CN116924943A - Preparation and application of amino acid isocyanate derivative - Google Patents

Preparation and application of amino acid isocyanate derivative Download PDF

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CN116924943A
CN116924943A CN202210328696.5A CN202210328696A CN116924943A CN 116924943 A CN116924943 A CN 116924943A CN 202210328696 A CN202210328696 A CN 202210328696A CN 116924943 A CN116924943 A CN 116924943A
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reaction
agent
amino acid
esterification
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马俊辉
马楠
汤艳
张维
刘军
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Technical Institute of Physics and Chemistry of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/10—Isocyanides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids

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Abstract

The invention discloses a preparation and application of an amino acid isocyanate derivative. The invention takes amino acid as raw material for the first time, and finally prepares the amino acid isocyanate derivative containing isocyano group, carboxylate group and different side chains through 5 steps of reactions of esterification, neutralization, formylation, isocyanation and saponification.

Description

Preparation and application of amino acid isocyanate derivative
Technical Field
The invention relates to the field of new material synthesis. More particularly, it relates to the preparation and application of amino acid isocyanate derivatives.
Background
Heretofore, isocyanic acid compounds have been a relatively few chemical species under investigation, not only because they have a daunting malodor, but also because there is a lack of a systematic and mature preparation method, which results in a relatively small number of isocyanate species on the market, and are expensive, difficult to obtain, and limit the application and development of isocyanic acid compounds. The classical method for preparing isocyanic acid compound is Huffman isocyanic acid synthesis, and the reaction is carried out by primary amine and chloroform under the action of a stronger alkali (potassium ethoxide or potassium tert-butoxide), in the reaction, the dichloro carbene attacks amino, then alpha elimination and beta elimination are carried out in sequence, and finally the target product is generated. Similarly, aromatic amines can react with sodium trichloroacetate to produce responsive aromatic isocyanic acid compounds, but the synthetic method has poor universality and low yield.
Amino acid is used as an organic compound containing basic amino and acidic carboxyl, has wide sources, is low in cost and easy to obtain, and is often used as an initial raw material by researchers to carry out radical substitution modification to obtain different types of high-added-value compounds.
Therefore, it is important to study a method for preparing an isocyanate compound from an amino acid as a starting material.
Disclosure of Invention
Based on the above drawbacks, a first object of the present invention is to provide a process for the preparation of an amino acid isocyanate derivative. The preparation method has the advantages of simple operation, low raw material cost, mild reaction conditions, novel synthetic route, higher product yield, various product varieties and good industrial conversion prospect.
A second object of the present invention is to provide an amino acid isocyanate derivative prepared by the above method.
A third object of the present invention is to provide the use of the above amino acid isocyanate derivative for the preparation of antibacterial materials. The antibacterial material is a polyamino acid derivative or copolymer with an alternate structure, has a definite and adjustable structure, widens the variety and structure of the polymer, and has good antibacterial effect, biocompatibility and degradability.
In order to achieve the first object, the present invention adopts the following technical scheme:
the invention discloses a preparation method of amino acid isocyanate derivative, which uses amino acidThe amino acid isocyanate derivative is prepared by the reactions of esterification, neutralization, formylation, isocyanation and saponification as the initial raw materialThe preparation process comprises the following steps:
(1) Esterification reaction
Amino acids are addedAdding into esterification solvent X1, adding chlorinating agent X2, reacting at 0-100deg.C for 0.1-24 hr, and rotary steaming to obtain esterification product +.>
(2) Neutralization reaction
The esterified product is then reacted withDissolving in organic solvent X3, adding neutralizing agent amine A, reacting at 0-100deg.C for 0.1-24 hr, rotary evaporating to precipitate a large amount of solid, adding low polarity solvent, stirring, filtering, collecting filtrate, rotary evaporating to obtain neutralized product->
(3) Formylation reaction
The product is neutralizedDissolving in formylating agent B, reacting at 0-100deg.C for 0.1-48 hr, and rotary steaming to obtain formylating product ∈>
(4) Isocyanation reaction
The formylated productDissolving in organic solvent X4, adding amine X5 for activation, adding dehydrating agent C for isocyanation, reacting at 0-100deg.C for 0.1-12 hr, adding saturated sodium bicarbonate solution and methyl tert-butyl ether for extraction, collecting organic phase, sequentially washing with saturated sodium bicarbonate solution and water, drying the organic phase, and rotary evaporating to obtain isocyanation product%>
(5) Saponification reaction
The isocyanation product is subjected to isocyanationDissolving in organic solvent X6, adding alkali liquor D, reacting at 0-100deg.C for 0.1-24 hr, extracting with dichloromethane after reaction, collecting water layer, steaming, and lyophilizing;
wherein R is 1 Selected from the group consisting of
R is selected from
M is selected from Na or K.
The invention takes amino acid as raw material for the first time, and finally prepares the amino acid isocyanate derivative containing isocyano group, carboxylate group and different side chains through 5 steps of reactions of esterification, neutralization, formylation, isocyanation and saponification.
In the step 1 reaction, since different amino acids have different side chains R 1 Radicals, if R 1 The active group is protected by a protecting group when the isocyanate derivative is sold in a factory, such as protecting an amino group by using benzyloxycarbonyl, tert-butyloxycarbonyl, or a benzyloxycarbonyl group, protecting a hydroxyl group by using benzyl or triphenylmethyl, and the like, and the protecting group does not participate in the reaction in the preparation process of the isocyanate derivative.
The esterification solvent X1 is an anhydrous alcohol reagent;
further, the esterification solvent X1 is selected from one or more of absolute methanol, absolute ethanol or absolute isopropanol;
further, the chlorinating agent X2 is selected from thionyl chloride or phosphorus pentachloride;
further, the amino acidThe molar ratio of the chloridizing agent X2 to the chloridizing agent X2 is 1:1-5;
further, the amino acidThe molar ratio of the chloridizing agent X2 to the chloridizing agent X2 is 1:1.5-3; illustratively, the amino acid +.>The molar ratio to chlorinating agent X2 may also be 1:1.75,1:2,1:2.25,1:2.5,1:2.75, etc.And any intervals formed thereby.
Further, the temperature of the esterification reaction is 0-25 ℃, and the reaction time is 4-8h.
In the step 2, the organic solvent X3 is selected from one or more of chloroform, tetrahydrofuran, ethyl acetate or methyl tertiary butyl ether;
further, the neutralizing agent amine A is selected from one or more of triethylamine, diisopropylamine, diethylamine or trimethylamine;
further, the esterification productThe molar ratio of the neutralizing agent amine A is 1:1-10;
further, the esterification productThe molar ratio of the neutralizing agent amine A is 1:1.5-3; illustratively, the esterification product +.>The molar ratio to the neutralizing agent amine a may also be 1:1.75,1:2,1:2.25,1:2.5,1:2.75, etc. and any interval formed thereby.
Further, the temperature of the neutralization reaction is 20-40 ℃ and the reaction time is 2-5h.
In step 3, the formylating agent B is selected from one or more of ethyl formate, formic acid, formyl chloride or formic anhydride;
further, the neutralization productThe volume ratio of the formylating agent B to the formylating agent B is 1:1-100;
further, the neutralization productThe volume ratio of the formylating agent B to the formylating agent B is 1:5-20; illustratively, said neutralization product +.>The volume ratio to formylating reagent B may also be 1:6,1:7,1:8,1:9,1:10, 1:11,1:12,1:13,1:14,1:15,1:16,1:17,1:18,1:19, etc. and any intervals formed thereby.
Further, the formylation reaction temperature is 45-65 ℃ and the reaction time is 20-30h.
In step 4, the organic solvent X4 is selected from one or more of tetrahydrofuran, dichloromethane, chloroform or ethyl acetate;
further, the amine X5 is selected from one or more of triethylamine, diisopropylamine, diethylamine or trimethylamine;
further, the dehydrating agent C is selected from one or more of phosphorus oxychloride, phosgene, diphosgene, triphosgene, triphenylphosphine, methylsulfonyl chloride or oxalyl chloride;
further, the formylated productThe molar ratio of the catalyst to the amine X5 and the dehydrating agent C is 1:2-12, (1/3-2);
further, the formylated productThe molar ratio of the catalyst to the amine X5 and the dehydrating agent C is 1:6-9:1-1.5;
further, the temperature of the isocyanation reaction is 0-30 ℃ and the reaction time is 4-8h.
In step 5, the organic solvent X6 is selected from water-miscible or miscible solvents;
further, the organic solvent X6 is selected from one or more of tetrahydrofuran, acetone, N-dimethylformamide and dimethyl sulfoxide;
further, the alkaline solution D is selected from strong alkali solutions; the strong alkali solution is selected from sodium hydroxide solution or potassium hydroxide solution;
further, the isocyanated productThe molar ratio of the alkali liquor D to the alkali liquor D is 1:1-5;
further, the volume ratio of the organic solvent X6 to the alkali liquor is 1-10:1;
further, the temperature of the saponification reaction is 20-40 ℃ and the reaction time is 3-8h.
In order to achieve the second object, the present invention adopts the following technical scheme:
the invention provides an amino acid isocyanate derivative prepared by the method, which is shown in a formula I:
wherein R is 1 Selected from the group consisting of
M is selected from Na or K.
In order to achieve the third object, the present invention adopts the following technical scheme:
the invention provides an application of the amino acid isocyanate derivative in preparing antibacterial materials.
Further, the antibacterial material is a polyamino acid derivative or copolymer with an alternating structure, and the structural formula of the antibacterial material is shown as formula II:
wherein R is 1 Selected from the group consisting of
R 2 Selected from the group consisting of
R 3 Selected from the group consisting of
n is a positive integer, n=5-100.
As will be appreciated by those skilled in the art, when R 2 The radicals beingIn the case of R, corresponding polyamino acid copolymers 2 The radicals are not->When the amino acid is a polyamino acid derivative; r is R 1 The groups are used for adjusting the hydrophilicity and hydrophobicity, degradability, strength and the like of the polyamino acid derivative or copolymer material; side chain R of repeating unit 3 The free amino group or the positive charge can adjust the antibacterial property of the polyamino acid derivative or copolymer material.
In the preparation of polyamino acid derivatives or copolymers according to the invention, the preparation route is prepared by means of the one-pot process according to CN110804175a, namely: combining the amino acid isocyanate derivative with an aldehyde as described aboveAmine->Polymerizing under the action of acid E, and removing protective groups from the polymerization product;
further, the acid E is selected from one or more of trifluoromethanesulfonic acid, methanesulfonic acid, hydrofluoric acid or trifluoroacetic acid;
further, amino acid isocyanate derivative formula I and aldehydeAmine->The molar ratio of the acid E is 1:1-2:1-2:1-2；
Further, the solvent system of the polymerization reaction is one or more of isopropanol, methanol, deionized water, dimethyl sulfoxide, N-dimethylformamide and tetrahydrofuran;
further, the temperature of the polymerization reaction is 0-100 ℃, and the reaction time is 0.1-240h;
further, the temperature of the polymerization reaction is 20-50 ℃ and the reaction time is 24-120h.
Further, the deprotection agent is one or more of trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, phenylthiomethane, dichloro dicyanobenzoquinone and acetic acid;
further, the deprotection reaction temperature is 0-120 ℃, and the reaction time is 0.1-150h;
further, the deprotection reaction temperature is 40-80 ℃ and the reaction time is 5-20h.
The beneficial effects of the invention are as follows:
the invention takes amino acid as raw material for the first time, and finally prepares the amino acid isocyanate derivative containing isocyano group, carboxylate group and different side chains through 5 steps of reactions of esterification, neutralization, formylation, isocyanation and saponification.
Drawings
The following describes the embodiments of the present invention in further detail with reference to the drawings.
FIG. 1 shows nuclear magnetic resonance spectra of an esterification product, a formylation product, an isocyanation product, and a saponification product of ornithine in example 1;
wherein a is an esterification product, b is a formylation product, c is an isocyanation product, and d is a saponification product.
FIG. 2 shows the nucleic acid hydrogen profile of the lysine starting material and isocyanate product of example 2;
wherein a is lysine raw material, and b is saponified product isocyanate.
FIG. 3 shows the nuclear magnetic resonance spectrum of O-benzyl-L-serine feed and isocyanate product of example 3;
wherein a is O-benzyl-L-serine raw material, and b is saponified product isocyanate.
FIG. 4 shows nuclear magnetic resonance hydrogen spectra of ornithine valine alternating copolymer and its polymerization products in example 4;
wherein a is a polymerization product, and b is ornithine valine alternating copolymer.
Figure 5 shows cytotoxicity test of ornithine valine alternating copolymer in example 5.
Fig. 6 shows the test of the anti-pseudomonas aeruginosa performance of ornithine valine alternating copolymer of example 5.
FIG. 7 shows the test of the anti-pneumobacilli performance of ornithine valine alternating copolymer of example 5.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments and the accompanying drawings. Like parts in the drawings are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1
Synthesis of potassium N '-Cbz-L-ornithine isocyanate from N' -Cbz-L-ornithine (CAS: 3304-51-6)
(1) Esterification of N' -Cbz-L-ornithine: taking 5g of N' -Cbz-L-ornithine, adding 100ml of methanol, dropwise adding 4ml of thionyl chloride under the ice bath condition, continuing the ice bath reaction for 1h, and then heating to 65 ℃ for reflux reaction for 3h. Removing unreacted methanol and byproducts by rotary evaporation of the reaction liquid to obtain N' -Cbz-L-ornithine methyl ester hydrochloride;
(2) And (3) neutralization: 5g of N' -Cbz-L-ornithine methyl ester hydrochloride was taken and dissolved in 50ml of chloroform, and 11ml of triethylamine was added dropwise at room temperature to continue the reaction for 1.5 hours. The reaction solution is directly and rotationally steamed until a large amount of sediment appears, the sediment is washed with 50ml of methyl tertiary ether for three times, and the methyl tertiary ether phase is collected and rotationally steamed to obtain a pale yellow oily liquid product, namely N' -Cbz-L-ornithine methyl ester;
(3) Formylation: 5g of N' -Cbz-L-ornithine methyl ester was taken, 30ml of ethyl formate was added thereto, and the mixture was refluxed at 65℃for 24 hours in an oil bath. The reaction solution is distilled to constant weight, and a light brown oily liquid formylation product is obtained;
(4) Isocyanation: 5g of formylation product is taken and dissolved in tetrahydrofuran, 7ml of triethylamine and 7ml of tetrahydrofuran solution containing 2.4g of triphosgene are added dropwise under the ice bath condition, the ice bath is continued to react for 1h, and the reaction is carried out at room temperature for 2h. Stopping the reaction, adding 35ml of saturated sodium bicarbonate solution, stirring, adding 70ml of methyl tertiary ether, extracting the residual water layer continuously with 50ml of methyl tertiary ether, collecting and combining organic layers, washing with 120ml of saturated sodium bicarbonate solution and 100ml of deionized water, drying the obtained organic layer by anhydrous magnesium sulfate, and steaming to obtain a black red isocyanide product;
(5) Saponification: 5g of isocyanation product is taken and dissolved in 50ml of tetrahydrofuran, 2.3g of KOH is taken and dissolved in 25ml of deionized water, and after uniform mixing, the reaction is stirred at room temperature for 3 hours. After the reaction, 25ml of deionized water is added and stirred uniformly, 50ml of dichloromethane is added for layering, the water layer is collected, the organic layer is washed by the deionized water and then combined, the water layer is distilled off by spin to remove the residual organic solvent, and the obtained products of each stage are freeze-dried, wherein the nuclear magnetic diagram is shown in figure 1.
The specific reaction equation is shown below:
wherein PG represents an amino protecting group: benzyloxycarbonyl.
Example 2
N epsilon-Cbz-L-lysine isocyanate was prepared from N epsilon-Cbz-L-lysine (CAS: 1155-64-2).
(1) Esterification of N ε -Cbz-L-lysine: 5g of N epsilon-Cbz-L-lysine is taken, 100ml of methanol is added, 4ml of thionyl chloride is dropwise added under the ice bath condition, the ice bath reaction is continued for 1h, and then the temperature is raised to 65 ℃ for reflux reaction for 3h. Removing unreacted methanol and byproducts by rotary evaporation of the reaction liquid to obtain N epsilon-Cbz-L-lysine methyl ester hydrochloride;
(2) And (3) neutralization: 5g of N epsilon-Cbz-L-lysine methyl ester hydrochloride is taken and dissolved in chloroform, 10.5ml of triethylamine is added dropwise at room temperature, and the reaction is continued for 1.5 hours. The reaction solution was directly distilled until a large amount of precipitate appeared, the precipitate was washed three times with 50ml of methyl tertiary ether, and the methyl tertiary ether phase was collected and distilled to obtain a pale yellow oily liquid product, i.e., N-. Epsilon. -Cbz-L-lysine methyl ester.
(3) Formylation: 5g of N epsilon-Cbz-L-lysine methyl ester was taken, 30ml of ethyl formate was added thereto, and the mixture was refluxed for 24 hours at 65℃in an oil bath. The reaction mixture was distilled to constant weight to give a pale brown oily liquid formylated product.
(4) Isocyanation: 5g of formylation product is taken and dissolved in tetrahydrofuran, 7ml of triethylamine and 7ml of tetrahydrofuran solution containing 2.30g of triphosgene are added dropwise under the ice bath condition, the ice bath is continued to react for 1h, and the reaction is carried out at room temperature for 2h. The reaction was stopped, 35ml of saturated sodium bicarbonate solution was added and stirred, 70ml of methyl tertiary ether was added for extraction, the remaining aqueous layer was continued to be extracted with 50ml of methyl tertiary ether, the combined organic layers were collected, washed with 120ml of saturated sodium bicarbonate solution, 100ml of deionized water, and the obtained organic layer was dried over anhydrous magnesium sulfate and evaporated by rotary evaporation to give a dark red isocyanide product.
(5) Saponification: 5g of isocyanation product is taken and dissolved in 50ml of tetrahydrofuran, 1.1g of KOH is taken and dissolved in 25ml of deionized water, and after uniform mixing, the reaction is stirred at room temperature for 3 hours. After the reaction, 25ml of deionized water is added and stirred uniformly, 50ml of dichloromethane is added for layering, the water layer is collected, the organic layer is washed by the deionized water and then combined, the water layer is distilled off to remove the residual organic solvent, and the obtained product is freeze-dried, wherein the nuclear magnetic resonance chart of the obtained product is shown in figure 2.
Example 3
Preparation of O-benzyl-L-serine isocyanate from O-benzyl-L-serine (CAS. NO: 4726-96-9)
(1) O-benzyl-L-serine esterification: taking 5g of O-benzyl-L-serine, adding 100ml of methanol, dropwise adding 5.6ml of thionyl chloride under the ice bath condition, continuing the ice bath reaction for 1h, and then heating to 65 ℃ for reflux reaction for 3h. The reaction solution is distilled to remove unreacted methanol and byproducts, and O-benzyl-L-serine methyl ester hydrochloride is obtained.
(2) And (3) neutralization: 5g of O-benzyl-L-serine methyl ester hydrochloride is taken and dissolved in chloroform, 13ml of triethylamine is added dropwise at room temperature, and the reaction is continued for 1.5 hours. The reaction mixture was directly distilled until a large amount of precipitate appeared, the precipitate was washed three times with 50ml of methyl tertiary ether, and the methyl tertiary ether phase was collected and distilled to obtain a pale yellow oily liquid product, i.e., O-benzyl-L-serine methyl ester.
(3) Formylation: 5g of O-benzyl-L-serine methyl ester was taken, 30ml of ethyl formate was added thereto, and the mixture was refluxed at 65℃for 24 hours in an oil bath. The reaction mixture was distilled to constant weight (all unreacted ethyl formate, by-product ethanol, etc. were removed) to give a pale brown oily liquid formylated product.
(4) Isocyanation: 5g of formylation product is taken and dissolved in tetrahydrofuran, 8ml of triethylamine and 8ml of tetrahydrofuran solution containing 2.92g of triphosgene are added dropwise under the ice bath condition, the ice bath is continued to react for 1h, and the reaction is carried out at room temperature for 2h. The reaction was stopped, 40ml of saturated sodium bicarbonate solution was added and stirred for 5min, 80ml of methyl tertiary ether was added for extraction, the remaining aqueous layer was continued to be extracted with 50ml of methyl tertiary ether, the combined organic layers were collected, washed with 120ml of saturated sodium bicarbonate solution, 100ml of deionized water, and the obtained organic layer was dried over anhydrous magnesium sulfate and rotary distilled to obtain a dark red isocyanide product.
(5) Saponification: 5g of isocyanide product, i.e. isocyanide, is taken and dissolved in 50ml of tetrahydrofuran, 1.6g of KOH is taken and dissolved in 25ml of deionized water, and after uniform mixing, the mixture is stirred at room temperature for reaction for 3 hours. After the reaction, 25ml of deionized water is added and stirred uniformly, 50ml of dichloromethane is added for layering, the water layer is collected, the organic layer is washed by the deionized water and then combined, the water layer is distilled off to remove the residual organic solvent, and the obtained product is freeze-dried, wherein the nuclear magnetic resonance chart of the obtained product is shown in figure 3.
Example 4
An ornithine valine alternating copolymer was synthesized, and the raw material was the saponification product N' -Cbz-L-ornithine potassium isocyanate prepared in example 1.
Polymerization reaction: at 0℃5g of potassium N' -Cbz-L-ornithine isocyanate was added to 25ml of isopropanol, followed by 1.4ml of trifluoromethanesulfonic acid, 0.8ml of isobutyraldehyde, 1.3ml of 1- (4-methoxyphenyl) ethylamine, and the mixture was warmed to room temperature and stirred for 4d. Adding 25ml of water and 25ml of chloroform into the reaction solution, layering, centrifugally collecting an organic layer, separating out in 300ml of normal hexane, and washing for multiple times; the aqueous layer is purified and freeze-dried by anion resin column chromatography to obtain a polymerization product.
Deprotection reaction: the organic phase of the polymerization product was taken at 4g, 40ml of trifluoroacetic acid was added thereto, and the temperature was raised to 60℃and the reaction was stirred for 6 hours. The reaction solution is separated out in 300ml of methyl tertiary butyl ether, the precipitate is collected by centrifugation and washed with 40ml of methyl tertiary butyl ether until the solvent is colorless, the precipitate is collected and dried, and the final product ornithine valine alternating copolymer is obtained, and the nuclear magnetic diagram of the obtained product is shown in figure 4.
The reaction equation is as follows:
example 5
Orn-Val was obtained as an ornithine valine alternating copolymer of example 4 n To test the samples, their cytotoxicity and antibacterial properties were tested.
Cytotoxicity test was ornithine valine alternating copolymer (Orn-Val) n After co-culturing with mouse fibroblasts (L929 cells) for 24 hours at concentrations of 1ppm, 5ppm, 10ppm and 50ppm, respectively, the relative growth rates of the cells were tested, and the results are shown in FIG. 5, and the cell growth rate of the sample at different concentrations is over 90%, i.e., the sample has very low cytotoxicity.
The antibacterial property test is ornithine valine alternating copolymer (Orn-Val) n After shaking co-cultivation with Pseudomonas aeruginosa or Klebsiella pneumoniae at concentrations of 1ppm, 5ppm, 10ppm, and 50ppm, respectively, for 24 hours, the number of bacterial colonies remaining and the antibacterial rate were calculated, and the results are shown in FIG. 6 and FIG. 7, and the sample still had an antibacterial rate of approximately 80% even at 1 ppm. The alternating copolymer has excellent biocompatibility and antibacterial activity.
It should be understood that the foregoing examples of the present invention are provided merely for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention, and that various other changes and modifications may be made therein by one skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims (10)

1. A preparation method of amino acid isocyanate derivative is characterized in that,
by amino acidsThe amino acid isocyanate derivative is prepared by the steps of esterification, neutralization, formylation, isocyanation and saponification as the initial raw material>The preparation process comprises the following steps:
(1) Esterification reaction
Amino acids are addedAdding into esterification solvent X1, adding chlorinating agent X2, reacting at 0-100deg.C for 0.1-24 hr, and rotary steaming to obtain esterification product +.>
(2) Neutralization reaction
The esterified product is then reacted withDissolving in organic solvent X3, adding neutralizing agent amine A, reacting at 0-100deg.C for 0.1-24 hr, rotary evaporating to obtain a large amount of solid, adding low polarity solvent, stirring, filtering, collecting filtrate, rotary evaporating to obtain neutralized product
(3) Formylation reaction
Will neutralizeProduct(s)Dissolving in formylating agent B, reacting at 0-100deg.C for 0.1-48 hr, and rotary steaming to obtain formylating product ∈>
(4) Isocyanation reaction
The formylated productDissolving in organic solvent X4, adding amine X5 for activation, adding dehydrating agent C for isocyanation, reacting at 0-100deg.C for 0.1-12 hr, adding saturated sodium bicarbonate solution and methyl tert-butyl ether for extraction, collecting organic phase, sequentially washing with saturated sodium bicarbonate solution and water, drying the organic phase, and rotary evaporating to obtain isocyanation product%>
(5) Saponification reaction
The isocyanation product is subjected to isocyanationDissolving in organic solvent X6, adding alkali liquor D, reacting at 0-100deg.C for 0.1-24 hr, extracting with dichloromethane after reaction, collecting water layer, steaming, and lyophilizing;
wherein R is 1 Selected from the group consisting of
R is selected from
M is selected from Na or K.
2. The preparation method according to claim 1, wherein in step 1, the esterification solvent X1 is an anhydrous alcohol reagent;
preferably, the esterification solvent X1 is selected from one or more of anhydrous methanol, anhydrous ethanol, or anhydrous isopropanol;
preferably, the chlorinating agent X2 is selected from thionyl chloride or phosphorus pentachloride;
preferably, the amino acidThe molar ratio of the chloridizing agent X2 to the chloridizing agent X2 is 1:1-5;
preferably, the amino acidThe molar ratio of the chloridizing agent X2 to the chloridizing agent X2 is 1:1.5-3;
preferably, the temperature of the esterification reaction is 0-25 ℃ and the reaction time is 4-8h.
3. The preparation method according to claim 1, wherein in the step 2, the organic solvent X3 is one or more selected from chloroform, tetrahydrofuran, ethyl acetate and methyl tert-butyl ether;
preferably, the neutralizing agent amine A is selected from one or more of triethylamine, diisopropylamine, diethylamine or trimethylamine;
preferably, the esterification productThe molar ratio of the neutralizing agent amine A is 1:1-10;
preferably, the esterification productThe molar ratio of the neutralizing agent amine A is 1:1.5-3;
preferably, the neutralization reaction temperature is 20-40 ℃ and the reaction time is 2-5h.
4. The preparation method according to claim 1, wherein in step 3, the formylating agent B is selected from one or more of ethyl formate, formic acid, formyl chloride or formic anhydride;
preferably, the neutralization productThe volume ratio of the formylating agent B to the formylating agent B is 1:1-100;
preferably, the neutralization productThe volume ratio of the formylating agent B to the formylating agent B is 1:5-20;
preferably, the formylation reaction is carried out at a temperature of 45-65 ℃ for a reaction time of 20-30h.
5. The preparation method according to claim 1, wherein in step 4, the organic solvent X4 is selected from one or more of tetrahydrofuran, dichloromethane, chloroform or ethyl acetate;
preferably, the amine X5 is selected from one or more of triethylamine, diisopropylamine, diethylamine or trimethylamine;
preferably, the dehydrating agent C is selected from one or more of phosphorus oxychloride, phosgene, diphosgene, triphosgene, triphenylphosphine, methylsulfonyl chloride or oxalyl chloride;
preferably, the formylation productThe molar ratio of the catalyst to the amine X5 and the dehydrating agent C is 1:2-12, (1/3-2);
preferably, the formylation productThe molar ratio of the catalyst to the amine X5 and the dehydrating agent C is 1:6-9:1-1.5;
preferably, the temperature of the isocyanation reaction is 0-30 ℃ and the reaction time is 4-8h.
6. The method of claim 1, wherein in step 5, the organic solvent X6 is selected from water-miscible or miscible solvents;
preferably, the organic solvent X6 is selected from one or more of tetrahydrofuran, acetone, N-dimethylformamide and dimethyl sulfoxide;
preferably, the lye D is selected from a strong alkali solution; the strong alkali solution is selected from sodium hydroxide solution or potassium hydroxide solution;
preferably, the isocyanation productThe molar ratio of the alkali liquor D to the alkali liquor D is 1:1-5;
preferably, the volume ratio of the organic solvent X6 to the alkali liquor is 1-10:1;
preferably, the saponification reaction temperature is 20-40 ℃ and the reaction time is 3-8h.
7. An amino acid isocyanate derivative prepared by the method of any one of claims 1-6, wherein said amino acid isocyanate derivative is represented by formula I:
wherein R is 1 Selected from the group consisting of
M is selected from Na or K.
8. Use of the amino acid isocyanate derivative according to claim 7 for the preparation of an antibacterial material.
9. The use according to claim 8, wherein the antibacterial material is a polyamino acid derivative or copolymer having an alternating structure, the structural formula of which is shown in formula II:
wherein R is 1 Selected from the group consisting of
R 2 Selected from the group consisting of
R 3 Selected from the group consisting of
n is a positive integer, n=5-100.
10. The use according to claim 8, wherein the polyamino acid derivative or copolymer is prepared by the following method:
combining the amino acid isocyanate derivative of claim 7 with an aldehydeAmine->Polymerizing under the action of acid E, and removing protective groups from the polymerization product;
preferably, the acid E is selected from one or more of trifluoromethanesulfonic acid, methanesulfonic acid, hydrofluoric acid or trifluoroacetic acid;
preferably, the amino acid isocyanate derivative is combined with an aldehydeAmine->And the molar ratio of the acid E is 1:1-2:1-2:1-2;
preferably, the polymerization reaction temperature is 0-100 ℃ and the reaction time is 0.1-240h;
preferably, the polymerization reaction temperature is 20-50℃and the reaction time is 24-120 hours.
CN202210328696.5A 2022-03-31 2022-03-31 Preparation and application of amino acid isocyanate derivative Pending CN116924943A (en)

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