CN108034009A - One kind contains more structure functional group chitosan analog derivatives and preparation method - Google Patents
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Abstract
本发明提供的是一种含有多结构官能团壳聚糖类衍生物及制备方法。先采用三苯基氯甲烷对壳聚糖6‑位进行保护,再与苯基异氰酸酯或具有侧基的苯基异氰酸酯反应,最后对壳聚糖6‑位进行脱保护,得到壳聚糖类‑2‑苯基脲‑3‑苯基氨基甲酸酯‑6‑羟基衍生物。本发明采用一步法直接对壳聚糖6‑位羟基进行保护,避免了多步骤反应可能带来的期间损失和副产物;所制备的壳聚糖类衍生物6‑位羟基可进一步修饰,用于制备结构更为多样化的壳聚糖类衍生物。
The invention provides a chitosan derivative containing multi-structural functional groups and a preparation method. First use triphenylchloromethane to protect the 6-position of chitosan, then react with phenyl isocyanate or phenyl isocyanate with side groups, and finally deprotect the 6-position of chitosan to obtain chitosan- 2-Phenylurea-3-Phenylcarbamate-6-Hydroxy Derivatives. The present invention adopts a one-step method to directly protect the 6-position hydroxyl of chitosan, avoiding the period loss and by-products that may be brought by the multi-step reaction; the 6-position hydroxyl of the prepared chitosan derivatives can be further modified, with for the preparation of chitosan derivatives with more diverse structures.
Description
技术领域technical field
本发明涉及的是一种壳聚糖类衍生物,本发明也涉及的是一种壳聚糖类衍生物的制备方法。具体地说是一种基于区域选择性化学修饰的同时含有不同种侧基的壳聚糖类衍生物及合成方法。The invention relates to a chitosan derivative, and also relates to a preparation method of the chitosan derivative. Specifically, it is a chitosan derivative containing different kinds of side groups based on regioselective chemical modification and a synthetic method.
背景技术Background technique
区域选择性化学修饰方法是指在一定反应条件下,由于分子中各个位置反应活性不同,修饰基团会优先与反应活性较高位置处的基团反应,从而实现对该位置的选择性修饰。直至目前,区域选择性化学修饰已经被广泛应用于多糖类如纤维素和直链淀粉类衍生物的制备。纤维素与直链淀粉的2,3,6-位上分别为反应活性不同的羟基,通过引入保护基团如三苯基甲基优先修饰6-位最活泼羟基,未被保护的羟基可进一步被其他基团修饰。1993年,Kaida和Okamoto等人采用三苯基甲基对纤维素和淀粉的6-位羟基进行修饰保护与脱保护,控制合成了两大类带有不同种侧基的新型纤维素类和淀粉类衍生物并将其制备成手性固定相。研究发现:纤维素类手性固定相的手性拆分能力主要取决于药物对映体本身的结构与性质,而纤维素衍生物本身2,3,6-位上的侧基对识别能力的影响作用很复杂。除此之外,对于淀粉类手性固定相而言,其手性拆分能力很大程度上取决于淀粉的2,3-位上的侧基种类,而6-位的影响较小。这是区域选择性化学修饰方法首次被应用于纤维素类和淀粉类衍生物的制备,其成功揭示了该类衍生物所制备的手性固定相在HPLC上的手性拆分机理,这对于用于拆分不同药物对映体而进行手性固定相的有针对性的设计与制备具有重要意义。The regioselective chemical modification method refers to that under certain reaction conditions, due to the different reactivity of each position in the molecule, the modification group will preferentially react with the group at the higher reactivity position, thereby achieving selective modification of the position. Until now, regioselective chemical modification has been widely used in the preparation of polysaccharides such as cellulose and amylose derivatives. The 2, 3, and 6-positions of cellulose and amylose are hydroxyl groups with different reactivity, and the most active hydroxyl group at the 6-position is preferentially modified by introducing a protective group such as triphenylmethyl, and the unprotected hydroxyl group can be further modified. Modified by other groups. In 1993, Kaida and Okamoto et al. used triphenylmethyl to modify, protect and deprotect the 6-hydroxyl of cellulose and starch, and controlled the synthesis of two new types of cellulose and starch with different side groups. derivatives and prepare them as chiral stationary phases. The study found that the chiral resolution ability of the cellulose chiral stationary phase mainly depends on the structure and properties of the drug enantiomer itself, while the recognition ability of the side group on the 2,3,6-position of the cellulose derivative itself depends on Influence is complex. In addition, for the starch chiral stationary phase, its chiral resolution ability largely depends on the type of side group on the 2,3-position of the starch, while the 6-position has little influence. This is the first time that the regioselective chemical modification method has been applied to the preparation of cellulose and starch derivatives, which successfully revealed the chiral resolution mechanism of the chiral stationary phase prepared by such derivatives on HPLC, which is very important for The targeted design and preparation of chiral stationary phases for the separation of different drug enantiomers is of great significance.
壳聚糖作为地球上资源仅次于纤维素的第二大天然生物大分子甲壳素的脱乙酰化产物,其本身无毒无害,且拥有良好的生物相容性、抗菌性、可降解性等性能,因此被广泛应用于医药、食品、环保、农业化学品等多种领域。然而,壳聚糖在水和绝大多数有机溶剂中的溶解性差,使得其在实际应用当中受到一定限制,因此,必须对其进行一定的化学修饰。Chitosan is the deacetylation product of chitin, the second largest natural biomacromolecule after cellulose on earth. It is non-toxic and harmless, and has good biocompatibility, antibacterial property and degradability. And other properties, so it is widely used in various fields such as medicine, food, environmental protection, and agricultural chemicals. However, chitosan has poor solubility in water and most organic solvents, which limits its practical application. Therefore, it must be chemically modified.
壳聚糖除了糖单元2-位上为氨基之外,其他的结构与纤维素的结构类似,因此,区域选择性化学修饰方法同样可以应用于壳聚糖的改性及其衍生物的制备。1991年,Nishimura等先采用邻苯二甲酸酐在N,N-二甲基甲酰胺溶剂体系中对壳聚糖2-位进行修饰,再在以吡啶为溶剂的条件下于壳聚糖6-位引入三苯基甲基作为保护基团,进一步地,采用酸酐与壳聚糖3-位羟基进行反应,合成了2,3,6-位上拥有不同种侧基的壳聚糖类衍生物。2015年,柏正武等人报道了壳聚糖-烃基脲的制备方法,首先采用壳聚糖在甲醇中与氯甲酸甲酯反应,于2-位接入甲氧基甲酰基,然后在N,N-二甲基乙酰胺溶剂中与胺反应。所制得的壳聚糖类衍生物取代度高,结构规整。另外,对该类衍生物3-、6-位进一步修饰,就可制备出新型的功能高分子材料。2016年,申请人采用一系列苯基异氰酸酯修饰2-位被邻苯二甲酰亚胺修饰并保护的壳聚糖,合成了5种糖单元2-位具有邻苯二甲酰亚胺,而3,6-位同时具有4种不同苯基氨基甲酸酯基团(2-氯、3-氯、4-氯和3,5-二氯取代的苯基氨基甲酸酯)和一种无取代的苯基氨基甲酸酯基团的壳聚糖类衍生物。这些衍生物依靠于取代基的位置和结构不同显示出独特的手性识别能力。以上报道的都是首先在氨基上引入取代基进行区域选择性合成方法,对于在6-位羟基上采用一步法直接引入保护基团进行区域选择性化学修饰的方法目前尚未见报道,此方法对扩大壳聚糖类衍生物的种类与应用范围具有重要意义。Except for the amino group at the 2-position of the sugar unit, the structure of chitosan is similar to that of cellulose. Therefore, the regioselective chemical modification method can also be applied to the modification of chitosan and the preparation of its derivatives. In 1991, Nishimura first used phthalic anhydride to modify the 2-position of chitosan in N,N-dimethylformamide solvent system, and then modified chitosan 6-position under the condition of pyridine as solvent. The triphenylmethyl group was introduced as a protecting group, and the acid anhydride was used to react with the 3-hydroxyl group of chitosan to synthesize chitosan derivatives with different side groups at the 2,3,6-position . In 2015, Bai Zhengwu and others reported the preparation method of chitosan-hydrocarbyl urea. First, chitosan was used to react with methyl chloroformate in methanol, and a methoxyformyl group was inserted at the 2-position, and then at the N, Reaction with amines in N-dimethylacetamide solvent. The prepared chitosan derivatives have high degree of substitution and regular structure. In addition, by further modifying the 3- and 6-positions of this kind of derivatives, new functional polymer materials can be prepared. In 2016, the applicant used a series of phenyl isocyanates to modify chitosan modified and protected by phthalimide at the 2-position, and synthesized five sugar units with phthalimide at the 2-position, while The 3,6-position simultaneously has 4 different phenyl carbamate groups (2-chloro, 3-chloro, 4-chloro and 3,5-dichloro substituted phenyl carbamates) and one without Chitosan derivatives with substituted phenyl carbamate groups. These derivatives show unique chiral recognition ability depending on the position and structure of substituents. The above-mentioned reports are all at first introducing a substituent on the amino group to carry out a regioselective synthetic method. For the method of directly introducing a protecting group on the 6-position hydroxyl to carry out a regioselective chemical modification, there is no report yet. It is of great significance to expand the types and application range of chitosan derivatives.
发明内容Contents of the invention
本发明的目的在于提供一种可以作为壳聚糖类手性固定相等的制备中间体的含有多结构官能团壳聚糖类衍生物。本发明的目的还在于提供一种能够能够使壳聚糖类衍生物的6-位上的羟基保留较高的反应活性的含有多结构官能团壳聚糖类衍生物的制备方法。The object of the present invention is to provide a chitosan derivative containing multi-structural functional groups that can be used as a preparation intermediate for chitosan chiral immobilization. The object of the present invention is also to provide a preparation method of chitosan derivatives containing multi-structural functional groups that can keep the hydroxyl group at the 6-position of chitosan derivatives with high reactivity.
本发明的含有多结构官能团壳聚糖类衍生物具有如下结构:The chitosan derivative containing multi-structural functional groups of the present invention has the following structure:
其中,R表示苯基或带有取代基的苯基,所述取代基为1至4个,当取代基的个数大于1时,各取代基相同或不相同,所述取代基为卤素原子、烷基、烷氧基、硝基、氨基或烷硫基。Wherein, R represents a phenyl group or a phenyl group with a substituent, and the number of substituents is 1 to 4. When the number of substituents is greater than 1, each substituent is the same or different, and the substituent is a halogen atom , alkyl, alkoxy, nitro, amino or alkylthio.
本发明的含有多结构官能团壳聚糖类衍生物的制备方法为:The preparation method of chitosan derivative containing multi-structural functional group of the present invention is:
先采用三苯基氯甲烷对壳聚糖6-位进行保护,再与苯基异氰酸酯或具有侧基的苯基异氰酸酯反应,最后对壳聚糖6-位进行脱保护,得到结构式为的壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-羟基衍生物,其中,R表示苯基或带有取代基的苯基,所述取代基为1至4个,当取代基的个数大于1时,各取代基相同或不相同,所述取代基为卤素原子、烷基、烷氧基、硝基、氨基或烷硫基。First use triphenylchloromethane to protect the 6-position of chitosan, then react with phenylisocyanate or phenylisocyanate with side groups, and finally deprotect the 6-position of chitosan to obtain the structural formula: Chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl derivatives, wherein R represents phenyl or phenyl with substituents, and the substituents are 1 to 4 When the number of substituents is greater than 1, each substituent is the same or different, and the substituents are halogen atoms, alkyl groups, alkoxy groups, nitro groups, amino groups or alkylthio groups.
本发明的含有多结构官能团壳聚糖类衍生物的制备方法还可以包括:The preparation method of chitosan derivative containing multi-structural functional group of the present invention can also comprise:
1、所述采用三苯基氯甲烷对壳聚糖6-位进行保护具体包括:取完全脱乙酰化的壳聚糖在60~100℃真空干燥,加入反应溶剂进行溶胀,于室温下加入氢键消除剂,加入三苯基氯甲烷,在反应温度为80~100℃反应6-24h,将反应产物滴入隔离溶剂中,得到壳聚糖-6-OTr。1. The protection of the 6-position of chitosan by using triphenylchloromethane specifically includes: taking the fully deacetylated chitosan and drying it in vacuum at 60-100°C, adding a reaction solvent for swelling, adding hydrogen at room temperature bond elimination agent, adding triphenylchloromethane, reacting at a reaction temperature of 80-100° C. for 6-24 hours, dropping the reaction product into an isolation solvent to obtain chitosan-6-OTr.
2、所述与苯基异氰酸酯或具有侧基的苯基异氰酸酯反应具体包括:取壳聚糖6-OTr,加入反应溶剂进行溶胀,于室温下加入氢键消除剂,加入苯基异氰酸酯或具有侧基的苯基异氰酸酯,在反应温度为40~150℃反应,反应时间为0.5~24h,将反应产物滴入隔离溶剂中,得到壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-OTr。2. The reaction with phenyl isocyanate or phenyl isocyanate with side groups specifically includes: taking chitosan 6-OTr, adding a reaction solvent for swelling, adding a hydrogen bond elimination agent at room temperature, adding phenyl isocyanate or a side group The base phenyl isocyanate is reacted at a reaction temperature of 40-150°C, and the reaction time is 0.5-24 hours. The reaction product is dropped into an isolation solvent to obtain chitosan-2-phenylurea-3-phenylcarbamate Ester-6-OTr.
3、所述对壳聚糖6-位进行脱保护具体包括:取壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-OTr,加入浓盐酸与甲醇,在反应温度为30~70℃反应,反应时间为12~24h,将反应产物滴入隔离溶剂中,得到壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-羟基。3. The deprotection of the 6-position of chitosan specifically includes: taking chitosan-2-phenylurea-3-phenylcarbamate-6-OTr, adding concentrated hydrochloric acid and methanol, at the reaction temperature The reaction is performed at 30-70° C., and the reaction time is 12-24 hours. The reaction product is dropped into an isolation solvent to obtain chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl.
4、加入的三苯基氯甲烷的摩尔质量是壳聚糖6-位羟基的摩尔质量的1.5~3倍。4. The molar mass of the added triphenylchloromethane is 1.5 to 3 times the molar mass of the 6-hydroxyl group of chitosan.
5、加入的苯基异氰酸酯或具有侧基的苯基异氰酸酯的摩尔质量是壳聚糖的2-位氨基与3-位羟基总摩尔质量的1.5~3倍。5. The molar mass of the added phenyl isocyanate or phenyl isocyanate with side groups is 1.5 to 3 times the total molar mass of the 2-position amino group and the 3-position hydroxyl group of chitosan.
6、具有侧基的苯基异氰酸酯选自4-甲氧基苯基异氰酸酯、4-乙基苯基异氰酸酯、4-甲基苯基异氰酸酯、4-氟苯基异氰酸酯、4-氯苯基异氰酸酯、4-溴苯基异氰酸酯、4-硝基苯基异氰酸酯、2-氯苯基异氰酸酯、2-甲基苯基异氰酸酯、3-氯苯基异氰酸酯、3-甲基苯基异氰酸酯、3,5-二氯苯基异氰酸酯或3,5-二甲基苯基异氰酸酯。6. Phenyl isocyanates with side groups are selected from 4-methoxyphenyl isocyanate, 4-ethylphenyl isocyanate, 4-methylphenyl isocyanate, 4-fluorophenyl isocyanate, 4-chlorophenyl isocyanate, 4-Bromophenylisocyanate, 4-nitrophenylisocyanate, 2-chlorophenylisocyanate, 2-methylphenylisocyanate, 3-chlorophenylisocyanate, 3-methylphenylisocyanate, 3,5-di Chlorophenylisocyanate or 3,5-dimethylphenylisocyanate.
作为反应原料的壳聚糖是完全脱乙酰化的壳聚糖,分子量在50000~300000。The chitosan used as the reaction raw material is a completely deacetylated chitosan with a molecular weight of 50,000-300,000.
所述的壳聚糖6-位羟基的保护中,三苯基氯甲烷直接对完全脱乙酰化的壳聚糖6-位进行修饰,一步法引入三苯基甲基作为保护基团。In the protection of the 6-position hydroxyl group of chitosan, triphenylchloromethane directly modifies the 6-position of chitosan which is completely deacetylated, and introduces triphenylmethyl group as a protecting group in one-step method.
壳聚糖或壳聚糖类衍生物中加入反应溶剂配成质量浓度为0.013~0.025g/mL,反应溶剂为二甲基亚砜(DMSO)。A reaction solvent is added to the chitosan or chitosan derivatives to form a mass concentration of 0.013-0.025 g/mL, and the reaction solvent is dimethyl sulfoxide (DMSO).
所述的氢键消除剂是氯化锂,其中氯化锂的浓度为0.075~0.100g/mL。The hydrogen bond eliminating agent is lithium chloride, wherein the concentration of lithium chloride is 0.075-0.100 g/mL.
壳聚糖类衍生物中加入浓盐酸和甲醇混合溶剂的混合比例为1:32。The mixing ratio of concentrated hydrochloric acid and methanol mixed solvent was added to chitosan derivatives was 1:32.
各步骤所述的隔离溶剂选自甲醇、异丙醇和乙酸乙酯中的一种或多种。The isolating solvent described in each step is selected from one or more of methanol, isopropanol and ethyl acetate.
得到的是壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-羟基衍生物。The chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl derivative was obtained.
本发明基于区域选择性化学修饰方法,利用壳聚糖葡萄糖单元上各个位置取代基反应活性的不同,以壳聚糖、三苯基氯甲烷以及具有侧基的苯基异氰酸酯为主要原料,控制合成了壳聚糖上2-位氨基与3-位羟基分别完全转化为苯基脲与苯基氨基甲酸酯,同时6-位为羟基的壳聚糖类衍生物。这样的壳聚糖类衍生物由于6-位上的羟基而依旧保留较高的反应活性,对其进一步修饰后就能够生成功能高分子材料,因此可以作为许多材料如壳聚糖类手性固定相的制备中间体。Based on the regioselective chemical modification method, the present invention utilizes the difference in reactivity of substituents at various positions on the glucose unit of chitosan, and uses chitosan, triphenylchloromethane and phenyl isocyanate with side groups as main raw materials to control the synthesis The 2-position amino group and the 3-position hydroxyl group on chitosan are completely transformed into phenyl urea and phenyl carbamate respectively, and the chitosan derivatives whose 6-position is a hydroxyl group are obtained. Such chitosan derivatives still retain high reactivity due to the hydroxyl group at the 6-position. After further modification, they can generate functional polymer materials, so they can be used as chitosan for many materials such as chitosan immobilization. Phase preparation intermediates.
本发明的有益效果在于:The beneficial effects of the present invention are:
1.本发明上述得到的壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-羟基衍生物结构规整,取代度高,壳聚糖上2-位氨基与3-位羟基分别完全转化为苯基脲与苯基氨基甲酸酯,同时6-位为羟基,衍生物依旧保留较高的反应活性。1. The chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl derivative obtained above in the present invention has a regular structure and a high degree of substitution, and the 2-position amino group and the 3- The hydroxyl group at the position is completely transformed into phenyl urea and phenyl carbamate respectively, while the 6-position is a hydroxyl group, and the derivatives still retain high reactivity.
2.本发明采用一步法,直接引入三苯基甲基对壳聚糖6-位羟基进行保护,避免了多步骤反应可能带来的期间损失和副反应。2. The present invention adopts a one-step method to directly introduce a triphenylmethyl group to protect the 6-hydroxyl group of chitosan, thereby avoiding possible period losses and side reactions caused by multi-step reactions.
3.本发明提供的一系列壳聚糖类衍生物,6-位处为活性基团羟基,对其进一步修饰后,可以制备结构与种类更为多样化的新型壳聚糖类衍生物。3. In a series of chitosan derivatives provided by the present invention, the 6-position is an active hydroxyl group. After further modification, novel chitosan derivatives with more diverse structures and types can be prepared.
附图说明Description of drawings
图1为本发明实施例步骤(1)所制备的壳聚糖-6-OTr的1H-NMR谱图。Fig. 1 is the 1 H-NMR spectrum of chitosan-6-OTr prepared in the step (1) of the embodiment of the present invention.
图2为本发明实施例步骤(2)所制备的壳聚糖-2-(3,5-二甲基苯基脲)-3-(3,5-二甲基苯基氨基甲酸酯)-6-OTr的红外光谱图。Fig. 2 is chitosan-2-(3,5-dimethylphenylurea)-3-(3,5-dimethylphenylcarbamate) prepared by step (2) of the embodiment of the present invention Infrared spectrum of -6-OTr.
图3为本发明实施例步骤(3)所制备的壳聚糖-2-(3,5-二甲基苯基脲)-3-(3,5-二甲基苯基氨基甲酸酯)-6-羟基的1H-NMR谱图。Fig. 3 is chitosan-2-(3,5-dimethylphenylurea)-3-(3,5-dimethylphenylcarbamate) prepared by step (3) of the embodiment of the present invention 1 H-NMR spectrum of -6-hydroxyl.
图4为本发明所涉及的反应方程式。Fig. 4 is the reaction equation involved in the present invention.
图5为优选的取代基的苯基。Figure 5 is a preferred substituent for phenyl.
具体实施方式Detailed ways
本发明合成的是一种新型的壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-羟基衍生物,所述的壳聚糖类衍生物的结构可如式1所示。What the present invention synthesizes is a kind of novel chitosan class-2-phenylurea-3-phenylcarbamate-6-hydroxy derivative, and the structure of described chitosan class derivative can be as formula 1 shown.
本发明所涉及的反应方程式如图4所述。上述式1及图4中其中,R表示苯基或任选取代基的苯基。取代基可以在苯环的适当位置,例如2-、3-、4-、5-、和/或6-位等。取代基的个数可以为1个、2个、3个或4个,优选1-2个。所述的苯基上的各取代基可以相同或不同,可以选自氢原子、卤素原子、烷基、烷氧基、硝基、氨基、烷硫基等。作为烷基,优选为C1-12烷基,更优选C1-6烷基,更优选C1-4烷基(例如甲基、乙基)。作为烷氧基,优选C1-12烷氧基,更优选C1-6烷氧基,更优选C1-4烷氧基(例如甲氧基、乙氧基)。作为卤素原子,可以为氟原子、氯原子、溴原子、碘原子,优选为氟原子、氯原子和溴原子。作为烷硫基,优选C1-12烷硫基,更优选C1-6烷硫基,更优选C1-4烷硫基(例如甲硫基、乙硫基)。The reaction equation involved in the present invention is as shown in FIG. 4 . In the above formula 1 and Fig. 4, R represents a phenyl group or a phenyl group optionally substituted. The substituents can be at appropriate positions of the benzene ring, such as 2-, 3-, 4-, 5-, and/or 6-positions, etc. The number of substituents can be 1, 2, 3 or 4, preferably 1-2. The substituents on the phenyl group may be the same or different, and may be selected from hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups, nitro groups, amino groups, alkylthio groups, and the like. The alkyl group is preferably a C 1-12 alkyl group, more preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group (eg methyl, ethyl). The alkoxy group is preferably a C 1-12 alkoxy group, more preferably a C 1-6 alkoxy group, and more preferably a C 1-4 alkoxy group (eg, methoxy, ethoxy). Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom, chlorine atom and bromine atom. The alkylthio group is preferably a C 1-12 alkylthio group, more preferably a C 1-6 alkylthio group, and more preferably a C 1-4 alkylthio group (eg methylthio, ethylthio).
优选地,R表示任选被1个或2个卤原子取代的苯基、任选被1个或2个C1-4烷基(例如甲基、乙基)取代的苯基、任选被1个或2个C1-4烷氧基(例如甲氧基、乙氧基)取代的苯基、或任选被1个或2个硝基取代的苯基等。Preferably, R represents phenyl optionally substituted by 1 or 2 halogen atoms, phenyl optionally substituted by 1 or 2 C 1-4 alkyl (such as methyl, ethyl), optionally substituted by 1 or 2 C 1-4 alkoxy (eg methoxy, ethoxy) substituted phenyl groups, or 1 or 2 nitro substituted phenyl groups, etc.
更进一步地,R优选为图5所述的基团。Furthermore, R is preferably the group described in FIG. 5 .
所述的壳聚糖类衍生物的制备方法,包括以下步骤:The preparation method of described chitosan derivatives, comprises the following steps:
(1)壳聚糖6-位羟基的保护;(1) protection of chitosan 6-position hydroxyl;
(2)壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-OTr衍生物的制备;(2) Preparation of chitosan-2-phenylurea-3-phenylcarbamate-6-OTr derivatives;
(3)壳聚糖6-位羟基的脱保护。(3) Deprotection of the 6-hydroxyl group of chitosan.
本发明步骤(1)中,作为壳聚糖原料,优选采用完全脱乙酰化的壳聚糖。壳聚糖原料的分子量优选30000~600000,更优选50000~300000。In the step (1) of the present invention, as the chitosan raw material, preferably fully deacetylated chitosan is used. The molecular weight of the chitosan raw material is preferably 30,000-600,000, more preferably 50,000-300,000.
本发明步骤(1)中,反应前在壳聚糖原料中加入反应溶剂来进行溶胀。溶胀时间优选10-60小时,优选24-55小时,进一步优选40-48小时。In the step (1) of the present invention, a reaction solvent is added to the chitosan raw material before the reaction to swell. The swelling time is preferably 10-60 hours, preferably 24-55 hours, more preferably 40-48 hours.
进一步地,优选在反应前,特别是溶胀前,将壳聚糖原料在高温进行真空干燥,温度优选为60-100℃,更优选为70-90℃,进一步优选80℃左右。干燥时间优选为1-20小时,更优选为4-10小时,进一步优选为4-6小时。Further, it is preferable to vacuum-dry the chitosan raw material at high temperature before reaction, especially before swelling, the temperature is preferably 60-100°C, more preferably 70-90°C, more preferably about 80°C. The drying time is preferably 1-20 hours, more preferably 4-10 hours, even more preferably 4-6 hours.
本发明步骤(1)中,作为反应加入的三苯基氯甲烷的量,加入的三苯基氯甲烷的摩尔质量优选是壳聚糖6-位羟基的摩尔质量的1.5-3倍,更优选2.0-3倍,进一步优选2.5-3倍。In step (1) of the present invention, as the amount of the triphenylchloromethane added in reaction, the molar mass of the triphenylchloromethane added is preferably 1.5-3 times of the molar mass of chitosan 6-position hydroxyl, more preferably 2.0-3 times, more preferably 2.5-3 times.
本发明步骤(1)中,作为反应时间,优选0.5-36小时,更优选12-24小时,进一步优选20-24小时。In step (1) of the present invention, the reaction time is preferably 0.5-36 hours, more preferably 12-24 hours, further preferably 20-24 hours.
本发明步骤(1)中,作为反应温度,适宜在高温下进行反应,优选50-120℃,更优选75-105℃,进一步优选80-100℃。In the step (1) of the present invention, as the reaction temperature, it is suitable to carry out the reaction at a high temperature, preferably 50-120°C, more preferably 75-105°C, even more preferably 80-100°C.
本发明步骤(2)中,作为苯基异氰酸酯或具有侧链的苯基异氰酸酯,优选为式(2)所示的具有与式(1)所示的R相对应的基团的苯基异氰酸酯。In the step (2) of the present invention, the phenyl isocyanate or the phenyl isocyanate having a side chain is preferably a phenyl isocyanate represented by formula (2) having a group corresponding to R represented by formula (1).
在式(2)中,基团表示与式(1)中的R相同的基团。R1即对应于基团R中所述的苯环上的氢或取代基。In formula (2), the group represents the same group as R in formula (1). R 1 corresponds to the hydrogen or substituent on the benzene ring described in the group R.
本发明步骤(2)中,优选的苯基异氰酸酯或具有侧链的苯基异氰酸酯示例选自苯基异氰酸酯、4-甲氧基苯基异氰酸酯、4-乙基苯基异氰酸酯、4-甲基苯基异氰酸酯、4-氟苯基异氰酸酯、4-氯苯基异氰酸酯、4-溴苯基异氰酸酯、4-硝基苯基异氰酸酯、2-氯苯基异氰酸酯、2-甲基苯基异氰酸酯、3-氯苯基异氰酸酯、3-甲基苯基异氰酸酯、3,5-二氯苯基异氰酸酯和3,5-二甲基苯基异氰酸酯中的一种或多种。In step (2) of the present invention, preferred phenyl isocyanates or phenyl isocyanates with side chains are exemplified from phenyl isocyanates, 4-methoxyphenyl isocyanates, 4-ethylphenyl isocyanates, 4-methylbenzene phenyl isocyanate, 4-fluorophenyl isocyanate, 4-chlorophenyl isocyanate, 4-bromophenyl isocyanate, 4-nitrophenyl isocyanate, 2-chlorophenyl isocyanate, 2-methylphenyl isocyanate, 3-chloro One or more of phenyl isocyanate, 3-methylphenyl isocyanate, 3,5-dichlorophenyl isocyanate and 3,5-dimethylphenyl isocyanate.
本发明步骤(2)中,作为反应加入的苯基异氰酸酯或具有侧链的苯基异氰酸酯的量,加入的苯基异氰酸酯或具有不同侧链的苯基异氰酸酯的摩尔质量优选是壳聚糖2-位氨基和3-位羟基的总摩尔质量的1.5-3倍,更优选2.0-3倍,进一步优选2.5-3倍。In step (2) of the present invention, the phenyl isocyanate added as reaction or the amount of the phenyl isocyanate with side chain, the molar mass of the phenyl isocyanate that adds or the phenyl isocyanate with different side chain is preferably chitosan 2- 1.5-3 times, more preferably 2.0-3 times, and even more preferably 2.5-3 times the total molar mass of the amino group at the 3-position and the hydroxyl group at the 3-position.
本发明步骤(2)中,作为反应时间,优选0.5-24小时,更优选0.5-20小时,进一步优选1-12小时。In step (2) of the present invention, the reaction time is preferably 0.5-24 hours, more preferably 0.5-20 hours, further preferably 1-12 hours.
本发明步骤(2)中,作为反应温度,适宜在高温下进行反应,优选40-150℃,更优选55-105℃,进一步优选60-100℃。In the step (2) of the present invention, as the reaction temperature, it is suitable to carry out the reaction at a high temperature, preferably 40-150°C, more preferably 55-105°C, further preferably 60-100°C.
本发明步骤(1)-(2)中,反应优选在溶剂中进行,作为反应溶剂,优选为二甲基亚砜,例如无水二甲基亚砜。In steps (1)-(2) of the present invention, the reaction is preferably carried out in a solvent, and the reaction solvent is preferably dimethyl sulfoxide, such as anhydrous dimethyl sulfoxide.
本发明步骤(1)-(2)中,在反应前,任选地加入氢键消除剂,优选进行搅拌。氢键消除剂优选为氯化锂。搅拌时间优选为1-20小时,优选3-15小时,更优选4-12小时。In the steps (1)-(2) of the present invention, before the reaction, a hydrogen bond eliminating agent is optionally added, preferably under stirring. The hydrogen bond breaker is preferably lithium chloride. The stirring time is preferably 1-20 hours, preferably 3-15 hours, more preferably 4-12 hours.
本发明步骤(3)中,作为反应加入的浓盐酸与甲醇的体积比优选为1:20~50,更优选1:20~35,进一步优选1:30~35。In the step (3) of the present invention, the volume ratio of the concentrated hydrochloric acid and methanol added as the reaction is preferably 1:20-50, more preferably 1:20-35, further preferably 1:30-35.
本发明步骤(3)中,作为反应时间,优选1-24小时,更优选12-24小时,进一步优选20-24小时。In the step (3) of the present invention, the reaction time is preferably 1-24 hours, more preferably 12-24 hours, and even more preferably 20-24 hours.
上述各步骤任选在非活性气体条件下进行。所述非活性气体可以选自氮气、氦气和氩气。优选为氮气。The above steps are optionally carried out under inert gas conditions. The inert gas may be selected from nitrogen, helium and argon. Nitrogen is preferred.
在反应完成后,任选将反应溶液加入到隔离溶剂中,形成壳聚糖类衍生物沉淀析出。反应溶液与隔离溶剂的体积比优选为1:2~40,更优选1:5~30,进一步优选1:10~20。隔离溶剂优选为选自乙醚、甲醇、乙酸乙酯、异丙基中的一种或多种。After the reaction is completed, the reaction solution is optionally added to the isolation solvent to form chitosan derivatives to precipitate out. The volume ratio of the reaction solution to the isolation solvent is preferably 1:2-40, more preferably 1:5-30, further preferably 1:10-20. The isolating solvent is preferably one or more selected from diethyl ether, methanol, ethyl acetate, and isopropyl.
任选将得到的沉淀在35-100℃、优选40-80℃,更优选60-80℃下真空干燥24~60小时,优选40-48小时。Optionally, the obtained precipitate is vacuum-dried at 35-100°C, preferably 40-80°C, more preferably 60-80°C, for 24-60 hours, preferably 40-48 hours.
具体地,本发明的制备方法可以包括以下步骤:Specifically, the preparation method of the present invention may comprise the following steps:
(1)壳聚糖6-位羟基的保护:取完全脱乙酰化的壳聚糖在60-100℃真空干燥,加入反应溶剂进行溶胀,于室温下加入氢键消除剂,加入三苯基氯甲烷,在反应温度为80-100℃反应6-24h,将反应产物滴入隔离溶剂中,得到壳聚糖-6-OTr。(1) Protection of the 6-hydroxyl group of chitosan: take the completely deacetylated chitosan and dry it in vacuum at 60-100°C, add a reaction solvent for swelling, add a hydrogen bond elimination agent at room temperature, and add triphenyl chloride methane, react at a reaction temperature of 80-100° C. for 6-24 hours, and drop the reaction product into an isolation solvent to obtain chitosan-6-OTr.
(2)壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-OTr衍生物的制备:向步骤(1)得到的壳聚糖6-OTr中加入反应溶剂进行溶胀,于室温下加入氢键消除剂,加入所述的苯基异氰酸酯或具有侧基的苯基异氰酸酯,在反应温度为40-150℃反应,反应时间为0.5-24h,将反应产物滴入隔离溶剂中,得到壳聚糖2-苯基脲-3-苯基氨基甲酸酯-6-OTr。(2) Preparation of chitosan-2-phenylurea-3-phenylcarbamate-6-OTr derivatives: adding reaction solvent to the chitosan 6-OTr obtained in step (1) to swell , add a hydrogen bond elimination agent at room temperature, add the phenyl isocyanate or phenyl isocyanate with side groups, react at a reaction temperature of 40-150°C, and a reaction time of 0.5-24h, drop the reaction product into an isolation solvent In, chitosan 2-phenylurea-3-phenylcarbamate-6-OTr was obtained.
(3)壳聚糖6-位羟基的脱保护:向步骤(2)得到的壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-OTr中加入甲醇与浓盐酸,在反应温度为30-70℃反应,反应时间为12-24h,将反应产物滴入隔离溶剂中,得到壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-羟基。(3) Deprotection of the 6-position hydroxyl of chitosan: add methanol and concentrated hydrochloric acid in the chitosan-2-phenylurea-3-phenylcarbamate-6-OTr that step (2) obtains, The reaction temperature is 30-70 DEG C, the reaction time is 12-24h, and the reaction product is dropped into the isolation solvent to obtain chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl.
例如,本发明的制备方法可以如下进行:For example, the preparation method of the present invention can be carried out as follows:
(1)壳聚糖6-位羟基的保护:在真空高温下,搅拌完全脱乙酰化的壳聚糖原料4-6小时,非活性气体保护下加入无水二甲基亚砜溶胀壳聚糖24-48小时,室温下加入无水氯化锂4-12小时,高温非活性气体下,加入三苯基氯甲烷反应1-36h。之后将壳聚糖类衍生物反应溶液逐滴滴入隔离溶剂中进行隔离,析出壳聚糖类衍生物,采用离心机进行离心获得壳聚糖类衍生物,在40-80℃下真空干燥24-48小时。即获得壳聚糖-6-OTr。(1) Protection of the 6-hydroxyl group of chitosan: Stir the completely deacetylated chitosan raw material for 4-6 hours under vacuum and high temperature, and add anhydrous dimethyl sulfoxide to swell the chitosan under the protection of inert gas 24-48 hours, add anhydrous lithium chloride at room temperature for 4-12 hours, under high-temperature inactive gas, add triphenylchloromethane to react for 1-36 hours. After that, the reaction solution of chitosan derivatives was dropped dropwise into the isolation solvent for isolation, and the chitosan derivatives were separated out, and the chitosan derivatives were obtained by centrifugation with a centrifuge, and vacuum-dried at 40-80°C for 24 -48 hours. That is to obtain chitosan-6-OTr.
(2)壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-OTr衍生物的制备:取步骤(1)得到的壳聚糖6-OTr,高温非活性气体保护下加入无水二甲基亚砜溶胀壳聚糖24-48小时,室温下加入无水氯化锂4-12小时,高温非活性气体下,加入带有不同侧链的苯基异氰酸酯反应1-24h。之后将壳聚糖类衍生物反应溶液逐滴滴入隔离溶剂中进行隔离,析出壳聚糖类衍生物,采用离心机进行离心获得壳聚糖类衍生物,在40-80℃下真空干燥24-48小时。即获得壳聚糖2-苯基脲-3-苯基氨基甲酸酯-6-OTr。(2) Preparation of chitosan-2-phenylurea-3-phenylcarbamate-6-OTr derivatives: get the chitosan 6-OTr that step (1) obtains, high temperature non-reactive gas protection Add anhydrous dimethyl sulfoxide to swell chitosan at low temperature for 24-48 hours, add anhydrous lithium chloride at room temperature for 4-12 hours, and add phenylisocyanate with different side chains to react 1- 24h. After that, the reaction solution of chitosan derivatives was dropped dropwise into the isolation solvent for isolation, and the chitosan derivatives were separated out, and the chitosan derivatives were obtained by centrifugation with a centrifuge, and vacuum-dried at 40-80°C for 24 -48 hours. That is, chitosan 2-phenylurea-3-phenylcarbamate-6-OTr was obtained.
(3)壳聚糖6-位羟基的脱保护:取步骤(2)得到的壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-OTr,非活性气体保护下,加入体积比为1:30~35的浓盐酸与甲醇混合溶剂,在30-70℃下反应12-24h,之后将壳聚糖类衍生物反应溶液逐滴滴入隔离溶剂中进行隔离,采用离心机进行离心获得壳聚糖类衍生物,在40-80℃下真空干燥24-48小时。即得到壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-羟基。(3) deprotection of the 6-position hydroxyl group of chitosan: get the chitosan-2-phenylurea-3-phenylcarbamate-6-OTr that step (2) obtains, under the protection of inert gas, Add a mixed solvent of concentrated hydrochloric acid and methanol with a volume ratio of 1:30~35, react at 30-70°C for 12-24h, then drop the reaction solution of chitosan derivatives into the isolation solvent for isolation, and use centrifugation Machine centrifugation to obtain chitosan derivatives, vacuum drying at 40-80 ° C for 24-48 hours. That is, chitosan-2-phenylurea-3-phenylcarbamate-6-hydroxyl was obtained.
本发明可以运用核磁共振氢谱对所获得壳聚糖类衍生物进行测试分析,确定其结构以及2-位氨基与3-位羟基是否完全转化为苯基脲与氨基甲酸酯,6-位是否为羟基。The present invention can test and analyze the obtained chitosan derivatives by proton nuclear magnetic resonance spectrum to determine whether its structure and the 2-position amino group and the 3-position hydroxyl group are completely converted into phenylurea and carbamate, and whether the 6-position Is it hydroxyl.
下面以实施例对本发明做更详细地描述,但本发明并不局限于此。The present invention is described in more detail with examples below, but the present invention is not limited thereto.
壳聚糖-2-(3,5-二甲基苯基脲)-3-(3,5-二甲基苯基氨基甲酸酯)-6-羟基衍生物的合成步骤:The synthetic steps of chitosan-2-(3,5-dimethylphenylurea)-3-(3,5-dimethylphenylcarbamate)-6-hydroxy derivatives:
(1)壳聚糖6-位羟基的保护。(1) Protection of the 6-hydroxyl group of chitosan.
a.在80℃下,0.20g完全脱乙酰化壳聚糖(分子量50000~300000),搅拌并且真空干燥4h。a. At 80° C., 0.20 g of completely deacetylated chitosan (molecular weight: 50,000 to 300,000), stirred and vacuum-dried for 4 hours.
b.氮气保护下,加入12mL无水二甲基亚砜(DMSO),溶胀48h。b. Under nitrogen protection, add 12 mL of anhydrous dimethyl sulfoxide (DMSO), and swell for 48 hours.
c.室温下,加入0.60g氯化锂,搅拌4h。c. At room temperature, add 0.60 g of lithium chloride and stir for 4 hours.
d.在100℃下,氮气保护,加入三苯基氯甲烷0.70g(摩尔质量为6-位羟基的2.0倍量),反应24h。d. At 100°C, under nitrogen protection, add 0.70 g of triphenylchloromethane (the molar mass is 2.0 times that of the 6-hydroxyl group), and react for 24 hours.
e.将上述溶液采用滴管滴加到200mL乙酸乙酯/异丙醇(V/V,70/30)中,析出壳聚糖类衍生物沉淀物。e. The above solution was added dropwise into 200 mL of ethyl acetate/isopropanol (V/V, 70/30) with a dropper, and a chitosan derivative precipitate was precipitated.
f.采用离心机进行离心,并在离心过程中用大量乙酸乙酯洗涤产物。f. Use a centrifuge to centrifuge, and wash the product with a large amount of ethyl acetate during the centrifugation process.
g.在60℃下,真空干燥48h,即获得产率为84.49%的壳聚糖-6-OTr衍生物。g. Vacuum drying at 60° C. for 48 hours to obtain a chitosan-6-OTr derivative with a yield of 84.49%.
1H-NMR谱图如附图1所示:1H-NMR(500MHz,80℃,氘代DMSO,δ/ppm):3.78-5.08(m,7H,Glucose-H),7.26(s,15H,Phenyl-H)。从核磁图中ppm=7.26处出现苯基峰可以说明壳聚糖6-位被三苯基甲基修饰并保护。 The 1 H-NMR spectrum is shown in Figure 1: 1 H-NMR (500MHz, 80°C, deuterated DMSO, δ/ppm): 3.78-5.08(m, 7H, Glucose-H), 7.26(s, 15H , Phenyl-H). The appearance of a phenyl peak at ppm=7.26 in the NMR diagram indicates that the 6-position of chitosan is modified and protected by a triphenylmethyl group.
(2)壳聚糖类-2-苯基脲-3-苯基氨基甲酸酯-6-OTr衍生物的制备。(2) Preparation of chitosan-2-phenylurea-3-phenylcarbamate-6-OTr derivatives.
a.取步骤(1)得到的壳聚糖类衍生物0.20g。a. Get 0.20 g of chitosan derivatives obtained in step (1).
b.氮气保护下,加入8mL无水二甲基亚砜(DMSO),溶胀48h。b. Under nitrogen protection, add 8 mL of anhydrous dimethyl sulfoxide (DMSO), and swell for 48 hours.
c.室温下,加入0.60g氯化锂,搅拌4h。c. At room temperature, add 0.60 g of lithium chloride and stir for 4 hours.
d.在80℃下,氮气保护,加入3,5-二甲基苯基异氰酸酯0.32mL(摩尔质量为2-位氨基和3-位羟基的的总摩尔质量的2.5倍量),反应24h。d. At 80°C, under nitrogen protection, add 0.32 mL of 3,5-dimethylphenylisocyanate (the molar mass is 2.5 times the total molar mass of the 2-position amino group and the 3-position hydroxyl group), and react for 24 hours.
e.将上述溶液采用滴管滴加到160mL甲醇溶剂中,析出壳聚糖类衍生物沉淀物。e. The above solution was added dropwise into 160mL of methanol solvent with a dropper, and the chitosan derivative precipitate was precipitated.
f.采用离心机进行离心,并在离心过程中用大量甲醇洗涤产物。f. Use a centrifuge to carry out centrifugation, and wash the product with a large amount of methanol during the centrifugation process.
g.在60℃下,真空干燥48h,即获得产率为62.09%的壳聚糖-2-苯基脲-3-苯基氨基甲酸酯-6-OTr衍生物。g. Vacuum drying at 60° C. for 48 hours to obtain a chitosan-2-phenylurea-3-phenylcarbamate-6-OTr derivative with a yield of 62.09%.
1H-NMR谱图如附图2所示:1H-NMR(400MHz,80℃,氘代DMSO,δ/ppm):2.13(s,12H,-CH3),3.63-4.94(m,7H,Glucose-H),6.56-6.98(d,21H,Phenyl-H),5.89(s,1H,Urea-H),7.94(s,1H,Urea-H),8.78(s,1H,Carbamate-H)。 The 1 H-NMR spectrum is shown in Figure 2: 1 H-NMR (400MHz, 80°C, deuterated DMSO, δ/ppm): 2.13 (s, 12H, -CH 3 ), 3.63-4.94 (m, 7H , Glucose-H), 6.56-6.98 (d, 21H, Phenyl-H), 5.89 (s, 1H, Urea-H), 7.94 (s, 1H, Urea-H), 8.78 (s, 1H, Carbamate-H ).
(3)壳聚糖6-位羟基的脱保护。(3) Deprotection of the 6-hydroxyl group of chitosan.
a.取步骤(2)得到的壳聚糖类衍生物0.20g。a. get the chitosan derivative 0.20g that step (2) obtains.
b.在50℃下,氮气保护,加入甲醇/HCl(V/V,97/3)12mL,反应24h。b. At 50°C, under nitrogen protection, 12 mL of methanol/HCl (V/V, 97/3) was added and reacted for 24 h.
c.将上述混合物采用滴管滴加到200mL甲醇中,搅拌0.5h。c. Add the above mixture dropwise into 200mL of methanol with a dropper, and stir for 0.5h.
d.采用离心机进行离心,并在离心过程中用大量甲醇将产物洗涤至中性。d. Use a centrifuge to centrifuge, and wash the product to neutrality with a large amount of methanol during the centrifugation process.
e.在60℃下,真空干燥48h,即获得产率为78.06%的壳聚糖-2-(3,5-二甲基苯基脲)-3-(3,5-二甲基苯基氨基甲酸酯)-6-羟基衍生物e. At 60°C, vacuum-dried for 48 hours to obtain chitosan-2-(3,5-dimethylphenylurea)-3-(3,5-dimethylphenylurea) with a yield of 78.06% Carbamate)-6-hydroxy derivatives
1H-NMR谱图如附图3所示:1H-NMR(400MHz,80℃,氘代DMSO,δ/ppm):2.15(s,12H,-CH3),3.32-4.88(m,8H,Glucose-H),6.49-7.00(d,6H,Phenyl-H),5.92(s,1H,Urea-H),8.04(s,1H,Urea-H),8.80(s,1H,Carbamate-H)。由质子峰的峰面积可以得出结论,反应的取代率大于80%。 The 1 H-NMR spectrum is shown in Figure 3: 1 H-NMR (400MHz, 80°C, deuterated DMSO, δ/ppm): 2.15 (s, 12H, -CH 3 ), 3.32-4.88 (m, 8H , Glucose-H), 6.49-7.00 (d, 6H, Phenyl-H), 5.92 (s, 1H, Urea-H), 8.04 (s, 1H, Urea-H), 8.80 (s, 1H, Carbamate-H ). From the peak area of the proton peak it can be concluded that the substitution rate of the reaction is greater than 80%.
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