WO2021088723A1 - 一种交替结构抗菌聚氨基酸衍生物或共聚物及其制备方法 - Google Patents

一种交替结构抗菌聚氨基酸衍生物或共聚物及其制备方法 Download PDF

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WO2021088723A1
WO2021088723A1 PCT/CN2020/125120 CN2020125120W WO2021088723A1 WO 2021088723 A1 WO2021088723 A1 WO 2021088723A1 CN 2020125120 W CN2020125120 W CN 2020125120W WO 2021088723 A1 WO2021088723 A1 WO 2021088723A1
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acid
polyamino acid
copolymer
acid derivative
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张维
刘富强
曲巍
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中国科学院理化技术研究所
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    • 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
    • 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

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  • the invention relates to the field of antibacterial materials. More specifically, it relates to an antibacterial polyamino acid derivative or copolymer with an alternating structure and a preparation method thereof.
  • antibacterial materials In addition to antibacterial properties, antibacterial materials often require higher biological and environmental safety, such as antibacterial products. Medical devices not only need to effectively inhibit the growth and reproduction of bacteria, but also need good safety. At present, most antibacterial materials are mainly materials that can release antibacterial metal ions and antibacterial materials of quaternary ammonium salts. These materials all have strong antibacterial properties, but due to their certain cytotoxicity to the human body, the development of drug resistance and other shortcomings, there is an urgent need to develop antibacterial materials that meet the requirements of the industry.
  • polyamino acid polypeptide As a polyamino acid polypeptide, antibacterial peptides can be degraded into small amino acid molecules in the body, which are absorbed or excreted by the body. It is an ideal antibacterial material and meets the biocompatibility and degradability of the body.
  • This type of polypeptide contains a large number of basic amino acids, such as ornithine, lysine, arginine, and histidine.
  • the obtained polyamino acid has cationic groups on the side chains, such as amino or indolyl groups, which have very Good antibacterial effect.
  • most of the polyamino acids are obtained by anionic polymerization to obtain block copolymers composed of two or more amino acid repeating units.
  • the polyamino acid copolymers obtained by this method have different segments on any main chain of different amino acids.
  • the sequence of repeating unit arrangement, by adding different amino acids can not precisely adjust the structure of the polyamino acid copolymer, and can not effectively control the hydrophilicity and hydrophobicity of the polymer, material strength, degradation rate, antibacterial activity, biological safety and other properties.
  • the polyamino acid copolymer obtained by this method is degraded in vivo or in vitro, the structure of the degraded fragments is different, and the antibacterial mechanism cannot be explored.
  • the present invention obtains polyamino acid derivatives or copolymers with different properties by precisely adjusting the structure, and designs and synthesizes a polyamino acid derivative or copolymer material with antibacterial function.
  • the synthesis of this polyamino acid derivative or copolymer is through the terminal
  • the aldehydes with protective groups on the amino groups, primary amines, and isocyanates are polymerized and deprotected by Ugi's 4CC method to obtain an alternating structure polyamino acid derivative or copolymer rich in amino groups.
  • Polyamino acid derivatives or copolymers have alternating structural units and the same conformation. Among the alternating repeating structural units, one is a basic amino acid or a derivative of a basic amino acid.
  • a polyamino antibacterial material with different hydrophilicity and hydrophobicity, material strength, degradation rate, and antibacterial activity can be obtained.
  • the small molecule fragments of the polyamino acid derivatives or copolymers synthesized by this method have the same conformation and are still alternating structural repeating units, which are finally degraded by the human body to obtain small amino acid molecules.
  • This structural feature ensures this The biocompatibility and degradability of similar materials, as well as the clarity and controllability of the structure, are conducive to the exploration of biological activity and antibacterial mechanisms.
  • An object of the present invention is to provide an antibacterial polyamino acid derivative or copolymer with an alternating structure, which has a clear and adjustable structure, and at the same time has good antibacterial effects and biocompatibility and degradability.
  • Another object of the present invention is to provide a method for preparing the above-mentioned alternating structure polyamino acid derivative or copolymer.
  • the present invention provides an antibacterial polyamino acid derivative or copolymer with an alternating structure.
  • the polyamino acid derivative or copolymer has the following structure:
  • the end of the R 1 group contains an amino group, including but not limited to the following structures:
  • the R 2 group includes but is not limited to the following structures:
  • R 2 group when the R 2 group is -H, it corresponds to a polyamino acid copolymer, and when the R 2 group is not -H, it corresponds to a polyamino acid derivative.
  • the side chain of the repeating unit A has free amino groups and positive charges, which can adjust the antibacterial properties of polyamino acid derivatives or copolymer materials;
  • the R 3 group includes but is not limited to the following structures: -H,
  • the function of the R 3 group is to adjust the hydrophilicity, hydrophobicity, degradability, strength, etc. of the polyamino acid derivative or copolymer material.
  • the present invention provides a method for preparing a degradable antibacterial polyamino acid derivative or copolymer with an alternating structure, which includes two steps of polymerization reaction and deprotection reaction, as follows:
  • the end of R 1 contains an amino group, and the amino protecting group R 4 is connected to the nitrogen atom on the end of R 1;
  • polyamino acid derivatives containing amino protecting groups R 4 and R 5 are reacted with the deprotecting agent P in the temperature range of 0-120°C for 0.1-150 hours and then the R 4 group is removed to obtain a polyamino acid derivative without R 4 group.
  • step 2) further includes:
  • the obtained polyamino acid derivative without R 4 group is reacted with a deprotecting agent Q in the temperature range of 0-120° C. for 0.1-150 hours to remove the R 5 group to obtain a polyamino acid copolymer.
  • R 4 protecting group is removed to obtain a polyamino acid derivative.
  • R 2 and R 5 are the same; continue removing the R 5 protecting group to obtain Is a polyamino acid copolymer, which corresponds to the case where R 2 is -H.
  • step 2) when preparing the polyamino acid copolymer, both the R 4 group and the R 5 group need to be removed, and the order of removal of the two can be interchanged. That is, when preparing the polyamino acid copolymer, step 2) includes:
  • the polyamino acid derivatives containing amino protecting groups R 4 and R 5 are reacted with deprotecting agent Q in the temperature range of 0-120°C for 0.1-150 hours, and then the R 5 group is removed to obtain a polyamino acid derivative without R 5 group.
  • Amino acid copolymer; the obtained polyamino acid copolymer without R 5 group is reacted with a deprotecting agent P in the temperature range of 0-120°C for 0.1-150 hours to remove the R 4 group to obtain a polyamino acid copolymer.
  • step 1) polymerization reaction can also be a one-pot method, including the following steps:
  • step 1) the primary amine Strong acid Y, isocyanate And aldehyde
  • the molar ratio of is (1-3):(1-3):(1-3):(1-3); preferably 1:1:1:1.
  • the aldehyde The molar ratio with the deprotecting agent P is 1:(1-10), preferably 1:3; the primary amine
  • the molar ratio to the deprotecting agent Q is 1:(1-10), preferably 1:3.
  • R 5 includes but is not limited to the following structures:
  • the amino protecting group R 4 includes but is not limited to the following structures: benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, trifluoroacetyl;
  • isocyanate Where M is an alkali metal cation, including but not limited to potassium ion and sodium ion.
  • the organic solvent W includes, but is not limited to, one or a mixture of two or more of tetrahydrofuran, ethyl acetate, toluene, dichloromethane, chloroform, n-butanol, and acetone.
  • the solvent X includes but is not limited to one of methanol, water, N,N-dimethylformamide, 2,4-dimethyl-3-pentanol, isopropanol, o-chlorophenol, or Two or more mixtures.
  • the strong acid Y includes, but is not limited to, hydrofluoric acid, fluorosulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, ethanesulfonic acid, methyl phenyl One or a mixture of two or more sulfides.
  • step 1) after the completion of the polymerization reaction further includes: purifying the obtained polyamino acid derivative containing amino protecting groups R 4 and R 5 , and the purification method includes but not limited to the following methods:
  • Method 1 Add the water extraction product, purify the water layer, and obtain purified polyamino acid derivatives containing amino protecting groups R 4 and R 5 after freeze-drying;
  • Method 2 Adding water to extract the product, drying the organic layer, removing water, evaporating the solvent, and drying the obtained product to obtain a purified polyamino acid derivative containing amino protecting groups R 4 and R 5.
  • Step 1) In the case of less organic solvents used in the polymerization reaction, those skilled in the art understand that in order to smoothly carry out the extraction and increase the yield, a part of the organic solvent is generally added at the same time as water is added in the extraction.
  • the organic solvent Z is added while adding water;
  • the organic solvent Z includes but is not limited to one or more of chloroform, ethyl acetate, toluene, n-butanol, and dichloromethane Mixture;
  • the purification treatment includes, but is not limited to, dialysis bag treatment or anion resin treatment.
  • the R 4 group deprotecting agent P is an acidic reagent, including but not limited to trifluoroacetic acid/33% hydrobromic acid in acetic acid, trichloroacetic acid, benzene One or a mixture of two or more of sulfonic acid, methanesulfonic acid, thioanisole, dichlorodicyanobenzoquinone, and acetic acid;
  • the R 4 group deprotecting agent P includes, but is not limited to, 20% piperidine solution or concentrated ammonia, dioxane/4M NaOH (30:9:1), and with 50% piperidine, diethanolamine, cyclohexylamine, morpholine, pyrrolidone, DBU and the like amines in CH 2 Cl 2 solution, Bu 4 N + F - / DMF solution;
  • the R 4 group deprotecting agent P is an alkaline solution, including but not limited to sodium hydroxide aqueous solution, sodium hydroxide ethanol aqueous solution, potassium hydroxide solution, potassium hydroxide Ethanol aqueous solution, piperidine solution, potassium carbonate methanol aqueous solution, sodium carbonate methanol aqueous solution;
  • the deprotecting agent Q of the R 5 group includes, but is not limited to, one of trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, methanesulfonic acid, thioanisole, dichlorodicyanobenzoquinone, and acetic acid or Two or more mixtures.
  • the reaction of removing the R 4 protecting group is finished, and/or after the reaction of removing the R 5 protecting group is finished, it also includes purifying the obtained product, and the purification method includes but not limited to the following methods:
  • Method 1 Add a large amount of solvent U to the solution to precipitate the product, wash it, purify it, and freeze-dry to obtain a polyamino acid derivative or copolymer;
  • Method 2 Purify the solution and freeze-dry to obtain polyamino acid derivatives or copolymers
  • the solvent U may be an ether or alkane solvent, including but not limited to: methyl tert-butyl ether and ethanol; the purification treatment includes, but is not limited to, dialysis bag treatment and anion resin treatment.
  • the polyamino acid derivative or polyamino acid copolymer of the present invention has good compatibility and antibacterial properties, and can be degraded into amino acid monomers in the body without toxic and side effects.
  • the present invention prepares a multifunctional material with a clear and adjustable structure that has antibacterial function, good biocompatibility, and degradation performance.
  • Figure 1 shows the structural formula of the polyamino acid derivative or copolymer of the present invention.
  • Figure 2 shows the relative molecular weight test results of the polyamino acid copolymer prepared in Example 1.
  • Figure 3 shows the antibacterial rate of the polyamino acid copolymer prepared in Example 1 against Staphylococcus aureus.
  • Figure 4 shows the antibacterial rate of the polyamino acid copolymer prepared in Example 1 against Escherichia coli.
  • Figure 5 shows the relative survival rate of the polyamino acid copolymer prepared in Example 1 on mouse fibroblast L929.
  • the obtained polyamino acid derivative was dissolved in 5 mL of methanesulfonic acid and reacted at 100°C for 2 days.
  • the product was precipitated with methyl tert-butyl ether, washed with ethanol three times, and dialyzed against a 1000 molecular weight dialysis bag for 3 days to obtain a polyamino acid copolymer.
  • the products were prepared with sterilized distilled water to obtain four concentrations of 200 ppm, 100 ppm, 50 ppm and 25 ppm.
  • Figure 3 shows the antibacterial rate of polyamino acid copolymer at 20 ppm, 10 ppm, 5 ppm and 2.5 ppm against Staphylococcus aureus.
  • concentration is greater than 10 ppm, the antibacterial rate is 100%, when the concentration is 5 ppm, the antibacterial rate is 96.75%, and when the concentration is 2.5 ppm, the antibacterial rate is 63.46%.
  • Figure 4 shows the antibacterial rate of the polyamino acid copolymer at 20 ppm, 10 ppm, 5 ppm, and 2.5 ppm.
  • concentration is greater than 10 ppm, the antibacterial rate is 100%, and when the concentration is 5 ppm, the antibacterial rate is 87.53%.
  • concentration is 2.5 ppm, the antibacterial rate is 38.19%.
  • mice fibroblast L929 at a concentration of 5 ⁇ 10 5 CFU/mL to each well of a 96-well plate, and culture in a carbon dioxide biochemical incubator.
  • the polymer solution is prepared with culture broth, containing four concentrations of 20 ppm, 10 ppm, 5 ppm and 2.5 ppm.
  • the original cell culture medium in the 96-well plate was aspirated, and 100 ⁇ L of the newly prepared polymer-containing culture solution of different concentrations was added to the wells.
  • the culture medium was also added to the zero adjustment group (without cells) and the control group. Make six parallel samples, add 10uL of CCK-8 reagent to each well after one day of culture, and incubate for 2h.
  • relative cell survival rate (%) (A 1 -A 2 )/(A 3 -A 1 ) ⁇ 100%;
  • a 1 represents the absorbance value of the solution when the polymer concentration is not 0 ppm;
  • a 2 represents the absorbance value of the culture solution and CCK-8;
  • a 3 represents the absorbance value of the solution when the polymer concentration is 0 ppm.
  • Figure 5 shows the relative survival rate of mouse fibroblast L929 when the polyamino acid copolymer concentrations are 20 ppm, 10 ppm, 5 ppm, and 2.5 ppm. They are 86.24%, 100.25%, 101.63%, and 104.27%, respectively. When the concentration is less than 10 ppm, it is non-toxic to mouse fibroblasts.
  • the polyamino acid derivative prepared in this example has a number average molecular weight of 23758 and a polyamino acid copolymer material with a weight concentration of 2%. After 24 hours of action on Staphylococcus aureus at a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.
  • Deprotection reaction Dissolve the polyamino acid derivative containing the trifluoroacetyl protecting group with 40mL 1mol/L sodium hydroxide solution, react at 50°C for 5 hours, and dialyze the product with a 1000 molecular weight dialysis bag for 3 days to obtain Deprotected polyamino acid derivatives.
  • the polyamino acid derivative prepared in this embodiment has a number average molecular weight of 10679 and a polyamino acid copolymer material with a weight concentration of 4%. After 24 hours of action on Staphylococcus aureus with a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.
  • Deprotection reaction Dissolve the polyamino acid derivative containing the trifluoroacetyl protecting group with 40mL 1mol/L sodium hydroxide solution, react at 50°C for 5 hours, and dialyze the product with a 1000 molecular weight dialysis bag for 3 days to obtain Deprotected polyamino acid derivatives.
  • the polyamino acid derivative prepared in this embodiment has a number average molecular weight of 13591 and a weight concentration of 4% polyamino acid copolymer material. After 24 hours of action on Staphylococcus aureus at a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.
  • Deprotection reaction Dissolve the polyamino acid derivative containing the trifluoroacetyl protecting group with 40mL 1mol/L sodium hydroxide solution, react at 50°C for 5 hours, and dialyze the product with a 1000 molecular weight dialysis bag for 3 days to obtain Deprotected polyamino acid derivatives.
  • the polyamino acid derivative prepared in this example has a number average molecular weight of 37341 and a weight concentration of 5% polyamino acid copolymer material. After 24 hours of action on Staphylococcus aureus with a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.
  • Deprotection reaction Dissolve the polyamino acid derivative containing the trifluoroacetyl protecting group with 40mL 1mol/L sodium hydroxide solution, react at 50°C for 5 hours, and dialyze the product with a 1000 molecular weight dialysis bag for 3 days to obtain Deprotected polyamino acid derivatives.
  • the polyamino acid derivative prepared in this example has a number average molecular weight of 18764 and a polyamino acid copolymer material with a weight concentration of 5%. After 24 hours of action on Staphylococcus aureus with a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.
  • Deprotection reaction Dissolve the polyamino acid derivative containing the trifluoroacetyl protecting group with 40mL 1mol/L sodium hydroxide solution, react at 50°C for 5 hours, and dialyze the product with a 1000 molecular weight dialysis bag for 3 days to obtain Deprotected polyamino acid derivatives.
  • the polyamino acid derivative prepared in this example has a number average molecular weight of 25623 and a polyamino acid copolymer material with a weight concentration of 2%. After 24 hours of action on Staphylococcus aureus at a concentration of 1.0 ⁇ 10 5 cfu/mL in physiological saline, the bacteria The concentration is reduced by more than 50%, and it is non-toxic to mouse fibroblast L929; the experimental method is as in Example 1.

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Abstract

一种交替结构抗菌聚氨基酸衍生物或共聚物及其制备方法，该聚氨基酸衍生物或共聚物具有交替结构单元和相同的构象。交替重复结构单元中，一种为碱性氨基酸或碱性氨基酸的衍生物，通过改变另一种氨基酸的种类获得不同亲疏水性、材料强度、降解率、抗菌活性的聚氨基抗菌材料。同时，这种方法合成的聚氨基酸衍生物或共聚物在体内降解得到的小分子片段具有一样的构象，且依然为交替结构重复单元，最终被人体降解得到氨基酸小分子，该结构特征保证了这类材料的生物相容性和可降解性以及结构的明确性和可控性，有利于探索生物活性和抗菌机理。

Description

一种交替结构抗菌聚氨基酸衍生物或共聚物及其制备方法 技术领域
本发明涉及抗菌材料领域。更具体地，涉及一种交替结构抗菌聚氨基酸衍生物或共聚物及其制备方法。
背景技术
随着人们健康意识及医疗卫生水平的不断提高，人们对于抗菌材料的需求和要求也不断提高，抗菌材料除了需要具有抗菌性能，往往还需要较高的生物安全性和环境安全性，比如抗菌类医疗器械，不仅需要有效抑制细菌的生长和繁殖，还需要良好的安全性。目前大多数抗菌材料主要为可以释放抗菌金属离子的材料和季铵盐类的抗菌材料。这些材料都具有较强的抗菌性能，但由于对人体具有一定的细胞毒性，产生耐药性等缺点，急需开发出满足行业要求的抗菌材料。
抗菌肽作为一种聚氨基酸多肽，在体内能够降解为氨基酸小分子，被人体吸收或排出体外，是一种比较理想的抗菌材料，满足体内的生物相容性和可降解性。这类多肽中含有大量的碱性氨基酸，如鸟氨酸、赖氨酸、精氨酸、组氨酸，得到的聚氨基酸侧链上带有阳离子基团，如氨基或吲哚基，具有很好的抗菌效果。目前大部分的聚氨基酸都通过阴离子聚合得到两种或两种以上氨基酸重复单元组成的嵌段类共聚物，这种方法得到的聚氨基酸共聚物其任一主链上的不同片段具有不同的氨基酸重复单元排列顺序，通过添加不同的氨基酸，无法精确地调节聚氨基酸共聚物的结构，也就无法有效控制聚合物的亲疏水性、材料强度、降解速率、抗菌活性、生物安全性等性能。这类方法得到的聚氨基酸共聚物在体内或体外降解时，其降解后的片段其结构各不相同，也就无法进行其抗菌机理的探索。
发明内容
本发明通过精确调节结构得到不同性能的聚氨基酸衍生物或共聚物，设计合成了一种具有抗菌功能的聚氨基酸衍生物或共聚物材料，这种聚氨基酸衍生物或共聚物的合成是通过末端氨基上带有保护基的醛类与伯胺类、异氰酸盐类由Ugi’s 4CC法进行聚合反应以及脱保护基反应，得到结构中富含氨基的交替结构聚氨基酸衍生物或共聚物，该聚氨基酸衍生物或共聚物具有交替结构单元和相同的构象。交替重复结构单元中，一种为碱性氨基酸或碱性氨基酸的衍生物，通过改变另一种氨基酸的种类获得不同亲疏水性、材料强度、降解率、抗菌活性的聚氨基抗菌材料。同时，这种方法合成的聚氨基酸衍生物或共聚物在体内降解得到的小分子片段具有一样的构象，且依然为交替结构重复单元，最终被人体降解得到氨基酸小分子，该结构特征保证了这类材料的生物相容性和可降解性以及结构的明确性和可控性，有利于探索生物活性和抗菌机理。
本发明的一个目的在于提供一种交替结构抗菌聚氨基酸衍生物或共聚物，该聚氨基酸衍生物或共聚物具有明确可调的结构，同时具有良好的抗菌效果以及生物相容性和降 解性。
本发明的另一个目的在于提供一种制备上述交替结构聚氨基酸衍生物或共聚物的方法。
为达到上述目的，本发明采用下述技术方案：
第一方面，本发明提供一种交替结构抗菌聚氨基酸衍生物或共聚物，所述聚氨基酸衍生物或共聚物具有如下结构：
Figure PCTCN2020125120-appb-000001
简写为[AB] n；
其中，A和B分别代表聚氨基酸衍生物或共聚物的两种重复单元；n为AB重复单元的重复单元数；n为正整数，n＝2-10000。
A、B的化学结构式分别如下：
A：
Figure PCTCN2020125120-appb-000002
B：
Figure PCTCN2020125120-appb-000003
进一步，所述重复单元A中，R 1基团的末端含有氨基，包括但不限于以下结构：
Figure PCTCN2020125120-appb-000004
R 2基团包括但不限于以下结构：
Figure PCTCN2020125120-appb-000005
本领域技术人员理解的，当R 2基团为-H时，对应为聚氨基酸共聚物，R 2基团不为-H时，对应为聚氨基酸衍生物。
重复单元A上侧链带有自由氨基，带有正电荷，可以调节聚氨基酸衍生物或共聚物材料的抗菌性能；
所述重复单元B中，R 3基团包括但不限于以下结构：-H，
Figure PCTCN2020125120-appb-000006
Figure PCTCN2020125120-appb-000007
R 3基团的作用在于调节聚氨基酸衍生物或共聚物材料的亲疏水性、降解性，强度等。
第二方面，本发明提供一种交替结构可降解抗菌聚氨基酸衍生物或共聚物的制备方法，包括聚合反应和脱保护基反应两步，如下：
1)聚合反应
将伯胺
Figure PCTCN2020125120-appb-000008
和醛
Figure PCTCN2020125120-appb-000009
加入有机溶剂W中，在0-100℃温度区间内反应0.1-120小时后得到含碳氮双键的中间产物F；将中间产物F、异氰酸盐
Figure PCTCN2020125120-appb-000010
和强酸Y溶于溶剂X中，在0-100℃温度区间内反应0.1-240小时，得到含有氨基保护基R 4和R 5的聚氨基酸衍生物；
其中R 1末端包含氨基，且氨基保护基R 4与R 1末端氨基上的氮原子相连；
2)脱保护基反应：
将含氨基保护基R 4和R 5的聚氨基酸衍生物用脱保护剂P在0-120℃温度区间内反应0.1-150小时后脱去R 4基团，得到不含R 4基团的聚氨基酸衍生物；
或者，步骤2)进一步包括：
将所得不含R 4基团的聚氨基酸衍生物用脱保护剂Q在0-120℃温度区间内反应0.1-150小时脱去R 5基团，得到聚氨基酸共聚物。
本领域技术人员理解的，只脱去R 4保护基得到的为聚氨基酸衍生物，此时相应于R 2不为-H的情况，R 2与R 5一致；继续脱除R 5保护基得到的为聚氨基酸共聚物，此时相应于R 2为-H的情况。
可选的，在制备聚氨基酸共聚物时，R 4基团和R 5基团都需要脱除，两者脱除的先后顺序可以互换。即在制备聚氨基酸共聚物时，步骤2)包括：
将含氨基保护基R 4和R 5的聚氨基酸衍生物用脱保护剂Q在0-120℃温度区间内反应 0.1-150小时后脱去R 5基团，得到不含R 5基团的聚氨基酸共聚物；将所得不含R 5基团的聚氨基酸共聚物用脱保护剂P在0-120℃温度区间内反应0.1-150小时脱去R 4基团，得到聚氨基酸共聚物。
优选地，步骤1)聚合反应还可以为一锅法，包括以下步骤：
将伯胺
Figure PCTCN2020125120-appb-000011
强酸Y、异氰酸盐
Figure PCTCN2020125120-appb-000012
和醛
Figure PCTCN2020125120-appb-000013
加入溶剂X中，在0-100℃温度区间内反应0.1-360小时，得到含有氨基保护基团R 4和R 5基团的聚氨基酸衍生物。
优选地，步骤1)中，所述伯胺
Figure PCTCN2020125120-appb-000014
强酸Y、异氰酸盐
Figure PCTCN2020125120-appb-000015
和醛
Figure PCTCN2020125120-appb-000016
的摩尔比为(1-3)：(1-3)：(1-3)：(1-3)；优选为1：1：1：1。
优选地，步骤2)中，所述醛
Figure PCTCN2020125120-appb-000017
与脱保护剂P的摩尔比为1：(1-10)，优选1:3；所述伯胺
Figure PCTCN2020125120-appb-000018
和脱保护剂Q的摩尔比为1：(1-10)，优选1:3。
优选地，所述伯胺
Figure PCTCN2020125120-appb-000019
中，R 5包括但不限于以下结构：
Figure PCTCN2020125120-appb-000020
优选地，氨基保护基R 4包括但不限于以下结构：苄氧羰基、叔丁氧羰基、笏甲氧羰基、三氟乙酰基；
优选地，异氰酸盐
Figure PCTCN2020125120-appb-000021
中M为碱金属阳离子，包括但不限于钾离子、钠离子。
优选地，所述有机溶剂W包括但不限于四氢呋喃、乙酸乙酯、甲苯、二氯甲烷、三氯甲烷、正丁醇、丙酮中一种或两种以上的混合物。
优选地，所述溶剂X包括但不限于甲醇、水、N,N-二甲基甲酰胺、2,4-二甲基-3-戊醇、异丙醇、邻氯苯酚中的一种或两种以上混合物。
优选地，所述强酸Y包括但不限于氢氟酸、氟磺酸、甲磺酸、三氟甲磺酸、三氟乙酸、五氟乙酸、七氟丙酸、乙磺酸、甲基苯基硫醚中的一种或两种以上混合物。
优选地，步骤1)聚合反应结束后还包括：对得到的含氨基保护基R 4和R 5的聚氨基酸衍生物进行纯化，其纯化方法包括但不限于以下方法：
方法1：加入水萃取产物，将水层进行纯化处理，冷冻干燥后得到纯化的含氨基保护基R 4和R 5的聚氨基酸衍生物；
方法2：加入水萃取产物，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，得到纯化的含氨基保护基R 4和R 5的聚氨基酸衍生物。
步骤1)聚合反应所使用的有机溶剂较少的情况下，本领域技术人员理解的，为了萃取的顺利进行和提高收率，一般会在萃取加入水的同时加入部分有机溶剂，优选地，方法1和方法2中，加入水的同时加入有机溶剂Z；所述有机溶剂Z包括但不限于三氯甲烷、乙酸乙酯、甲苯、正丁醇、二氯甲烷中的一种或两种以上的混合物；所述纯化处理包括但不限于透析袋处理或阴离子树脂处理。
优选地，当R 4基团为苄氧羰基时，所述R 4基团脱保护剂P为酸性试剂，包括但不限于三氟乙酸/33％氢溴酸的乙酸溶液、三氯乙酸、苯磺酸、甲磺酸、苯硫基甲烷、二氯二氰基苯醌、醋酸中的一种或两种以上混合物；
当R 4基团为叔丁氧羰基时，所述R 4基团脱保护剂P包括但不限于TFA或50％TFA(TFA:CH 2Cl 2＝1:1,v/v)，HCl/二氧六环，HCl/EtOAc(甲醇作为溶剂)，Me 3SiI的CHCl 3或CH 3CN溶液；
当R 4基团为笏甲氧羰基时，所述R 4基团脱保护剂P包括但不限于20％哌啶溶液或浓氨水、二氧六环/4M NaOH(30:9:1)以及用哌啶、乙醇胺、环己胺、吗啡啉、吡咯烷酮、DBU等胺类的50％CH 2Cl 2的溶液，Bu 4N +F -/DMF溶液；
当R 4基团为三氟乙酰基时，所述R 4基团脱保护剂P为碱性溶液，包括但不限于氢氧化钠水溶液、氢氧化钠乙醇水溶液、氢氧化钾溶液、氢氧化钾乙醇水溶液、哌啶溶液、碳酸钾甲醇水溶液、碳酸钠甲醇水溶液；
所述R 5基团的脱保护剂Q包括但不限于三氟乙酸、三氯乙酸、苯磺酸、甲磺酸、苯硫基甲烷、二氯二氰基苯醌、醋酸中的一种或两种以上混合物。
进一步，脱去R 4保护基团的反应结束后，和/或脱去R 5保护基团的反应结束后，还包括将得到的产物进行纯化，其纯化方法包括但不限于以下方法：
方法1：溶液中加入大量溶剂U析出产物，洗涤后，纯化处理，冷冻干燥得到聚氨基酸衍生物或共聚物；
方法2：将溶液进行纯化处理，冷冻干燥后得到聚氨基酸衍生物或共聚物；
所述溶剂U可以为醚类或烷烃类溶剂，包括但不限于：甲基叔丁基醚、乙醇；所述纯化处理包括但不限于透析袋处理、阴离子树脂处理。
本发明的有益效果如下：
(1)本发明的聚氨基酸衍生物或聚氨基酸共聚物具有良好的相容性和抗菌性能，且在体内能够降解成氨基酸单体，无毒副作用。
(2)本发明通过改变异氰酸盐、胺、醛的种类、比例等因素，制备了结构明确可调的具有抗菌功能、良好生物相容性和降解性能等兼备多功能性材料。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1示出本发明聚氨基酸衍生物或共聚物的结构式。
图2示出实施例1制备的聚氨基酸共聚物的相对分子量测试结果。
图3示出实施例1制备的聚氨基酸共聚物对金黄色葡萄球菌的抗菌率。
图4示出实施例1制备的聚氨基酸共聚物对大肠杆菌的抗菌率。
图5示出实施例1制备的聚氨基酸共聚物对小鼠成纤维细胞L929的相对存活率。
具体实施方式
为使本发明的、技术方案和优点更加清楚，下面将结合附图对本发明实施方式作进一步地详细描述。
本发明提供的交替结构抗菌聚氨基酸衍生物或共聚物的结构图如图1所示；简写为[AB] n；其中，A和B分别代表聚氨基酸衍生物或共聚物的两种重复单元；n为AB重复单元的重复单元数；n为正整数，n＝2-10000。
A、B的化学结构式分别如下：A：
Figure PCTCN2020125120-appb-000022
B：
Figure PCTCN2020125120-appb-000023
以下提供几个示例性的制备过程及相应产物。
实施例1
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：将0.01moL 5-(苄氧羰基氨基)戊醛、0.01moL苯甲基胺依次加入10mL四氢呋喃中室温下反应。搅拌3天后，将溶液减压蒸馏除去溶剂，得到黄色油状 中间体。0℃下将0.01moL异氰酸钾溶于5mL甲醇中，依次加入0.01moL氢氟酸和黄色油状中间体。将上述混合物加热至室温，搅拌4天后停止反应。加入蒸馏水，提取纯化水层，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含苄氧羰基保护基的聚氨基酸衍生物用20mL三氟乙酸溶解，加入5mL 33％氢溴酸的乙酸溶液，25℃中反应4小时，产物用甲基叔丁基醚析出，乙醇洗涤三次，1000分子量透析袋透析3天，得到脱去苄氧羰基保护基的聚氨基酸衍生物。
将得到的聚氨基酸衍生物用5mL甲磺酸溶解，100℃中反应2天，产物用甲基叔丁基醚析出，乙醇洗涤三次，1000分子量透析袋透析3天，得到聚氨基酸共聚物。
反应式如下：
Figure PCTCN2020125120-appb-000024
本实施实例制得的聚氨基酸共聚物的相对分子量测试结果如图2所示，其中，W为质量，M为重均分子量；由图2可知本实施实例制得的聚氨基酸共聚物数均分子量为2835，重均分子量为13434。
用灭过菌的蒸馏水将产物分别配制得到200ppm、100ppm、50ppm和25ppm四个浓度。在离心管中加入4mL 0.03mmoL/L的无菌PBS溶液、0.5mL含聚合物的溶液和0.5mL的金黄色葡萄球菌液(浓度为1.5×10 6CFU/mL)，每组同时做三个平行样。空白组不加任何药物，加入4.5mL 0.03mmoL的无菌PBS溶液和0.5mL的菌液，做三个平行样。离心管盖均拧松后放入恒温振荡箱中，37℃条件下振荡，一天后取出，用生理盐水将每个样分别稀释十倍、百倍、千倍和万倍四个梯度。分别吸取1mL溶液加入培养皿中， 加入适量PCA培养基摇匀冷却，倒置培养一天后记录每个培养皿中长出的菌落数。
聚氨基酸共聚物浓度分别为20ppm，10ppm，5ppm，2.5ppm时对金黄色葡萄球菌的抗菌率如图3所示。浓度大于10ppm时，抗菌率为100％，当浓度为5ppm时，抗菌率为96.75％，当浓度为2.5ppm时，抗菌率为63.46％。
聚氨基酸共聚物浓度分别为20ppm，10ppm，5ppm，2.5ppm时对大肠杆菌的抗菌率如图4所示。浓度大于10ppm时，抗菌率为100％，当浓度为5ppm时，抗菌率为87.53％。当浓度为2.5ppm时，抗菌率为38.19％。
在96孔板中每孔加入100μL浓度在5×10 5CFU/mL的小鼠成纤维细胞L929，二氧化碳生化培养箱培养。用培养液配置聚合物的溶液，含20ppm、10ppm、5ppm和2.5ppm四个浓度。一天后吸除96孔板中原来的细胞培养液，孔中分别加入刚配置的不同浓度的含聚合物的培养溶液100μL，调零组(不含细胞)和对照组中也加入培养液，均做六个平行样，培养一天后每个孔均加入10uL的CCK-8试剂，培养2h。用酶标仪检测波长为450纳米处每个孔的吸光值A，根据公式如下计算细胞相对存活率：细胞相对存活率(％)＝(A 1-A 2)/(A 3-A 1)×100％；上面公式中A 1代表聚合物浓度不为0ppm时溶液的吸光值；A 2代表培养液和CCK-8的吸光值；A 3代表聚合物浓度为0ppm时溶液的吸光值。
聚氨基酸共聚物浓度分别为20ppm，10ppm，5ppm，2.5ppm时小鼠成纤维细胞L929的相对存活率如图5所示。分别为86.24％，100.25％，101.63％，104.27％。当浓度小于10ppm时，对小鼠成纤维细胞无毒性。
实施例2
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL 4-甲氧基苯甲基胺、0.01moL甲磺酸、0.01moL异氰酸钾、0.01moL 4-(苄氧羰基氨基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，提取纯化水层，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含苄氧羰基保护基的聚氨基酸衍生物用5mL甲磺酸溶解，50℃中反应3天，产物用甲基叔丁基醚析出，乙醇洗涤三次，1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
反应式如下：
Figure PCTCN2020125120-appb-000025
本实施实例制得的聚氨基酸衍生物数均分子量为23758，重量浓度为2％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
实施例3
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL 4-甲氧基苯甲基胺、0.01moL甲磺酸、0.01moL异氰酸钾、0.01moL 4-(三氟乙酰基氨基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，纯化，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含三氟乙酰基保护基的聚氨基酸衍生物用40mL 1mol/L的氢氧化钠溶液溶解，50℃中反应5小时，产物用1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
本实施实例制得的聚氨基酸衍生物数均分子量为10679，重量浓度为4％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
实施例4
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL 4-甲氧基苯甲基胺、0.01moL甲磺酸、0.01moL 2-(异氰基)丙酸钾、0.01moL 4-(三氟乙酰基氨基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，纯化，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含三氟乙酰基保护基的聚氨基酸衍生物用40mL 1mol/L的氢氧化钠溶液溶解，50℃中反应5小时，产物用1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
本实施实例制得的聚氨基酸衍生物数均分子量为13593，重量浓度为4％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
实施例5
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL 4-甲氧基苯甲基胺、0.01moL甲磺酸、0.01moL 2-(异氰基)-3-(苯基)丙酸钾、0.01moL 4-(三氟乙酰基氨基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，纯化，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含三氟乙酰基保护基的聚氨基酸衍生物用40mL 1mol/L的氢氧化钠溶液溶解，50℃中反应5小时，产物用1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
本实施实例制得的聚氨基酸衍生物数均分子量为37341，重量浓度为5％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
实施例6
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL丙烯基胺、0.01moL甲磺酸、0.01moL异氰酸钾、0.01moL 4-(三氟乙酰基氨基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，纯化，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含三氟乙酰基保护基的聚氨基酸衍生物用40mL 1mol/L的氢氧化钠溶液溶解，50℃中反应5小时，产物用1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
本实施实例制得的聚氨基酸衍生物数均分子量为18764，重量浓度为5％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
实施例7
本实施例制备一种交替结构可降解抗菌聚氨基酸共聚物
1)聚合反应：0℃下依次将0.01moL 4-甲氧基苯甲基胺、0.01moL甲磺酸、0.01moL异氰酸钾、0.01moL 4-(三氟乙酰基胍基)丁醛加入5mL四氢呋喃中，然后将混合物加热至室温，搅拌15天，停止反应，加入蒸馏水，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，纯化，得到带有保护基的氨基酸衍生物。
2)脱保护基反应：将含三氟乙酰基保护基的聚氨基酸衍生物用40mL 1mol/L的氢氧化钠溶液溶解，50℃中反应5小时，产物用1000分子量透析袋透析3天，得到脱去保护基的聚氨基酸衍生物。
本实施实例制得的聚氨基酸衍生物数均分子量为25623，重量浓度为2％的聚氨基酸共聚物材料对生理盐水中1.0×10 5cfu/mL浓度的金黄色葡萄球菌作用24小时后，细菌浓度减少50％以上，对小鼠成纤维细胞L929无毒性；实验方法如实施例1。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种交替结构抗菌聚氨基酸衍生物或共聚物，其特征在于，所述聚氨基酸衍生物或共聚物具有如下结构：
    Figure PCTCN2020125120-appb-100001
    简写为[AB] n；
    其中A为
    Figure PCTCN2020125120-appb-100002
    B为
    Figure PCTCN2020125120-appb-100003
    n为正整数，n＝2-10000；
    R 1的末端含有氨基；
    R 2为：
    -H，
    Figure PCTCN2020125120-appb-100004
    R 3为：
    Figure PCTCN2020125120-appb-100005
  2. 根据权利要求1所述的交替结构抗菌聚氨基酸衍生物或共聚物，其特征在于，R 1为：
    Figure PCTCN2020125120-appb-100006
  3. 一种权利要求1或2所述交替结构抗菌聚氨基酸衍生物或共聚物的制备方法，其特征在于，包括如下步骤：
    1)聚合反应
    将伯胺
    Figure PCTCN2020125120-appb-100007
    和醛
    Figure PCTCN2020125120-appb-100008
    加入有机溶剂W中，在0-100℃温度区间内反应0.1-120小时后得到含碳氮双键的中间产物F；将中间产物F、异氰酸盐
    Figure PCTCN2020125120-appb-100009
    和强酸Y溶于溶剂X中，在0-100℃温度区间内反应0.1-240小时，得到含有氨基保护基R 4和R 5的聚氨基酸衍生物；
    其中R 1末端包含氨基，且氨基保护基R 4与R 1末端氨基上的氮原子相连；
    2)脱保护基反应：
    将含氨基保护基R 4和R 5的聚氨基酸衍生物用脱保护剂P在0-120℃温度区间内反应0.1-150小时后脱去R 4基团，得到不含R 4基团的聚氨基酸衍生物；
    或者，步骤2)进一步包括：
    将所得不含R 4基团的聚氨基酸衍生物用脱保护剂Q在0-120℃温度区间内反应0.1-150小时脱去R 5基团，得到聚氨基酸共聚物；
    或者，步骤2)包括：
    将含氨基保护基R 4和R 5的聚氨基酸衍生物用脱保护剂Q在0-120℃温度区间内反应0.1-150小时后脱去R 5基团，得到不含R 5基团的聚氨基酸共聚物；将所得不含R 5基团的聚氨基酸共聚物用脱保护剂P在0-120℃温度区间内反应0.1-150小时脱去R 4基团，得到聚氨基酸共聚物。
  4. 根据权利要求3所述的制备方法，其特征在于，步骤1)聚合反应包括以下步骤：
    将伯胺
    Figure PCTCN2020125120-appb-100010
    强酸Y、异氰酸盐
    Figure PCTCN2020125120-appb-100011
    和醛
    Figure PCTCN2020125120-appb-100012
    加入溶剂X中，在0-100℃温度区间内反应0.1-360小时，得到含有氨基保护基团R 4和R 5基团的聚氨基酸衍生物。
  5. 根据权利要求3所述的制备方法，其特征在于，步骤1)中，所述伯胺
    Figure PCTCN2020125120-appb-100013
    强酸Y、异氰酸盐
    Figure PCTCN2020125120-appb-100014
    和醛
    Figure PCTCN2020125120-appb-100015
    的摩尔比为(1-3)：(1-3)：(1-3)：(1-3)，优选1：1：1：1；
    优选地，步骤2)中，所述醛
    Figure PCTCN2020125120-appb-100016
    与脱保护剂P的摩尔比为1：(1-10)，优选1:3；所述伯胺
    Figure PCTCN2020125120-appb-100017
    和脱保护剂Q的摩尔比为1：(1-10)，优选1:3。
  6. 根据权利要求3所述的制备方法，其特征在于，所述伯胺
    Figure PCTCN2020125120-appb-100018
    中，R 5为：
    Figure PCTCN2020125120-appb-100019
  7. 根据权利要求3所述的制备方法，其特征在于，氨基保护基R 4为：苄氧羰基、叔丁氧羰基、笏甲氧羰基、三氟乙酰基；
    优选地，异氰酸盐
    Figure PCTCN2020125120-appb-100020
    中M为碱金属阳离子，为钾离子或钠离子；
    优选地，所述有机溶剂W为四氢呋喃、乙酸乙酯、甲苯、二氯甲烷、三氯甲烷、正丁醇、丙酮中一种或两种以上的混合物；
    优选地，所述溶剂X为甲醇、水、N,N-二甲基甲酰胺、2,4-二甲基-3-戊醇、异丙醇、邻氯苯酚中的一种或两种以上混合物；
    优选地，所述强酸Y为氢氟酸、氟磺酸、甲磺酸、三氟甲磺酸、三氟乙酸、五氟乙酸、七氟丙酸、乙磺酸、甲基苯基硫醚中的一种或两种以上混合物。
  8. 根据权利要求3所述的制备方法，其特征在于，步骤1)聚合反应结束后还包括：对得到的含氨基保护基R 4和R 5的聚氨基酸衍生物进行纯化，其纯化方法包括以下方法：
    方法1：加入水萃取产物，将水层进行纯化处理，冷冻干燥后得到纯化的含氨基保护基R 4和R 5的聚氨基酸衍生物；
    方法2：加入水萃取产物，将有机层干燥，除去水分，蒸发溶剂，得到的产物进行烘干，得到纯化的含氨基保护基R 4和R 5的聚氨基酸衍生物；
    优选地，方法1和方法2中，加入水的同时加入有机溶剂Z；所述有机溶剂Z包括但不限于三氯甲烷、乙酸乙酯、甲苯、正丁醇、二氯甲烷中的一种或两种以上的混合物；
    所述纯化处理包括透析袋处理或阴离子树脂处理。
  9. 根据权利要求3所述的制备方法，其特征在于，当R 4基团为苄氧羰基时，所述R 4基团脱保护剂P为三氟乙酸/33％氢溴酸的乙酸溶液、三氯乙酸、苯磺酸、甲磺酸、苯硫基甲烷、二氯二氰基苯醌、醋酸中的一种或两种以上混合物；
    当R 4基团为叔丁氧羰基时，所述R 4基团脱保护剂P为TFA或50％TFA、HCl/二氧六环、HCl/EtOAc、Me 3SiI的CHCl 3或CH 3CN溶液；
    当R 4基团为笏甲氧羰基时，所述R 4基团脱保护剂P为20％哌啶溶液或浓氨水、二氧六环/4M NaOH、以及用哌啶、乙醇胺、环己胺、吗啡啉、吡咯烷酮或DBU胺类的50％CH 2Cl 2的溶液或Bu 4N +F -/DMF溶液；
    当R 4基团为三氟乙酰基时，所述R 4基团脱保护剂P为氢氧化钠水溶液、氢氧化钠乙醇水溶液、氢氧化钾溶液、氢氧化钾乙醇水溶液、哌啶溶液、碳酸钾甲醇水溶液或碳酸钠甲醇水溶液；
    所述R 5基团的脱保护剂Q为三氟乙酸、三氯乙酸、苯磺酸、甲磺酸、苯硫基甲烷、二氯二氰基苯醌、醋酸中的一种或两种以上混合物。
  10. 根据权利要求3所述的制备方法，其特征在于，脱去R 4保护基团的反应结束后，和/或脱去R 5保护基团的反应结束后，还包括将得到的产物进行纯化，其纯化方法包括以下方法：
    方法1：溶液中加入大量溶剂U析出产物，洗涤后，纯化处理，冷冻干燥得到聚氨基酸衍生物或共聚物；
    方法2：将溶液进行纯化处理，冷冻干燥后得到聚氨基酸衍生物或共聚物；
    所述溶剂U为甲基叔丁基醚或乙醇；所述纯化处理为透析袋处理或阴离子树脂处理。
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