation are not specifically limited, as long as the solvent can be removed.

[0066] In this invention, during the ring-closing reaction, the molar ratio of the N-ethoxythiocarbonyl theanine intermediate to phosphorus tribromide is 1:1 to 3, preferably 1:1, 1:1.2, 1:1.5, 1:2, 1:2.5 or 1:3.

[0067] In this invention, the N-ethoxythiocarbonyl theanine intermediate is preferably dissolved in ethyl acetate for the cyclization reaction. In this invention, the phosphorus tribromide is preferably added under ice-water bath conditions.

[0068] In this invention, the temperature of the ring-closing reaction is preferably room temperature, that is, neither additional heating nor additional cooling is required; the time of the ring-closing reaction is preferably 0.5~24h, specifically preferably 0.5h, 1h, 2h, 3h, 6h, 9h, 12h, 15h, 18h, 21h or 24h.

[0069] In this invention, the cyclization reaction of the N-ethoxythiocarbonyltheanine intermediate under phosphorus tribromide conditions preferably includes the following steps: dissolving the N-ethoxythiocarbonyltheanine intermediate in ethyl acetate to obtain an intermediate solution; adding phosphorus tribromide to the intermediate solution under ice-water bath conditions to carry out the cyclization reaction.

[0070] Following the ring-closing reaction, the present invention preferably further includes: extracting the obtained ring-closing reaction solution using saturated brine to collect the organic phase; the organic phase is then washed, dried, concentrated, and recrystallized sequentially to obtain the structure shown in Formula I. In this invention, the washing reagent is preferably a saturated sodium bicarbonate aqueous solution. In this invention, the drying is preferably done with a desiccant, preferably anhydrous sodium sulfate. In this invention, the concentration method is preferably rotary evaporation. In this invention, the recrystallization reagent is preferably a mixed solvent of ethyl acetate and n-hexane, wherein the volume ratio of ethyl acetate to n-hexane in the mixed solvent is preferably 1:1 to 2, specifically preferably 1:1 or 1:2.

[0071] In this invention, the preparation formula of the structure shown in Formula I is as shown in Formula 1:

[0072] Formula 1.

[0073] In this invention, the preparation method of the structure shown in Formula II includes the following steps:

[0074] Theanine, phenyl chloroformate, and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II; the two-phase mixed solvent includes water and an organic solvent.

[0075] In this invention, the theanine is preferably L-theanine. In this invention, the molar ratio of theanine to phenyl chloroformate is preferably 2:1 to 1:2, specifically 2:1, 1:1, or 1:2. In this invention, the molar ratio of theanine to sodium bicarbonate is preferably 1:2 to 4, specifically 1:2, 1:3, or 1:4. In this invention, the organic solvent preferably includes one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane, dichloroethane, and trichloromethane. In this invention, the volume ratio of water to organic solvent in the two-phase mixed solvent is preferably 2:1 to 1:2, specifically 2:1, 1:1, or 1:2.

[0076] In this invention, the phenyl chloroformate is preferably added under ice-water bath conditions.

[0077] In this invention, the temperature of the elimination reaction is preferably 15~35℃, specifically 15℃, 20℃, 25℃, 30℃ or 35℃, and the time is preferably 3~24h, specifically 3h, 6h, 9h, 12h, 15h, 18h, 21h or 24h. In this invention, the elimination reaction is preferably carried out under stirring conditions.

[0078] In this invention, the elimination reaction of theanine, phenyl chloroformate, and sodium bicarbonate in a two-phase mixed solvent preferably includes the following steps: mixing theanine, sodium bicarbonate, and water, and then sequentially adding an organic solvent and phenyl chloroformate to carry out the elimination reaction.

[0079] After the elimination reaction, the present invention preferably further includes: washing, acidifying, and extracting the obtained aqueous phase with ethyl acetate in sequence to obtain an organic phase; and drying, rotary evaporating, and recrystallizing the organic phase in sequence to obtain the structure shown in Formula II. In the present invention, the washing reagent is preferably an organic solvent, and the type of organic solvent is preferably the same as the organic solvent in the two-phase mixed solvent, which will not be elaborated here. In the present invention, the acidifying reagent is preferably hydrochloric acid, and the target pH value of the acidification is preferably 1-2, specifically preferably 1 or 2. In the present invention, the drying is preferably drying with a desiccant, and the desiccant is preferably anhydrous sodium sulfate. In the present invention, the concentration method is preferably rotary evaporation. In the present invention, the recrystallization reagent is preferably a mixed solvent of ethyl acetate and n-hexane, and the volume ratio of ethyl acetate to n-hexane in the mixed solvent is preferably 1:1-2, specifically preferably 1:1, 1:1.5, or 1:2.

[0080] In this invention, the preparation formula of the structure shown in Formula II is as shown in Formula 2:

[0081] Equation 2.

[0082] The present invention also provides a polytheanine having the structure shown in Formula III:

[0083] Formula III;

[0084] In Formula III, R1 is one or more of alkyl, benzyl, silyl, polyamino acid chain, polyether chain or polyamide chain; R2 is hydrogen, silyl or C1~C8 alkyl; R3 is hydrogen.

[0085] In this invention, in Formula III, R1 and R2 are derived from the initiator.

[0086] In this invention, the alkyl group in R1 is preferably methyl, ethyl, n-propyl, neopentyl, or n-hexyl. In this invention, the silyl group in R1 is preferably trimethylsilyl.

[0087] In this invention, the C1-C8 alkyl group in R2 is preferably methyl, ethyl, n-propyl, neopentyl, or n-hexyl. In this invention, the silicon group in R2 is preferably trimethylsilyl.

[0088] The present invention does not impose specific limitations on the value of n in Equation III.

[0089] In this invention, the structure of the polytheanine includes, but is not limited to, homopolymers, diblock polymers, triblock polymers, multiblock polymers, random polymers, star polymers, cyclic polymers, and graft polymers. In this invention, the star polymer has multiple linear polymer chain arms (three or more) extending outward from a central core, resembling a radiating structure similar to a star. In this invention, the cyclic polymer is a polymer with no free chain ends, forming a closed-loop structure with the main chain connected end-to-end. In this invention, the graft polymer consists of a main chain and multiple side chains (graft chains), with the side chains connected to the main chain in the form of "branches".

[0090] In this invention, the polytheanine may exist in optical isomers, including: L-type, D-type, and racemic mixture (DL-type).

[0091] This invention also provides a method for preparing polytheanine as described in the above technical solution, comprising the following steps:

[0092] Polytheanine monomers, initiators, and polar solvents are mixed and polymerized to obtain the polytheanine.

[0093] The polymer monomer of polytheanine is the polymer monomer of polytheanine described in the above technical solution;

[0094] The initiator is one or more of the following: aliphatic primary amine, aliphatic secondary amine, benzylamine, silylamine, polyamino acid, polyetheramine, or polyamide.

[0095] In this invention, the aliphatic primary amine preferably includes methylamine, ethylamine, n-propylamine, n-butylamine, neopentylamine, or n-hexylamine.

[0096] In this invention, when the initiator is a fatty primary amine, in III, R1 is an alkyl group and R2 is hydrogen. Taking n-butylamine as an example, the specific structure is as follows:

[0097] .

[0098] In this invention, when the initiator is n-butylamine having the above structure, in Formula III, R1 is n-butyl and R2 is hydrogen.

[0099] In this invention, the aliphatic secondary amine preferably includes N-ethylmethylamine, diethylamine, N-ethyl-n-propylamine, N-ethyl-n-butylamine, N-ethylneopreneamine, or N-ethyl-n-hexylamine.

[0100] In this invention, when the initiator is an aliphatic secondary amine, in III, R1 is an alkyl group and R2 is a C1-C8 alkyl group. Taking diethylamine as an example, the specific structure is as follows:

[0101] .

[0102] In this invention, when the initiator is diethylamine having the above structure, R1 and R2 in Formula III are both ethyl.

[0103] In this invention, the benzylamine has the following structure:

[0104] .

[0105] In this invention, when the initiator is a benzylamine having the above structure, in Formula III, R1 is benzyl and R2 is hydrogen.

[0106] In this invention, the silane-based amine has the following structure:

[0107] .

[0108] In this invention, when the initiator is a silylamine having the above structure, R1 and R2 in Formula III are both trimethylsilyl.

[0109] In this invention, the polyamino acid preferably includes polysarcosine.

[0110] In this invention, when the initiator is a polyamino acid, in III, R1 is a polyamino acid chain, and R2 is hydrogen or a C1-C8 alkyl group. Taking polysarcosine as an example, the specific structure is as follows:

[0111] .

[0112] In this invention, when the initiator is polysarcosine having the above structure, in Formula III, R1 is a polysarcosine chain and R2 is a methyl group.

[0113] In this invention, when the initiator is a polyetheramine, in III, R1 is a polyether chain, and R2 is hydrogen or a C1-C8 alkyl group. Taking polyethylene glycolamine as an example, the specific structure is as follows:

[0114] .

[0115] In this invention, when the initiator is a polyethylene glycolamine having the above structure, in Formula III, R1 is a polyether chain and R2 is hydrogen.

[0116] In this invention, when the initiator is a polyamide, in III, R1 is a polyamide chain, and R2 is hydrogen or a C1-C8 alkyl group. Taking polyamide-6 (nylon 6) as an example, the specific structure is as follows:

[0117] .

[0118] In this invention, when the initiator is polyamide-6 having the above structure, in Formula III, R1 is a polyamide chain and R2 is hydrogen.

[0119] In this invention, the molar ratio of the polymerizing monomer and the initiator of the polytheanine is preferably 5 to 200:1, more preferably 10 to 100:1, and specifically preferably 5:1, 10:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1 or 200:1.

[0120] In this invention, the polar solvent preferably includes one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, trichloromethane, toluene, acetone, methanol, ethanol, ethylene glycol, and water, and is more preferably a mixture of acetonitrile and water, wherein the volume ratio of acetonitrile to water in the mixture is preferably 2:1.

[0121] In this invention, the mixing of the polytheanine monomer, initiator and polar solvent preferably includes the following steps: dissolving the polytheanine monomer in a polar solvent, and then adding a polar solvent solution of the initiator.

[0122] In this invention, the polymerization reaction temperature is preferably 20~100℃, specifically preferably 20℃, 30℃, 40℃, 45℃, 50℃, 60℃, 70℃, 80℃, 90℃, or 100℃; the time is preferably 0.5~72h, specifically preferably 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 12h, 18h, 24h, 36h, 48h, 60h, or 72h. In this invention, the polymerization reaction is preferably carried out under oil bath conditions.

[0123] Following the polymerization reaction, the present invention preferably further includes post-treatment. In the present invention, when the monomer of the polytheanine has the structure shown in Formula I, the post-treatment preferably includes: subjecting the obtained polymerization reaction solution to a first precipitation, collecting the oily substance; redissolving the oily substance and subjecting it to a second precipitation, collecting the precipitate and drying it to obtain polytheanine. In the present invention, the reagent for the first precipitation is preferably acetonitrile. In the present invention, the reagent for redissolving is preferably ethanol. In the present invention, the reagent for the second precipitation is preferably ethyl acetate. In the present invention, the drying is preferably vacuum drying, and the present invention does not specifically limit the parameters of the vacuum drying. In the present invention, when the monomer of the polytheanine has the structure shown in Formula II, the post-treatment preferably includes: subjecting the obtained polymerization reaction solution to a third precipitation, collecting the precipitate and drying it to obtain polytheanine. In the present invention, the reagent for the third precipitation is preferably diethyl ether. In the present invention, the drying is preferably vacuum drying, and the present invention does not specifically limit the parameters of the vacuum drying.

[0124] The following detailed descriptions, in conjunction with embodiments, illustrate the polymeric monomers of polytheanine provided by the present invention and their preparation methods, as well as polytheanine and its derivatives and their preparation methods. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0125] In the following examples, the polymer molecular weight ( M n ) and molecular weight distribution ( Ð The determination was performed by gel permeation chromatography (SEC). The system consisted of a Waters 1515 HPLC pump, a Waters 2414 differential refractive index indicator, and two Shodex KF columns. The mobile phase was hexafluoroisopropanol (containing 3 mg / mL potassium trifluoroacetate), the flow rate was 0.8 mL / min, and the column temperature was 40 °C. The standard curve was calibrated using narrowly distributed polymethyl methacrylate (PMMA) as a standard.

[0126] 1H NMR spectrum ( 1 H NMR) and carbon nuclear magnetic resonance (NMR) 13 C NMR was acquired using a Bruker Avance DMX 400 NMR spectrometer and analyzed using deuterated dimethyl sulfoxide (DMSO-). d 6) Used as a solvent as a deuterated reagent, and tetramethylsilane (TMS) as an internal standard.

[0127] In the embodiments S -Ethoxythiocarbonyl mercaptoacetic acid and various initiators are all commercially available products.

[0128] Example 1: Preparation of The-NTA monomer

[0129] L-theanine (17.4 g, 0.1 mol) and S 18.0 g (0.1 mol) of ethoxythiocarbonyl mercaptoacetic acid was dissolved in deionized water. Sodium hydroxide (8.0 g (0.2 mol) was slowly added under an ice-water bath, and the mixture was stirred thoroughly until completely dissolved. The reaction was carried out at room temperature for 72 h. After the reaction was complete, concentrated hydrochloric acid was used to adjust the pH of the reaction solution to approximately 1, yielding an acidified solution. The acidified solution was extracted with ethyl acetate. The combined organic phases were washed with a 5 wt% citric acid aqueous solution and dried with anhydrous sodium sulfate. The dried organic phase was concentrated by rotary evaporation to obtain a concentrated solution, which was 27.1 g of N-ethoxythiocarbonyl theanine intermediate, with a yield >99%.

[0130] The concentrated solution, calculated as 0.1 mol of N-ethoxythiocarbonyl theanine intermediate, was dissolved in ethyl acetate, and phosphorus tribromide (32.5 g, 0.12 mol) was slowly added dropwise under an ice-water bath. The reaction system was allowed to continue reacting at room temperature for 3 h. After the reaction was completed, saturated brine was added to the system for extraction, and the organic phase was collected. The organic phase was then washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude product. The crude product was recrystallized in a mixed solvent of ethyl acetate / n-hexane (ethyl acetate and n-hexane volume ratio of 1:1) to give 10.9 g of white solid, which was The-NTA, with a yield of 50.5%.

[0131] The-NTA 1 H NMR spectrum as shown Figure 1 As shown, 1 H NMR (400 MHz, DMSO-) d 6) δ: 0.99 (t, 3H), 1.78-2.05 (m, 2H), 2.05-2.31 (m, 2H), 3.04 (q, 2H), 4.59 (d, 1H), 7.85 (t, 1H), 9.31 (s, 1H) ppm.

[0132] Example 2: Preparation of The-NPC Monomer

[0133] Theanine (17.4 g, 0.1 mol) and sodium bicarbonate (25.2 g, 0.3 mol) were dissolved in 150 mL of deionized water. 150 mL of methyl tert-butyl ether was added to this solution, followed by the slow dropwise addition of phenyl chloroformate (15.6 g, 0.1 mol) under an ice-water bath. The reaction system was stirred at 30 °C for 3 h. After the reaction was complete, the aqueous phase was washed with methyl tert-butyl ether to remove the byproduct phenol, and then acidified with hydrochloric acid to obtain an acidified solution. The target product in the acidified solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude product. The crude product was recrystallized in an ethyl acetate / n-hexane mixed solvent (ethyl acetate to n-hexane volume ratio 1:2) to give 26.2 g of white solid, which was The-NPC, with a yield of 89%.

[0134] The-NPC 1 H NMR spectrum as shown Figure 2 As shown, 1 H NMR (400 MHz, DMSO-) d 6) δ: 1.00 (t, 3H), 1.69-2.13 (m, 2H), 2.20 (m, 2H), 3.06 (q, 2H), 3.82-4.1 7 (m, 1H), 6.98-7.46 (m, 5H), 7.84 (t, 1H), 8.09 (d, 1H), 12.71 (s, 1H) ppm.

[0135] Example 3: Preparation of linear polyamino acids (polytheanine)

[0136] The-NTA obtained in Example 1 (0.3249 g, 1.5024 mmol) was dissolved in 1.6 mL of a mixed solvent of acetonitrile and water, and then 0.31 mL of a benzylamine solution in acetonitrile (0.0982 mol / L, 0.0304 mmol) was added. The final volume ratio of acetonitrile to water in the reaction system was 2:1, and the molar ratio of The-NTA to benzylamine was 50:1. The reaction system was placed in an oil bath at 45 °C and reacted for 4 h. After the reaction was completed, the reaction solution was poured into acetonitrile to precipitate an oily substance. The oily substance was then dissolved in a small amount of ethanol, and then poured into ethyl acetate for precipitation. The resulting polymer was dried under vacuum to obtain 0.159 g of polytheanine, with a yield of 67%.

[0137] Testing showed that the polytheanine prepared in this embodiment had a SEC number-average molecular weight of 6.4 kg / mol and a molecular weight distribution of 1.19. The polytheanine... 1 H NMR spectrum as shown Figure 3 As shown.

[0138] The polytheanine obtained in this embodiment is soluble in water, with a solubility of 15g / 100g water at room temperature.

[0139] Example 4: Preparation of linear polyamino acids (polytheanine)

[0140] The preparation method was the same as in Example 3, except that the molar ratio of The-NTA monomer to benzylamine was 25:1, yielding 0.161g of polytheanine with a yield of 68%.

[0141] According to the test results, the polytheanine prepared in this embodiment has a SEC number-average molecular weight of 3.7 kg / mol and a molecular weight distribution of 1.19.

[0142] Optical photographs of polytheanine aqueous solution (150 mg / mL) are shown below. Figure 4 As shown, from Figure 4 It can be seen that polytheanine can be stably dissolved in water at this concentration to form a uniform and transparent solution, indicating that it has good water solubility and dispersibility.

[0143] Example 5: Preparation of linear polyamino acids (polytheanine)

[0144] The preparation method was the same as in Example 3, except that the solvent was N,N-dimethylacetamide and the reaction time was 24 h, yielding 0.135 g of polytheanine with a yield of 57%.

[0145] According to the test results, the polytheanine prepared in this embodiment has a SEC number-average molecular weight of 2.5 kg / mol and a molecular weight distribution of 1.31.

[0146] Example 6: Preparation of linear polyamino acids (polytheanine)

[0147] The preparation method was the same as in Example 3, except that the reaction conditions were 30°C oil bath reaction for 12 hours, yielding 0.147g of polytheanine with a yield of 62%.

[0148] According to the test results, the polytheanine prepared in this embodiment has a SEC number-average molecular weight of 4.7 kg / mol and a molecular weight distribution of 1.17.

[0149] Example 7: Preparation of linear polyamino acids (polytheanine)

[0150] The-NPC obtained in Example 2 (0.3404 g, 1.1566 mmol) was weighed and dissolved in 1.65 mL of N,N-dimethylacetamide, followed by the addition of 0.66 mL of a benzylamine solution in N,N-dimethylacetamide (0.0878 mol / L, 0.0579 mmol). The molar ratio of The-NPC to benzylamine was 20:1. The reaction system was sealed and placed in an oil bath at 70 °C for 24 h. After the reaction, the polymerization solution was poured into diethyl ether to precipitate the polymer. The resulting polymer was dried under vacuum to obtain 0.125 g of polytheanine, with a yield of 67%.

[0151] The polytheanine prepared in this embodiment has a SEC number-average molecular weight of 1.9 kg / mol and a molecular weight distribution of 1.15, as tested.

[0152] Example 8: Preparation of linear polyamino acids (polytheanine)

[0153] The preparation method was the same as in Example 7, except that the solvent was dimethyl sulfoxide, yielding 0.132 g of polytheanine with a yield of 71%.

[0154] According to the test results, the polytheanine prepared in this embodiment has a SEC number-average molecular weight of 2.1 kg / mol and a molecular weight distribution of 1.15.

[0155] Example 9: Diblock copolymer – linear polyamino acid (polysarcosine- b Preparation of poly(theanine)

[0156] The-NTA obtained in Example 1 (0.2359 g, 1.0908 mmol) was weighed and dissolved in 0.7 mL of water. Then, 1.4 mL of an acetonitrile solution of polysarcosine (polysarcosine number-average molecular weight 4.0 kg / mol, 0.1744 g, 0.0436 mmol) was added. The molar ratio of The-NTA to polysarcosine was 25:1. The reaction system was placed in an oil bath at 45 °C and reacted for 12 h. After the reaction was completed, the reaction solution was poured into acetonitrile to precipitate an oily substance. The oily substance was then dissolved in a small amount of ethanol, and then poured into ethyl acetate for precipitation. The resulting polymer was dried under vacuum to obtain polysarcosine- b - Polytheanine, yield 0.212g, yield 61%.

[0157] Testing showed that the polysarcosine- prepared in this embodiment... b The number-average molecular weight (SEC) of polytheanine is 14.1 kg / mol, and its molecular weight distribution is 1.28. Polysarcosine- b - Polytheanine 1 H NMR spectrum as shown Figure 5 As shown.

[0158] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing polytheanine, characterized in that, Includes the following steps: Polytheanine monomers, initiators, and polar solvents are mixed and polymerized to obtain the polytheanine. The polymer monomer of the polytheanine has the structure shown in Formula I: Equation I; The initiator is one or more of the following: aliphatic primary amine, aliphatic secondary amine, benzylamine, silylamine, polyamino acid, polyether amine, or polyamide; The polar solvent is a mixture of acetonitrile and water, wherein the volume ratio of acetonitrile to water in the mixture is 2:

1. The polytheanine has the structure shown in Formula III: Formula III; In Formula III, R1 is one or more of alkyl, benzyl, silyl, polyamino acid chain, polyether chain or polyamide chain; R2 is hydrogen, silyl or C1~C8 alkyl; R3 is hydrogen.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the polymer monomer to the initiator of the polytheanine is 5~200:

1.

3. The preparation method according to claim 1, characterized in that, The polymerization reaction is carried out at a temperature of 20~100℃ for a time of 0.5~72h.

4. The preparation method according to claim 1, characterized in that, The preparation method of the structure shown in Formula I includes the following steps: Theanine, S-ethoxythiocarbonyl mercaptoacetic acid, base and water were mixed and subjected to a nucleophilic substitution reaction to obtain N-ethoxythiocarbonyl theanine intermediate; The N-ethoxythiocarbonyl theanine intermediate under phosphorus tribromide conditions underwent a cyclization reaction to obtain the structure shown in Formula I.

5. The preparation method according to claim 4, characterized in that, In the nucleophilic substitution reaction, the theanine is L-theanine; the base includes one or more of inorganic and / or organic bases. The inorganic base includes sodium hydroxide and / or potassium hydroxide; The organic base includes one or more of sodium alkoxide, potassium alkoxide, and tetraalkylammonium hydroxide; The sodium alkoxide and potassium alkoxide each have 1 to 4 carbon atoms independently; The number of carbon atoms in the alkyl group of the tetraalkylammonium hydroxide is 2 to 8; The molar ratio of theanine to S-ethoxythiocarbonyl mercaptoacetic acid is 1~2:1, and the molar ratio of theanine to the base is 1:2~4. The nucleophilic substitution reaction takes 12 to 120 hours.

6. The preparation method according to claim 4 or 5, characterized in that, During the ring-closing reaction, the molar ratio of the N-ethoxythiocarbonyl theanine intermediate to phosphorus tribromide is 1:1~3, and the ring-closing reaction time is 0.5~24h.

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