WO2019001473A1 - Dendritic polyglycol derivative, preparation method therefor, and application thereof - Google Patents

Dendritic polyglycol derivative, preparation method therefor, and application thereof Download PDF

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WO2019001473A1
WO2019001473A1 PCT/CN2018/093134 CN2018093134W WO2019001473A1 WO 2019001473 A1 WO2019001473 A1 WO 2019001473A1 CN 2018093134 W CN2018093134 W CN 2018093134W WO 2019001473 A1 WO2019001473 A1 WO 2019001473A1
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dendritic
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polyglycol
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主辉
林美娜
赵宣
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北京键凯科技股份有限公司
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Abstract

Provided are a dendritic polyglycol derivative, a preparation method therefor, and an application thereof. The dendritic polyglycol derivative has a structure of formula (I), a plurality of terminal functional groups, and better water solubility when compared to straight-chain polyglycols. The dendritic polyglycol derivative can resolve the issue of insufficient water solubility caused by an increase in load when polyglycols are used to modify insoluble drugs. The preparation method further provided for the dendritic polyglycol derivative has mild reaction conditions, and is environmentally friendly, low cost, and easy to industrialize.

Description

一种树状多缩乙二醇衍生物及其制备方法和应用Dendritic polyglycol derivative and preparation method and application thereof 技术领域Technical field
本发明涉及化工技术领域，具体涉及一种树状多缩乙二醇衍生物及其制备方法和应用。The invention relates to the technical field of chemical industry, in particular to a dendritic polyglycol derivative and a preparation method and application thereof.
背景技术Background technique
树状(或称树枝状)聚合物是一类具有高度支化结构的非线形聚合物，其结构具有极好的几何对称性，而且分子的体积、形状可以得到精确控制。由于树状聚合物的独特结构，使其具有传统线形聚合物所不具备的低粘度、高流变性、含大量末端官能团等一系列独特的物理和化学特性，在超分子化学、生物医学、光化学、电化学、催化剂等领域具有广阔的应用前景。Dendritic (or dendritic) polymers are a class of non-linear polymers with highly branched structures that have excellent geometric symmetry and that the size and shape of the molecules can be precisely controlled. Due to the unique structure of the dendrimer, it has a series of unique physical and chemical properties such as low viscosity, high rheology and a large number of terminal functional groups which are not available in traditional linear polymers. In supramolecular chemistry, biomedicine, photochemistry , Electrochemistry, catalysts and other fields have broad application prospects.
而目前已成功制备的树枝状聚合物仍存在一定的不足：However, dendrimers that have been successfully prepared still have certain deficiencies:
(1)含大量N原子的树枝状聚合物的毒性(1) Toxicity of dendrimers containing a large amount of N atoms
以聚酰胺-胺型树枝状高分子(简称：PAMAM)为例，由于其含大量N原子，进入生物体后会形成阳离子，这种阳离子，特别是大分子的表面的阳离子，与细胞膜表面阴离子的相互作用，破坏了细胞的生物化学环境，因而呈现出了一定的毒性；Taking polyamide-amine dendrimer (abbreviation: PAMAM) as an example, since it contains a large amount of N atoms, it will form a cation after entering the organism. This cation, especially the surface cation of the macromolecule, and the anion on the cell membrane surface The interaction, which destroys the biochemical environment of the cells, and thus exhibits certain toxicity;
(2)含芳环的树枝状聚合物的生物降解性(2) Biodegradability of dendrimers containing aromatic rings
以谷氨酸-丙氨酸二肽树枝状聚合物为例，谷氨酸作为重复单元的构成部分，所合成的树枝状聚合物代数越高，则所携带的芳环越多，芳环在生物体内难以被迅速降解，也难以被完全排出，因而在生物体内滞留的时间变长，对生物体健康不利；Taking glutamic acid-alanine dipeptide dendrimer as an example, glutamic acid is a component of a repeating unit. The higher the dendrimer algebra synthesized, the more aromatic rings are carried, and the aromatic ring is It is difficult to be rapidly degraded in the living body, and it is difficult to be completely discharged, so that the time of staying in the living body becomes long, which is unfavorable to the health of the living body;
(3)与亲水性、强极性负载物的兼容性(3) Compatibility with hydrophilic and highly polar loads
现有的树枝状聚合物多数呈现出疏水性质，限制了其与大量亲水性、强极性药物的结合运用，虽然通过聚乙二醇的表面修饰可以解决接枝的问题，但其内部疏水空间却得不到利用，树枝状聚合物特有的包裹负载功能被浪费。Most of the existing dendrimers exhibit hydrophobic properties, which limits their combination with a large number of hydrophilic and highly polar drugs. Although the surface modification of polyethylene glycol can solve the problem of grafting, its internal hydrophobicity Space is not available, and the unique load-carrying function of dendrimers is wasted.
聚乙二醇(简称：PEG)是一种用途极为广泛的聚醚高分子化合物，能够溶解于水和许多溶剂中，由于其良好的水溶性及生物相容性，且无免疫原性，常常用于修饰难溶药物来增加其水溶性。有研究报道称，PEG40k对喜树碱的20-羟基进行修饰，修饰后的PEG-喜树碱在水中的溶解度约为2mg/mL，是原药喜树碱的溶解度(0.0025mg/mL)的800倍。喜树碱结构中的内酯和20位的叔醇都是抑制拓扑酶的基本活性部位，PEG对20-羟基的修饰在提高了药物的水溶性的同时，还提高了内酯的稳定性，并赋予了药物抗肿瘤的靶向性，动物实验发现前药在肿瘤部位的药物浓度是喜树碱的30倍，大大提高了其疗效，目前该药物已进入临床阶段。除了喜树碱，PEG对紫杉醇、灯盏乙素等的修饰同样也能大大增强其水溶性，改善油水分布情况，从而增加疗效，PEG修饰的紫杉醇、阿霉素和阿糖胞苷等前药也进入了临床试验阶段。Polyethylene glycol (abbreviation: PEG) is an extremely versatile polyether polymer compound that can be dissolved in water and many solvents. Due to its good water solubility and biocompatibility, it is not immunogenic. It is used to modify poorly soluble drugs to increase their water solubility. It has been reported that PEG40k modifies the 20-hydroxyl group of camptothecin, and the solubility of modified PEG-camptothecin in water is about 2 mg/mL, which is the solubility of the original drug camptothecin (0.0025 mg/mL). 800 times. The lactone in the camptothecin structure and the tertiary alcohol in the 20 position are the basic active sites for inhibiting the topoisomerase. The modification of the 20-hydroxyl group by PEG improves the water solubility of the drug and improves the stability of the lactone. And the drug is given anti-tumor targeting. Animal experiments have found that the drug concentration of the prodrug at the tumor site is 30 times that of camptothecin, which greatly improves its efficacy. At present, the drug has entered the clinical stage. In addition to camptothecin, the modification of PEG to paclitaxel, scutellarin, etc. can also greatly enhance its water solubility, improve oil-water distribution, thereby increasing the efficacy, and PEG-modified prodrugs such as paclitaxel, doxorubicin and cytarabine Entered the clinical trial phase.
本发明的发明人经过实验和研究制备得到一种树状多缩乙二醇衍生物，其具有良好的水溶性和生物相容性，且毒性非常低，可用作载体修饰难溶性药物，提高其水溶性的同时，由于该树状多缩乙二醇衍生物具有多个末端官能团，可增加药物负载量，提高其生物利用度。The inventors of the present invention have obtained a dendritic polyglycol derivative obtained by experiments and research, which has good water solubility and biocompatibility, and has very low toxicity, and can be used as a carrier for modifying poorly soluble drugs and improving At the same time of water solubility, since the dendritic polyglycol derivative has a plurality of terminal functional groups, the drug loading can be increased and the bioavailability can be improved.
发明内容Summary of the invention
本发明提供一种树状多缩乙二醇衍生物，其具有式(Ⅰ)的结构：The present invention provides a dendritic polyglycol derivative having the structure of formula (I):
Figure PCTCN2018093134-appb-000001
Figure PCTCN2018093134-appb-000001
其中，among them,
A 1、A 2、D 1和D 2为相同或不同的Y-X-结构，或相同或不同的
Figure PCTCN2018093134-appb-000002
结构；J、K为相同或不同的Y-X-结构； A 1 , A 2 , D 1 and D 2 are the same or different YX-structures, or the same or different
Figure PCTCN2018093134-appb-000002
Structure; J, K are the same or different YX-structures;
R a1-4、R b1-2和R d1-4(即R a1、R a2、R a3、R a4、R b1、R b2、R d1、R d2、R d3和R d4)、R j和R k为连接基团，独立地选自：-(CH 2) r-、-(CR 1R 2) r-、-(CH 2) rNH-、-NHCO(CH 2) r-、-(CH 2) rCONH-和-CO(CH 2) r-中的一种或多种的组合，r为0-30的整数(具体如0、1、2、3、4、5、6、7、8、9、10、15、20、25或30)， R a1-4 , R b1-2 and R d1-4 (ie R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R d1 , R d2 , R d3 and R d4 ), R j and R k is a linking group independently selected from: -(CH 2 ) r -, -(CR 1 R 2 ) r -, -(CH 2 ) r NH-, -NHCO(CH 2 ) r -, -( CH 2 ) r Combination of one or more of CONH- and -CO(CH 2 ) r -, r is an integer from 0 to 30 (specifically, 0, 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 15, 20, 25 or 30),
R 1和R 2独立地选自：-H、C1-C6的烷基、-OR'、-NHR'、-N(R') 2、-CN、-F、-Cl、-Br、-I、-COR'、-COOR'、-OCOR'、-CONHR'和-CON(R') 2中的一种或多种的组合， R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
R'选自：-H、C1-C6的烷基、-F、-Cl、-Br和-I，R' is selected from the group consisting of: -H, C1-C6 alkyl, -F, -Cl, -Br and -I,
B为与A 1、A 2、D 1和D 2(J、K)相同或不同的Y-X-结构； B is the same or different YX-structure as A 1 , A 2 , D 1 and D 2 (J, K);
X为连接基团，选自：-(CH 2) i-、-(CH 2) iNH-、-CO(CH 2) i-、-(CH 2) iOCOO-、-(CH 2) iOCONH-、-(CH 2) iNHCONH-、-OC(CH 2) iCOO-、-(CH 2) iCOO-和-(CH 2) iCONH-中的一种或两种以上的组合，i为0-10的整数(具体可为0、1、2、3、4、5、6、7、8、9或10)； X is a linking group selected from: -(CH 2 ) i -, -(CH 2 ) i NH-, -CO(CH 2 ) i -, -(CH 2 ) i OCOO-, -(CH 2 ) i One or a combination of two or more of OCONH-, -(CH 2 ) i NHCONH-, -OC(CH 2 ) i COO-, -(CH 2 ) i COO-, and -(CH 2 ) i CONH-, i is an integer from 0 to 10 (specifically 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
Y为端基，选自：C1-C6的烷基、C1-C6的烷氧基、H(氢原子)、羟基、氨基、氨甲基、马来酰亚胺基、羧基、酯基、巯基、琥珀酰亚胺碳酸酯、琥珀酰亚胺乙酸酯、琥珀酰亚胺丙酸酯、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸酯基、叠氮基、戊二酸基、酰肼基、炔基、对硝基苯碳酸酯基、异氰酸基、硅烷基、羧甲基、乙烯砜基和维生素H残基中的一种；Y is a terminal group selected from the group consisting of: C1-C6 alkyl group, C1-C6 alkoxy group, H (hydrogen atom), hydroxyl group, amino group, aminomethyl group, maleimide group, carboxyl group, ester group, fluorenyl group , succinimide carbonate, succinimide acetate, succinimide propionate, succinimide succinate, succinimidyl, dithiopyridyl, propionate, aldehyde, Anthranyl ester, acrylate group, acrylate group, azido group, glutaric acid group, hydrazide group, alkynyl group, p-nitrophenyl carbonate group, isocyanate group, silane group, carboxymethyl group, vinyl sulfone group And one of the vitamin H residues;
E 1-7、E j和E k为相同或不同的多缩乙二醇基团(OCH 2CH 2) m，m为0-100的整数(具体如0-20(如0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)、30-50(如30、35、40、45或50)或50-100(如50、60、70、80、90或100))； E 1-7 , E j and E k are the same or different polyglycol group (OCH 2 CH 2 ) m , m is an integer from 0 to 100 (specifically 0-20 (eg 0, 1, 2) , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), 30-50 (eg 30, 35, 40, 45 Or 50) or 50-100 (such as 50, 60, 70, 80, 90 or 100));
L 1-3和L n为支化点，独立地选自式(II)-(Ⅷ)的结构中的一种或两种以上的组合： L 1-3 and L n are branching points independently selected from one or a combination of two or more of the structures of the formulae (II) to (VIII):
Figure PCTCN2018093134-appb-000003
Figure PCTCN2018093134-appb-000003
Z选自：O、S、NH、NHCO、CO、COO、OC(O)和(CH 2) s中的一种，s为0-10的整数(具体如0、1、2、3、4、5、6、7、8、9或10)； Z is selected from one of: O, S, NH, NHCO, CO, COO, OC(O), and (CH 2 ) s , and s is an integer from 0 to 10 (specifically, 0, 1, 2, 3, 4) , 5, 6, 7, 8, 9 or 10);
p为0-10的整数(具体如0、1、2、3、4、5、6、7、8、9或10)；p is an integer from 0 to 10 (specifically, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
W为O或S；W is O or S;
V为O或NH。V is O or NH.
在本发明的一个实施方式中，所述R a1、R a2、R a3、R a4、R b1、R b2、R d1、R d2、R d3、R d4、R j和R k为相同或不同的-(CH 2) r-，r选自0-10的整数，更优选为0-5的整数，如0、1、2、3、4和5。 In one embodiment of the invention, the R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R d1 , R d2 , R d3 , R d4 , R j and R k are the same or different -(CH 2 ) r -,r is selected from an integer from 0 to 10, more preferably an integer from 0 to 5, such as 0, 1, 2, 3, 4 and 5.
在本发明的一个优选实施例中，所述A 1、A 2、D 1、D 2和B为相同或不同的Y-X-结构，所述树状多缩乙二醇衍生物为四臂树状多缩乙二醇衍生物。 In a preferred embodiment of the present invention, the A 1 , A 2 , D 1 , D 2 and B are the same or different YX-structures, and the dendritic polyglycol derivative is a four-armed tree Polyethylene glycol derivatives.
在本发明的另一个优选实施例中，所述A 1、A 2、D 1和D 2为相同或不同的
Figure PCTCN2018093134-appb-000004
结构，所述树状多缩乙二醇衍生物可为八臂树状多缩乙二醇衍生物。 In another preferred embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are the same or different
Figure PCTCN2018093134-appb-000004
In the structure, the dendritic polyglycol derivative may be an eight-arm dendritic polyglycol derivative.
本领域技术人员在现有技术和本发明的基础上对B采用支化结构(如
Figure PCTCN2018093134-appb-000005
)，还可得到六臂、八臂、十臂等树状多缩乙二醇衍生物，凡在本发明的精神和原则之内，无需创造性劳动所作出的任何修改、等同替换等，均应包含在本发明的保护范围内。 Those skilled in the art use branched structures for B on the basis of the prior art and the present invention (eg
Figure PCTCN2018093134-appb-000005
), it is also possible to obtain a tree-shaped polyglycol derivative such as a six-arm, an eight-arm, a ten-arm, etc., and any modifications, equivalent substitutions, etc., which are not required to be creatively worked within the spirit and principles of the present invention, should be obtained. It is included in the scope of protection of the present invention.
具体地，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，优选为-(CH 2) i-。 Specifically, the X is selected from a combination of one or more of -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 ) i NH-, and (CH 2 ) i CONH-, It is preferably -(CH 2 ) i -.
具体地，所述连接基团X中i为0、1、2、3或4。Specifically, i in the linking group X is 0, 1, 2, 3 or 4.
在本发明的一个优选实施例中，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 In a preferred embodiment of the invention, said X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
在本发明的一个实施方式中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。In one embodiment of the invention, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a fluorenyl group, a carboxyl group, an ester group, an aldehyde group, an acryl group, and a maleimide group. .
在本发明的一个优选实施例中，所述的A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种。 In a preferred embodiment of the invention, said A 1 , A 2 , D 1 and D 2 are independently selected from the group consisting of: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO And one of -CH 2 CH 2 CH 2 CHO.
在本发明的一个更优选的实施例中，所述的A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种。 In a more preferred embodiment of the invention, said A 1 , A 2 , D 1 and D 2 are independently selected from the group consisting of: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, -CH One of 2 CH 2 COOH and -CH 2 CH 2 N 3 .
在本发明的一个优选实施例中，所述的B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种。 In a preferred embodiment of the invention, said B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and - One of CH 2 CH 2 CH 2 CHO.
具体地，多缩乙二醇基团(OCH 2CH 2) m中m为0-20的整数，优选为0-12的整数；更具体地，m为0、1、2、3、4、5、6、7或8； Specifically, m in the polyglycol group (OCH 2 CH 2 ) m is an integer of 0-20, preferably an integer of 0-12; more specifically, m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
具体地，Z选自：O、NH、NHCO和(CH 2) s中的一种，更具体为O或NHCO； Specifically, Z is selected from the group consisting of: O, NH, NHCO, and (CH 2 ) s , more specifically O or NHCO;
具体地，s为0-5的整数，如0、1、2、3、4或5；Specifically, s is an integer of 0-5, such as 0, 1, 2, 3, 4 or 5;
具体地，p为0-5的整数，如0、1、2、3、4或5。Specifically, p is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例中，所述L 1-3和L n具有式(II)或式(III)的结构。 In a preferred embodiment of the invention, said L 1-3 and L n have the structure of formula (II) or formula (III).
在本发明的一个更优选的实施例中，所述L 1-3和L n独立地选自
Figure PCTCN2018093134-appb-000006
Figure PCTCN2018093134-appb-000007
In a more preferred embodiment of the invention, the L 1-3 and L n are independently selected from the group consisting of
Figure PCTCN2018093134-appb-000006
Figure PCTCN2018093134-appb-000007
在本发明的一个实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In one embodiment of the invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000008
Figure PCTCN2018093134-appb-000008
在本发明的另一个实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In another embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000009
Figure PCTCN2018093134-appb-000009
在本发明的另一个实施例中，所述树状多缩乙二醇衍生物具有如下结构：In another embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000010
Figure PCTCN2018093134-appb-000010
在本发明的另一个实施方式中所述树状多缩乙二醇衍生物具有如下结构：In another embodiment of the present invention, the dendritic polyethylene glycol derivative has the following structure:
Figure PCTCN2018093134-appb-000011
Figure PCTCN2018093134-appb-000011
上式Ⅸ-Ⅻ中所述连接基团R(R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R b1、R b2、R d1、R d2、R d3、R d4、R d5、R d6、R d7和R d8)、支化点L(L 1、L 2、L 3、L 4、L 5、L 6和L 7)、多缩乙二醇基团E(E 1-15)、基团A 1、A 2、A 3、A 4、D 1、D 2、D 3、D 4和B具有本发明上述相应的定义。 The linking group R (R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R b1 , R b2 , R d1 , R d2 , R) in the above formula IX-XII D3 , R d4 , R d5 , R d6 , R d7 and R d8 ), branching points L (L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 ), polyglycol The groups E(E 1-15 ), the groups A 1 , A 2 , A 3 , A 4 , D 1 , D 2 , D 3 , D 4 and B have the above corresponding definitions of the invention.
具体地，式Ⅸ-Ⅻ中，所述R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R b1、R b2、R d1、R d2、R d3、R d4、R d5、R d6、R d7和R d8为相同或不同的-(CH 2) r-，r选自0-10的整数，更优选为0-5的整数，如0、1、2、3、4和5。 Specifically, in Formula IX-XII, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R b1 , R b2 , R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 and R d8 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more preferably an integer of 0 to 5, such as 0, 1. 2, 3, 4 and 5.
具体地，式Ⅸ-Ⅻ中，所述L 1、L 2、L 3、L 4、L 5、L 6和L 7具有式(II)或式(III)的结构， 更优选自：
Figure PCTCN2018093134-appb-000012
Specifically, in the formula IX-XII, the L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 have the structure of the formula (II) or the formula (III), more preferably from:
Figure PCTCN2018093134-appb-000012
具体地，式Ⅸ-Ⅻ中，所述多缩乙二醇基团(OCH 2CH 2) m中m为0-20的整数，更优选为0-12的整数，最为优选地，m为0、1、2、3、4、5、6、7或8。 Specifically, in the formula IX-XII, m in the polyglycol group (OCH 2 CH 2 ) m is an integer of 0-20, more preferably an integer of 0-12, and most preferably, m is 0. 1, 2, 3, 4, 5, 6, 7, or 8.
具体地，式Ⅸ-Ⅻ中，所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，更优选为-(CH 2) i-；优选地，所述连接基团X中i为0、1、2、3或4；进一步优选地，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 Specifically, in the formula IX-XII, in the A 1 , A 2 , D 1 , D 2 and B, the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -( CH 2 ) a combination of one or more of i NH- and (CH 2 ) i CONH-, more preferably -(CH 2 ) i -; preferably, i in the linking group X is 0, 1, 2, 3 or 4; further preferably, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
具体地，式Ⅸ-Ⅻ中，所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。 Specifically, in the formula IX-XII, in the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a thiol group, a carboxyl group, and an ester group. One of an aldehyde group, an acryl group, and a maleimide group.
更具体地，式Ⅸ-Ⅻ中，所述A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；更具体地，所述A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种。 More specifically, in Formula IX-XII, the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and One of -CH 2 CH 2 CH 2 CHO; more specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 One of -, -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 .
具体地，式Ⅸ-Ⅻ中，所述B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种。 Specifically, in Formula IX-XII, the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 One of CH 2 CH 2 CHO.
在本发明的一个具体实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In a specific embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000013
Figure PCTCN2018093134-appb-000013
其中，所述R a1、R b1、R d1、A 1、A 2、D 1、D 2和B具有本发明上述定义； Wherein R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 and B have the above definitions of the invention;
m1-4独立地选自0-100的整数，具体如0-20的整数，特别是0-12的整数；在本发明的一个实施例中，所述m1-4均为3。M1-4 is independently selected from an integer from 0 to 100, specifically an integer from 0 to 20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-4 is 3.
具体地，式ⅩⅢ中，所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，更具体为-(CH 2) i-；具体地，所述连接基团X中i为0、1、2、3或4；在本发明的一个实施例中，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 Specifically, in the formula XIII, in the A 1 , A 2 , D 1 , D 2 and B, the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 a combination of one or more of i NH- and (CH 2 ) i CONH-, more specifically -(CH 2 ) i -; in particular, i in the linking group X is 0, 1, 2 3 or 4; In one embodiment of the invention, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
具体地，式ⅩⅢ中，所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。 Specifically, in the formula XIII, in the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a thiol group, a carboxyl group, an ester group, and an aldehyde. One of a group, an acryl group, and a maleimide group.
更具体地，式ⅩⅢ中，所述A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；进一步具体地，所述A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种；在本发明的一个实施例中，所述A 1、A 2、D 1和D 2均为-CH 3。 More specifically, in Formula XIII, the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; further specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, One of -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 3 .
更具体地，式ⅩⅢ中，所述B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；在本发明的一个实施例中，所述B为-OH。 More specifically, in Formula XIII, the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO; in one embodiment of the invention, the B is -OH.
具体地，式ⅩⅢ中，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r选自0-10的整数，更具体地，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r为0-5的整数；在本发明的一个实施例中，所述R a1、R b1和R d1均为-C 3H 6-。 Specifically, in the formula XIII, the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, the R a1 , R b1 and R d1 are both -C 3 H 6 -.
更具体地，式ⅩⅢ中，所述-R b1-B为-C 3H 6-OH。 More specifically, in the formula XIII, the -R b1 -B is -C 3 H 6 -OH.
在本发明的一个实施例中，所述树状多缩乙二醇衍生物具有如下结构：In one embodiment of the invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000014
Figure PCTCN2018093134-appb-000014
在本发明的一个具体实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In a specific embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000015
Figure PCTCN2018093134-appb-000015
其中，所述R a1、R b1、R d1、A 1、A 2、D 1、D 2和B具有本发明上述定义； Wherein R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 and B have the above definitions of the invention;
m1-6独立地选自0-100的整数，如，0-20的整数，特别是0-12的整数；在本发明的一个实施例中，所述m1-6均为3。M1-6 is independently selected from an integer from 0-100, such as an integer from 0-20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 3.
具体地，式ⅩⅣ中，所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合；更具体为-(CH 2) i-；具体地，所述连接基团X中i为0、1、2、3或4；在本发明的一个实施例中，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 Specifically, in the formula XIV, in the A 1 , A 2 , D 1 , D 2 and B, the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 a combination of one or more of i NH- and (CH 2 ) i CONH-; more specifically -(CH 2 ) i -; in particular, i in the linking group X is 0, 1, 2 3 or 4; In one embodiment of the invention, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
具体地，式ⅩⅣ中，所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。 Specifically, in the formula XIV, in the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, and an aldehyde. One of a group, an acryl group, and a maleimide group.
更具体地，式ⅩⅣ中，所述A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；进一步具体地，A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种；在本发明的一个实施例中，所述A 1、A 2、D 1和D 2均为-CH 2CH 2NH 2。 More specifically, in Formula XIV, the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; further specifically, A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, -CH One of 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 2 CH 2 NH 2 .
更具体地，式ⅩⅣ中，所述B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；在本发明的一个实施例中，所述B为-OH。 More specifically, in Formula XIV, the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO; in one embodiment of the invention, the B is -OH.
具体地，式ⅩⅣ中，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r选自0-10的整数，更具体地，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r为0-5的整数；在本发明的一个实施例中，所述R a1和R d1均为-C 2H 4-，所述R b1为-C 3H 6-。 Specifically, in the formula XIV, the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, R a1 and R d1 are both -C 2 H 4 -, R b1 is -C 3 H 6 -.
更具体地，式ⅩⅣ中，所述-R b1-B为-C 3H 6-OH。 More specifically, in the formula XIV, the -R b1 -B is -C 3 H 6 -OH.
在本发明的一个实施例中，所述树状多缩乙二醇衍生物具有如下结构：In one embodiment of the invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000016
Figure PCTCN2018093134-appb-000016
在本发明的一个具体实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In a specific embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000017
Figure PCTCN2018093134-appb-000017
其中，所述R a1、R b1、R d1、A 1、A 2、D 1、D 2、B和Z具有本发明上述定义； Wherein R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 , B and Z have the above definitions of the invention;
m1-4独立地选自0-100的整数，如0-20的整数，特别是0-12的整数；在本发明的一个实施例中，所述m1-6均为4。M1-4 is independently selected from an integer from 0-100, such as an integer from 0-20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 4.
具体地，式ⅩⅤ中，所述A 1、A 2、D 1、D 2和B中，所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，更具体为-(CH 2) i-；具体地，所述连接基团X中i为0、1、2、3或4；在本发明的一个实施例中，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 Specifically, in the formula XV, in the A 1 , A 2 , D 1 , D 2 and B, in the A 1 , A 2 , D 1 , D 2 and B, the X is selected from -(CH 2 a combination of one or more of i -, -CO(CH 2 ) i -, -(CH 2 ) i NH- and (CH 2 ) i CONH-, more specifically -(CH 2 ) i -; Wherein i is 0, 1, 2, 3 or 4 in the linking group X; in one embodiment of the invention, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or - CH 2 CH 2 CH 2 -.
具体地，式ⅩⅤ中，所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。 Specifically, in the formula XV, in the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, and an aldehyde. One of a group, an acryl group, and a maleimide group.
更具体地，式ⅩⅤ中，所述A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；更具体地，所述A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种；在本发明的一个实施例中，所述A 1、A 2、D 1和D 2均为-CH 3或-CH 2CH 2COOH； More specifically, in Formula XV, the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; more specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, One of -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 3 or -CH 2 CH 2 COOH;
更具体地，式ⅩⅤ中，所述B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；在本发明的一个实施例中，所述B为-H。 More specifically, in Formula XV, the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO; in one embodiment of the invention, the B is -H.
具体地，式ⅩⅤ中，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r选自0-10的整数，更具体地，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r为0-5的整数；在本发明的一个实施例中，所述R a1和R d1均为-C 2H 4-，R b1为单键。 Specifically, in the formula XV, the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, R a1 and R d1 are both -C 2 H 4 -,R B1 is a single bond.
具体地，式ⅩⅤ中，所述Z为O或NHCO。Specifically, in the formula XV, the Z is O or NHCO.
更具体地，式ⅩⅤ中，所述-Z-R b1-B为-OH。 More specifically, in the formula XV, the -ZR b1 -B is -OH.
在本发明的一个实施例中，所述树状多缩乙二醇衍生物具有如下结构：In one embodiment of the invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000018
Figure PCTCN2018093134-appb-000018
在本发明的一个具体实施方式中，所述树状多缩乙二醇衍生物具有如下结构：In a specific embodiment of the present invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000019
Figure PCTCN2018093134-appb-000019
其中，所述R a1、R b1、R d1、A 1、A 2、D 1、D 2、B和Z具有本发明上述定义； Wherein R a1 , R b1 , R d1 , A 1 , A 2 , D 1 , D 2 , B and Z have the above definitions of the invention;
m1-6独立地选自0-100的整数，如0-20的整数，特别是0-12的整数；在本发明的一个实施例中，所述m1-6均为3。M1-6 is independently selected from an integer from 0 to 100, such as an integer from 0 to 20, particularly an integer from 0 to 12; in one embodiment of the invention, the m1-6 is 3.
具体地，式ⅩⅥ中，所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，更具体为-(CH 2) i-；具体地，所述连接基团X中i为0、1、2、3或4；在本发明的一个实施例中，所述X为单键、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。 Specifically, in the formula XVI, in the A 1 , A 2 , D 1 , D 2 and B, the X is selected from -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 a combination of one or more of i NH- and (CH 2 ) i CONH-, more specifically -(CH 2 ) i -; in particular, i in the linking group X is 0, 1, 2 3 or 4; In one embodiment of the invention, the X is a single bond, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
具体地，式ⅩⅥ中，所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。 Specifically, in the formula XVI, in the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, and an aldehyde. One of a group, an acryl group, and a maleimide group.
更具体地，式ⅩⅥ中，所述A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；更具体地，所述A 1、A 2、D 1和D 2独立地选自：-CH 3、-OCH 3、-CH 2CH 2NH 2-、-CH 2CH 2COOH和-CH 2CH 2N 3中的一种；在本发明的一个实施例中，所述A 1、A 2、D 1和D 2均为-CH 3或-CH 2CH 2NH 2； More specifically, in Formula XVI, the A 1 , A 2 , D 1 and D 2 are independently selected from: -H, -CH 3 , -OCH 3 , -OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH One of 2 CH 2 CH 2 CHO; more specifically, the A 1 , A 2 , D 1 and D 2 are independently selected from: -CH 3 , -OCH 3 , -CH 2 CH 2 NH 2 -, One of -CH 2 CH 2 COOH and -CH 2 CH 2 N 3 ; in one embodiment of the invention, the A 1 , A 2 , D 1 and D 2 are both -CH 3 or -CH 2 CH 2 NH 2 ;
更具体地，式ⅩⅥ中，所述B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种，进一步具体为-H或-CH 2CH 2COOH。 More specifically, in Formula XVI, the B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO, and -CH 2 CH One of 2 CH 2 CHO, further specifically -H or -CH 2 CH 2 COOH.
具体地，式ⅩⅥ中，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r选自0-10的整数，更具 体地，所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r为0-5的整数；在本发明的一个实施例中，所述R a1和R d1均为-C 2H 4-，R b1为单键。 Specifically, in the formula XVI, the R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is an integer selected from 0 to 10, more specifically, the R a1 , R b1 And R d1 are the same or different -(CH 2 ) r -, r is an integer of 0-5; in one embodiment of the invention, R a1 and R d1 are both -C 2 H 4 -,R B1 is a single bond.
具体地，式ⅩⅥ中，所述Z为O或NHCO。Specifically, in the formula XVI, the Z is O or NHCO.
更具体地，式ⅩⅥ中，所述-Z-R b1-B为-OH或-NHCO-CH 2CH 2COOH。 More specifically, in Formula XVI, the -ZR b1 -B is -OH or -NHCO-CH 2 CH 2 COOH.
在本发明的一个实施例中，所述树状多缩乙二醇衍生物具有如下结构：In one embodiment of the invention, the dendritic polyglycol derivative has the following structure:
Figure PCTCN2018093134-appb-000020
Figure PCTCN2018093134-appb-000020
本发明还提供一种上述树状多缩乙二醇衍生物的制备方法，其采用收敛合成法，包括如下步骤：(1)将多缩乙二醇衍生物一端修饰后，与中心分子发生亲核取代反应或酰胺化反应连接，得到楔形结构；The invention also provides a preparation method of the above dendritic polyglycol derivative, which adopts a convergent synthesis method, comprising the following steps: (1) modifying one end of the polyglycol derivative to form a pro-center with the central molecule a nuclear substitution reaction or an amidation reaction to obtain a wedge-shaped structure;
(2)将步骤(1)的反应产物中中心分子部分的修饰后，与中心分子发生亲核取代反应或酰胺化反应连接，得到四臂树状多缩乙二醇衍生物；(2) after modifying the central molecular moiety in the reaction product of the step (1), and nucleophilic substitution reaction or amidation reaction with the central molecule to obtain a four-arm dendritic polyglycol derivative;
以此类推，可得到臂数呈指数增长的如八臂、十六臂的树状多缩乙二醇衍生物；By analogy, a dendritic polyglycol derivative such as an eight-armed or sixteen-armed arm with an exponential increase in the number of arms can be obtained;
步骤(1)中所述的多缩乙二醇衍生物，其结构为R-X-E-R t-OH、R-X-E-R t-NH 2或R-X-E-R t-COOH； The polyglycol derivative described in the step (1), which has the structure RXER t -OH, RXER t -NH 2 or RXER t -COOH;
其中，among them,
R t选自：-(CH 2) t-、-(CR 1R 2) t-、-(CH 2) tNH-、-NHCO(CH 2) t-、-(CH 2) tCONH-和-CO(CH 2) t-中的一种或多种的组合，t为0-30的整数； R t is selected from: -(CH 2 ) t -, -(CR 1 R 2 ) t -, -(CH 2 ) t NH-, -NHCO(CH 2 ) t -, -(CH 2 ) t CONH- and a combination of one or more of -CO(CH 2 ) t -, t is an integer from 0 to 30;
R 1和R 2独立地选自：-H、C1-C6的烷基、-OR'、-NHR'、-N(R') 2、-CN、-F、-Cl、-Br、-I、-COR'、-COOR'、-OCOR'、-CONHR'和-CON(R') 2中的一种或多种的组合， R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
R'选自：-H、C1-6的烷基、-F、-Cl、-Br和-I，R' is selected from the group consisting of: -H, C1-6 alkyl, -F, -Cl, -Br and -I,
X为连接基团，选自：-(CH 2) i-、-(CH 2) iNH-、-CO(CH 2) i-、-(CH 2) iOCOO-、-(CH 2) iOCONH-、-(CH 2) iNHCONH-、-OC(CH 2) iCOO-、-(CH 2) iCOO-和-(CH 2) iCONH-中的一种或两种以上的组合，i为0-10的整数； X is a linking group selected from: -(CH 2 ) i -, -(CH 2 ) i NH-, -CO(CH 2 ) i -, -(CH 2 ) i OCOO-, -(CH 2 ) i One or a combination of two or more of OCONH-, -(CH 2 ) i NHCONH-, -OC(CH 2 ) i COO-, -(CH 2 ) i COO-, and -(CH 2 ) i CONH-, i is an integer from 0-10;
R为本发明所述式(Ⅰ)结构中Y所定义的活性端基或者R选自以下基团：甲酯、乙酯、叔丁酯、缩醛基、苄氧基、叔丁氧基、亚胺基和卤素中的一种；R is a living end group defined by Y in the structure of the formula (I) of the present invention or R is selected from the group consisting of a methyl ester, an ethyl ester, a tert-butyl ester, an acetal group, a benzyloxy group, a t-butoxy group, One of an imido group and a halogen;
Y为端基，选自：C1-C6的烷基、C1-C6的烷氧基、H(氢原子)、羟基、氨基、氨甲基、马来酰亚胺、羧基、酯基、巯基、琥珀酰亚胺碳酸酯、琥珀酰亚胺乙酸酯、琥珀酰亚胺丙酸酯、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸酯基、叠氮基、戊二酸基、酰肼基、炔基、对硝基苯碳酸酯基、异氰酸基、硅烷基、羧甲基、乙烯砜基和维生素H残基中的一种；Y is a terminal group selected from the group consisting of: a C1-C6 alkyl group, a C1-C6 alkoxy group, H (hydrogen atom), a hydroxyl group, an amino group, an aminomethyl group, a maleimide, a carboxyl group, an ester group, a thiol group, Succinimide carbonate, succinimide acetate, succinimide propionate, succinimide succinate, succinimidyl, dithiopyridyl, propionate, aldehyde, hydrazine Ester group, acryl group, acrylate group, azido group, glutaric acid group, hydrazide group, alkynyl group, p-nitrophenyl carbonate group, isocyanate group, silane group, carboxymethyl group, vinyl sulfone group and One of the vitamin H residues;
E为多缩乙二醇基团，其结构为：(OCH 2CH 2) m，m为0-100的整数； E is a polyglycol group having a structure of: (OCH 2 CH 2 ) m and m is an integer of 0-100;
所述的修饰基团选自：
Figure PCTCN2018093134-appb-000021
(-OTs)、
Figure PCTCN2018093134-appb-000022
(-OMs)、
Figure PCTCN2018093134-appb-000023
(-OBs)、 The modifying group is selected from the group consisting of:
Figure PCTCN2018093134-appb-000021
(-OTs),
Figure PCTCN2018093134-appb-000022
(-OMs),
Figure PCTCN2018093134-appb-000023
(-OBs),
Figure PCTCN2018093134-appb-000024
(-OTf)、-F、-Cl、-Br、-I、-NH 2和-COOH中的一种；
Figure PCTCN2018093134-appb-000024
One of (-OTf), -F, -Cl, -Br, -I, -NH 2 and -COOH;
所述的中心分子为含氨基和/或羟基和/或羧基的化合物，优选地，所述化合物含有如下结构：-NH 2、
Figure PCTCN2018093134-appb-000025
Figure PCTCN2018093134-appb-000026
The central molecule is a compound containing an amino group and/or a hydroxyl group and/or a carboxyl group. Preferably, the compound has the following structure: -NH 2 ,
Figure PCTCN2018093134-appb-000025
Figure PCTCN2018093134-appb-000026
Z选自：O、S、NH、NHCO、CO、COO、OC(O)和(CH 2) s中的一种，s为0-10的整数； Z is selected from one of: O, S, NH, NHCO, CO, COO, OC(O), and (CH 2 ) s , and s is an integer from 0 to 10;
p为0-10的整数；p is an integer from 0 to 10;
W为O或S；W is O or S;
V为O或NH。V is O or NH.
具体地，所述R t为-(CH 2) t-。 Specifically, the R t is -(CH 2 ) t -.
具体地，所述t为0-10的整数，如0、1、2、3、4或5。Specifically, the t is an integer of 0-10, such as 0, 1, 2, 3, 4 or 5.
具体地，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合，优选为-(CH 2) i-。 Specifically, the X is selected from a combination of one or more of -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 ) i NH-, and (CH 2 ) i CONH-, It is preferably -(CH 2 ) i -.
具体地，所述连接基团X中i为0、1、2、3或4。Specifically, i in the linking group X is 0, 1, 2, 3 or 4.
具体地，所述的R选自：甲酯、乙酯、叔丁酯、叠氮基、缩醛基和苄氧基中的一种。Specifically, the R is selected from the group consisting of methyl ester, ethyl ester, tert-butyl ester, azido group, acetal group, and benzyloxy group.
具体地，所述m为0-20的整数，如，0-12的整数；更具体地，所述m为0、1、2、3、4、5、6、7或8。Specifically, the m is an integer of 0-20, such as an integer of 0-12; more specifically, the m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
具体地，所述Z选自：O、NH、NHCO和(CH 2) s中的一种，更具体为O或NHCO。 Specifically, the Z is selected from one of: O, NH, NHCO, and (CH 2 ) s , more specifically O or NHCO.
具体地，所述s为0、1、2、3、4或5。Specifically, the s is 0, 1, 2, 3, 4 or 5.
具体地，所述p为0、1、2、3、4或5。Specifically, the p is 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例中，所述的中心分子含有如下结构：-NH 2、
Figure PCTCN2018093134-appb-000027
In a preferred embodiment of the invention, the central molecule contains the structure: -NH 2 ,
Figure PCTCN2018093134-appb-000027
具体地，可将步骤(1)和/或步骤(2)得到的反应产物中中心分子部分的一端与离去基团修饰的多缩聚乙二醇发生亲和取代反应连接。Specifically, one end of the central molecular moiety in the reaction product obtained in the step (1) and/or the step (2) may be bonded to the leaving group-modified polyglycol glycol by an affinity substitution reaction.
上述制备方法中离子基团修饰的步骤及其与中心分子发生亲核取代反应的步骤可采用现有技术中公开的方法进行，本发明对此不作具体限定。The step of modifying the ionic group in the above preparation method and the step of nucleophilic substitution reaction with the central molecule can be carried out by the method disclosed in the prior art, which is not specifically limited in the present invention.
本领域技术人员可根据实际应用需求，对上述制备得到的树状多缩乙二醇衍生物的端基进行修饰和改造，也可在制备过程中对相应端基进行修饰和改造，端基修饰和改造的方法可以采用现有技术中已公开的合成方法，如羧基化及接下来的NHS化、胺基化、醛基化、巯基化、马来酰亚胺化或丙烯酸化等，本发明对此不做具体限定。Those skilled in the art can modify and modify the end groups of the dendritic polyglycol derivative obtained by the above-mentioned preparation according to the actual application requirements, and can also modify and modify the corresponding end groups in the preparation process, and the end group modification And the method of modification may employ the synthetic methods disclosed in the prior art, such as carboxylation and subsequent NHS, amination, aldehyde, thiolation, maleimidation or acrylation, etc., the present invention This is not specifically limited.
本发明还提供一种上述树状多缩乙二醇衍生物在超分子化学、生物医学、光化学、电化学或催化剂等领域中的应用。The invention also provides the use of the above dendritic polyglycol derivative in the fields of supramolecular chemistry, biomedicine, photochemistry, electrochemistry or catalyst.
在本发明的一个实施方式中，所述的应用为上述树状多缩乙二醇衍生物在生物医学中的应用。In one embodiment of the invention, the use is the use of the dendritic polyethylene glycol derivative described above in biomedical applications.
具体地，所述的应用为上述树状多缩乙二醇衍生物在修饰药物中的应用；更具体地，所述药物 为难溶性药物。Specifically, the application is the use of the above dendritic polyglycol derivative in a modified drug; more specifically, the drug is a poorly soluble drug.
本发明还提供一种共价结合物，其包括通过共价键连接的上述树状多缩乙二醇衍生物和药物分子。The present invention also provides a covalent conjugate comprising the above dendritic polyglycol derivative and a drug molecule linked by a covalent bond.
具体地，所述的药物为难溶性药物。Specifically, the drug is a poorly soluble drug.
在本发明的一个实施例中，所述药物为胆固醇、十六醇或薄荷醇。In one embodiment of the invention, the drug is cholesterol, cetyl alcohol or menthol.
本发明还提供一种上述树状多缩乙二醇衍生物在制备上述共价结合物中的应用。The present invention also provides the use of the above dendritic polyglycol derivative in the preparation of the above covalent combination.
本发明中所述的难溶药物为根据《中国药典》的检测方法检测为略溶、微溶和极微溶解的药物。The poorly soluble drug described in the present invention is a drug which is slightly soluble, slightly soluble, and extremely slightly soluble according to the detection method of the Chinese Pharmacopoeia.
本发明提供的树状多缩乙二醇衍生物具有多个端基官能团，与直链多缩乙二醇相比，具有更强的水溶性，能够解决多缩乙二醇修饰不溶性药物时，由于负载量的提高造成水溶性不足的问题。本发明提供的上述树状多缩乙二醇衍生物的制备方法，反应条件温和，绿色环保，成本低廉，易于实现工业化。The dendritic polyglycol derivative provided by the invention has a plurality of terminal functional groups, and has stronger water solubility than linear polyglycol glycol, and can solve the problem of polyglycol modified insoluble drugs. The problem of insufficient water solubility due to an increase in the amount of load. The preparation method of the above-mentioned dendritic polyglycol glycol derivative provided by the invention has mild reaction conditions, is environmentally friendly, has low cost, and is easy to realize industrialization.
附图说明DRAWINGS
图1所示为(mEG 3) 2N-C 3H 6-OH(1)的合成路线图。 Figure 1 shows the synthetic route of (mEG 3 ) 2 NC 3 H 6 -OH(1).
图2所示为(mEG 3) 2-OH的合成路线图。 Figure 2 shows the synthetic route map of (mEG 3 ) 2 -OH.
图3所示为(tBuOC-EG 4) 2N-C 3H 6-OH(2)的合成路线图。 Figure 3 shows the synthetic route of (tBuOC-EG 4 ) 2 NC 3 H 6 -OH(2).
图4所示为(N 3-EG 4) 2-EG 4-OH(3)的合成路线图。 Figure 4 shows the synthetic route of (N 3 -EG 4 ) 2 -EG 4 -OH(3).
图5所示为树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的合成路线图。 Figure 5 is a synthetic route diagram of a dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH.
图6所示为树状分子((mEG 3) 2-N-C 3H 6) 2-OH的合成路线图。 Figure 6 is a synthetic route diagram of a dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -OH).
图7所示为树状分子((mEG 3) 2-EG 4) 2-OH的合成路线图。 Figure 7 shows the synthetic route of the dendrimer ((mEG 3 ) 2 -EG 4 ) 2 -OH.
图8所示为树状分子((NH 2-EG 4) 2-EG 4) 2-N-C 3H 6-OH的合成路线图。 Figure 8 is a synthetic route diagram of a dendrimer ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NC 3 H 6 -OH.
图9所示为树状分子((HOOC-EG 4) 2N-C 3H 6) 2-OH的合成路线图。 Figure 9 is a synthetic route diagram of a dendrimer ((HOOC-EG 4 ) 2 NC 3 H 6 ) 2 -OH).
图10所示为树状分子((NH 2-EG 4) 2-EG 4) 2-NHCO-C 2H 4-COOH的合成路线图。 Figure 10 is a synthetic route diagram of a dendrimer ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NHCO-C 2 H 4 -COOH.
具体实施方式Detailed ways
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义，如：“烷基”指的是直链或支链的且不含不饱和键的烃链自由基，C1-C6的烷基指含有1-6个碳原子的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等；“烷氧基”指的是羟基中的氢被烷基取代后形成的取代基，C1-C6的烷氧基指含有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、丁氧基等；另外，本发明中涉及的部分基团及其化学结构对应如下：羟基，-OH；氨基，-NH 2；氨甲基-CH 2NH 2；马来酰亚胺基，
Figure PCTCN2018093134-appb-000029
羧基，
Figure PCTCN2018093134-appb-000030
酯基，
Figure PCTCN2018093134-appb-000031
(其中Q 1可为烷基、芳基或杂环基，如甲基、乙基、正丙基、叔丁基、
Figure PCTCN2018093134-appb-000032
等)；巯基，-SH；琥珀酰亚胺碳酸酯基，
Figure PCTCN2018093134-appb-000033
琥珀酰亚胺乙酸酯基，
Figure PCTCN2018093134-appb-000034
琥珀酰亚胺丙酸酯基，
Figure PCTCN2018093134-appb-000035
琥珀酰亚胺琥珀酸酯基，
Figure PCTCN2018093134-appb-000036
琥珀酰亚胺基，
Figure PCTCN2018093134-appb-000037
二硫吡啶基，如2-吡啶二硫基
Figure PCTCN2018093134-appb-000038
4-吡啶二硫基，
Figure PCTCN2018093134-appb-000039
丙酸基，
Figure PCTCN2018093134-appb-000040
醛基-CHO；巯酯基
Figure PCTCN2018093134-appb-000041
(其中Q 2可为烷基，如甲基、乙基、正丙基、叔丁基等)；丙烯酸基，
Figure PCTCN2018093134-appb-000042
丙烯酸酯基(丙烯酰氧基)
Figure PCTCN2018093134-appb-000043
叠氮基，
Figure PCTCN2018093134-appb-000044
(-N 3)；戊二酸基，如
Figure PCTCN2018093134-appb-000045
酰肼基，
Figure PCTCN2018093134-appb-000046
炔基，
Figure PCTCN2018093134-appb-000047
对硝基苯碳酸酯基，
Figure PCTCN2018093134-appb-000048
异氰酸基，
Figure PCTCN2018093134-appb-000049
硅烷基，
Figure PCTCN2018093134-appb-000050
(其中Q 3可为相同或不同的烷基或烷氧基，如甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、丁氧基等，优选地，Q 3均为甲基、乙基、正丙基、甲氧基、乙氧基、正丙氧基等)；羧甲基，
Figure PCTCN2018093134-appb-000051
乙烯砜基，
Figure PCTCN2018093134-appb-000052
维生素H残基，
Figure PCTCN2018093134-appb-000053
Unless defined otherwise, all scientific and technical terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates, such as "alkyl" refers to a straight or branched chain and does not A hydrocarbon chain radical containing an unsaturated bond, and a C1-C6 alkyl group means an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , tert-butyl, n-pentyl, n-hexyl, etc.; "alkoxy" refers to a substituent formed by the substitution of a hydrogen in a hydroxy group by an alkyl group, and a C1-C6 alkoxy group means a 1-6 carbon atom. The alkoxy group, such as methoxy, ethoxy, propoxy, butoxy, etc.; in addition, the partial groups involved in the present invention and their chemical structures correspond to the following: hydroxyl group, -OH; amino group, -NH 2 Aminomethyl-CH 2 NH 2 ; maleimide group,
Figure PCTCN2018093134-appb-000029
carboxyl,
Figure PCTCN2018093134-appb-000030
Ester group,
Figure PCTCN2018093134-appb-000031
(wherein Q 1 may be an alkyl group, an aryl group or a heterocyclic group such as methyl, ethyl, n-propyl, t-butyl,
Figure PCTCN2018093134-appb-000032
Etch); sulfhydryl, -SH; succinimide carbonate,
Figure PCTCN2018093134-appb-000033
Succinimide acetate group,
Figure PCTCN2018093134-appb-000034
Succinimide propionate group,
Figure PCTCN2018093134-appb-000035
Succinimide succinate group,
Figure PCTCN2018093134-appb-000036
Succinimide group,
Figure PCTCN2018093134-appb-000037
Dithiopyridyl, such as 2-pyridinedithio
Figure PCTCN2018093134-appb-000038
4-pyridyldithio,
Figure PCTCN2018093134-appb-000039
Propionic acid group,
Figure PCTCN2018093134-appb-000040
Aldehyde group-CHO; oxime ester group
Figure PCTCN2018093134-appb-000041
(wherein Q 2 may be an alkyl group such as methyl, ethyl, n-propyl, t-butyl, etc.); an acrylic group,
Figure PCTCN2018093134-appb-000042
Acrylate group (acryloyloxy)
Figure PCTCN2018093134-appb-000043
Azido group,
Figure PCTCN2018093134-appb-000044
(-N 3 ); glutaric acid group, such as
Figure PCTCN2018093134-appb-000045
Acyl hydrazino,
Figure PCTCN2018093134-appb-000046
Alkynyl,
Figure PCTCN2018093134-appb-000047
P-nitrophenyl carbonate group,
Figure PCTCN2018093134-appb-000048
Isocyanate group,
Figure PCTCN2018093134-appb-000049
Silyl group,
Figure PCTCN2018093134-appb-000050
(wherein Q 3 may be the same or different alkyl or alkoxy group, such as methyl, ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, etc. Preferably, Q 3 is methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, etc.; carboxymethyl,
Figure PCTCN2018093134-appb-000051
Vinyl sulfone group,
Figure PCTCN2018093134-appb-000052
Vitamin H residue,
Figure PCTCN2018093134-appb-000053
本发明中所述的收敛合成法，是指从所需合成的树状聚合物分子的边缘部分开始，逐步向内进行，先采用发散法合成树状高分子的一部分，即一个楔形结构，然后将其与核心连接，最后形成树状聚合物(如“王鹤童.树枝状聚合物的合成和应用[J].精细与专用化学品，2011，19(3)：6-9.”中所述)。The convergent synthesis method described in the present invention refers to a stepwise inward starting from the edge portion of the desired dendrimer molecule, and a part of the dendrimer is synthesized by a divergence method, that is, a wedge structure, and then It is connected to the core and finally forms a dendrimer (such as "Wang Hetong. Synthesis and application of dendrimers [J]. Fine and Specialty Chemicals, 2011, 19(3): 6-9." ).
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be described clearly and completely in conjunction with the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.
实施例1 原料的合成Example 1 Synthesis of raw materials
一、原料(mEG 3) 2N-C 3H 6-OH(1)的合成 I. Synthesis of raw material (mEG 3 ) 2 NC 3 H 6 -OH(1)
其合成路线如图1所示。Its synthetic route is shown in Figure 1.
1、mEG 3-OMs的合成 1. Synthesis of mEG 3 -OMs
在mEG 3-OH(32mL，200mmol)中加入TEA(32mL，230mmol)及150mL DCM，置于冰水浴中的反应瓶内。用DCM(50mL)溶解MsCl(17.5mL，220mmol)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。通过薄层色谱(TLC)检测反应完全。用水(150mL)洗三遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约52g。 TEA was added in mEG 3 -OH (32mL, 200mmol) (32mL, 230mmol) and 150mL DCM, the reaction flask was placed in an ice-water bath. MsCl (17.5 mL, 220 mmol) was dissolved in DCM (50 mL), and then dissolved, and then taken to the reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. The reaction was detected by thin layer chromatography (TLC). Wash three times with water (150 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave about 52 g of product.
2、(mEG 3) 2N-C 3H 6-OH的合成 2. Synthesis of (mEG 3 ) 2 NC 3 H 6 -OH
氨基丙醇(3.1g，41.3mmol)中加入由上述步骤1制得的mEG 3-OMs(21.6g，89.3mmol)及THF(150mL)。加热回流过夜后，倒出上层液，蒸干得粗品。柱纯化(取250g硅胶，流动相为MeOH/DCM体系，MeOH/DCM＝3-7％)，得到产品2.5g，产率：16％。 To the aminopropanol (3.1 g, 41.3 mmol), mEG 3 -OMs (21.6 g, 89.3 mmol) and THF (150 mL) obtained in the above step 1 were added. After heating to reflux overnight, the supernatant was poured and evaporated to dryness. Column purification (250 g of silica gel, mobile phase MeOH / DCM system, MeOH / DCM = 3-7%) afforded product 2.5 g, yield: 16%.
NMR(CDCl 3)δ：3.5-3.8(m,22H,OCH 2),3.37(s,6H,CH 3O),2.7-2.8(m,6H,N(CH 2) 3),1.6-1.7(m,2H,NCH 2CH 2CH 2OH)；ESI-MS：368.3(M+H) +,390.2(M+Na) +。 NMR (CDCl 3 ) δ: 3.5-3.8 (m, 22H, OCH 2 ), 3.37 (s, 6H, CH 3 O), 2.7-2.8 (m, 6H, N(CH 2 ) 3 ), 1.6-1.7 ( m, 2H, NCH 2 CH 2 CH 2 OH); ESI-MS: 368.3 (m + H) +, 390.2 (m + Na) +.
二、原料(mEG 3) 2-OH的合成 Second, the synthesis of raw materials (mEG 3 ) 2 -OH
其合成路线如图2所示。Its synthetic route is shown in Figure 2.
1、mEG 3-OMs的合成 1. Synthesis of mEG 3 -OMs
在mEG 3-OH(32mL，200mmol)中加入TEA(32mL，230mmol)及DCM(150mL)，置于冰水浴中的反应瓶内。用DCM(50mL)溶解MsCl(17.5mL，220mmol)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。通过薄层色谱(TLC)检测反应完全。用水(150mL)洗三遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约52g。 TEA was added in mEG 3 -OH (32mL, 200mmol) (32mL, 230mmol) and DCM (150mL), the reaction flask was placed in an ice-water bath. MsCl (17.5 mL, 220 mmol) was dissolved in DCM (50 mL), and then dissolved, and then taken to the reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. The reaction was detected by thin layer chromatography (TLC). Wash three times with water (150 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave about 52 g of product.
2、(mEG 3) 2-O-Allyl的合成 2. Synthesis of (mEG 3 ) 2 -O-Allyl
3-丙烯氧基-1,2-丙二醇(3.01mL)中加入甲苯(75mL)，冰水浴下加入NaH(60％，2.05g)，室温反应2小时，滴加含mEG 3-OMs(13g)的甲苯溶液(80mL)，60℃反应过夜，HPLC检测，蒸干甲苯，加入DCM及水各洗涤一次，蒸干DCM得到粗品。柱纯化(流动相为1％MeOH/DCM)得到产品8.8g(产率85％)。3、(mEG 3) 2-OH的合成 Toluene (75 mL) was added to 3-propenyloxy-1,2-propanediol (3.01 mL), NaH (60%, 2.05 g) was added under ice water, and the mixture was reacted at room temperature for 2 hours, and mEG 3 -OMs (13 g) was added dropwise. The toluene solution (80 mL) was reacted overnight at 60 ° C, and the toluene was evaporated to dryness, and then washed with DCM and water, and then evaporated to dryness. Column purification (mobile phase 1% MeOH / DCM) gave 8.8 g (yield: 85%). 3. Synthesis of (mEG 3 ) 2 -OH
将上述步骤2产物(8g)中加入Pd/C(0.8g)、TsOH(1.6g)，加入甲醇(80mL)/水(16mL)，回流24小时，HPLC发现反应完全，过滤回收Pd/C，浓缩得粗品。柱纯化(3％MeOH/DCM)得到产品5.8g(产率80.2％)。Pd/C (0.8 g) and TsOH (1.6 g) were added to the product of the above step 2 (8 g), and methanol (80 mL) / water (16 mL) was added and refluxed for 24 hours. The reaction was found to be complete by HPLC, and Pd/C was recovered by filtration. Concentrated to a crude product. Column purification (3% MeOH / DCM) gave 5.8 g (yield 80.2%).
NMR(CDCl 3)δ：3.89-3.50(m,29H),3.38(s,6H)；ESI-MS：385.4(M+H) +,407.2(M+Na)。 NMR (CDCl 3 ) δ: 3.89 - 3.50 (m, 29H), 3.38 (s, 6H); ESI-MS: 385.4 (M+H) + , 407.2 (M+Na).
三、原料(tBuOC-EG 4) 2N-C 3H 6-OH(2)的合成 3. Synthesis of raw material (tBuOC-EG 4 ) 2 NC 3 H 6 -OH(2)
其合成路线如图3所示。Its synthetic route is shown in Figure 3.
1、MsO-EG 4-OtBu的合成 1. Synthesis of MsO-EG 4 -OtBu
在HO-EG 4-tBu(39.4g，0.122mol)中加入DCM(350mL)及TEA(22.7mL，0.159mol，1.3eq)。冰水浴下加入MsCl(11.4mL，0.146mol，1.2eq)的DCM(150mL)溶液。室温反应过夜。依次用水(200mL)洗涤3次，无水硫酸钠干燥，过滤，蒸除溶剂得产物。 Was added DCM (350mL) and TEA (22.7mL, 0.159mol, 1.3eq) in HO-EG 4 -tBu (39.4g, 0.122mol). A solution of MsCl (11.4 mL, 0.146 mol, 1.2 eq) in DCM (150 mL) The reaction was carried out at room temperature overnight. It was washed three times with water (200 mL) successively, dried over anhydrous sodium sulfate, filtered, and evaporated.
2、(tBuO-EG 4) 2N-C 3H 6-OH的合成 2. Synthesis of (tBuO-EG 4 ) 2 NC 3 H 6 -OH
向上述步骤1制得的MsO-EG 4-OtBu(20g，50mmol)中加入氨基丙醇(1.9mL，25mmol)及DMF(200mL)，70℃搅拌过夜。浓缩得粗品。柱纯化(MeOH/DCM＝0-10％)得到产品2.3g，产率：12.0％。 To the MsO-EG 4 -OtBu (20 g, 50 mmol) obtained in the above step 1 was added aminopropanol (1.9 mL, 25 mmol) and DMF (200 mL). Concentrated to a crude product. Column purification (MeOH/DCM = 0-10%) gave product 2.3 g, yield: 12.0%.
NMR(CDCl 3)δ：3.5-3.8(m,34H,OCH 2)；3.3(m,6H,N(CH 2) 3)；2.5-(t,2H,CH 2COO)；1.7-1.8(m,2H,NCH 2CH 2CH 2OH)；1.4(s,18H,(CH 3) 3-)ESI-MS：706.3(M+Na) +。 NMR (CDCl 3 ) δ: 3.5-3.8 (m, 34H, OCH 2 ); 3.3 (m, 6H, N(CH 2 ) 3 ); 2.5-(t, 2H, CH 2 COO); 1.7-1.8 (m) , 2H, NCH 2 CH 2 CH 2 OH); 1.4 (s, 18H, (CH 3 ) 3 -) ESI-MS: 706.3 (M+Na) + .
四、原料(N 3-EG 4) 2-EG 4-OH(3)的合成 Synthesis of raw material (N 3 -EG 4 ) 2 -EG 4 -OH(3)
其合成路线如图4所示。Its synthetic route is shown in Figure 4.
1、TrO-EG 4-OH的合成 1. Synthesis of TrO-EG 4 -OH
EG 4(245g)加入甲苯，共沸除水后加入吡啶(30mL)，搅拌5min后加入三苯基氯甲烷(69.7g)，室温过夜。水洗三遍得到产物87g(产率80％)。 EG 4 (245 g) was added toluene, azeotropically water was added, then pyridine (30 mL) was added, and after stirring for 5 min, triphenylchloromethane (69.7 g) was added at room temperature overnight. Three times of washing with water gave 87 g of product (yield 80%).
2、TrO-EG 4-OMs的合成 2. Synthesis of TrO-EG 4 -OMs
TrO-EG 4-OH(87g)中加入DCM(500mL)及TEA(33mL)，冰水浴下滴加含甲磺酰氯(17mL)的DCM溶液(200mL)，室温反应过夜。水洗两遍，蒸干浓缩得到产物(产率近100％)。 In TrO-EG 4 -OH (87g) was added DCM (500 mL) and TEA (33mL), was added dropwise in DCM (200mL) containing methanesulfonyl chloride (17mL) under ice-water bath, at room temperature overnight. It was washed twice with water, and concentrated by evaporation to give a product (yield nearly 100%).
3、(N 3-EG 4) 2-O-Allyl的合成 3. Synthesis of (N 3 -EG 4 ) 2 -O-Allyl
3-丙烯氧基-1,2-丙二醇(1.22mL)中加入甲苯(40mL)，冰水浴下加入NaH(60％，0.79g)，室温反应2小时，滴加含N 3-EG 4-OMs(6.1g)的甲苯溶液(80mL)，60℃反应过夜，HPLC检测，蒸干甲苯，加入DCM及水各洗涤一次，蒸干DCM得到粗品。柱纯化(流动相为1％MeOH/DCM)得到产品4.3g(产率85％)。 Toluene (40 mL) was added to 3-propenyloxy-1,2-propanediol (1.22 mL), NaH (60%, 0.79 g) was added to the ice water bath, and reacted at room temperature for 2 hours, and N 3 -EG 4 -OMs was added dropwise. (6.1 g) of a toluene solution (80 mL), which was reacted overnight at 60 ° C, by HPLC, evaporated toluene, washed once with DCM and water, and evaporated to dryness. Column purification (mobile phase 1% MeOH / DCM) afforded product 4.3 g (yield 85%).
4、(N 3-EG 4) 2-OH的合成 4. Synthesis of (N 3 -EG 4 ) 2 -OH
上步产物(4g)中加入Pd/C(0.4g)、TsOH(0.8g)，加入甲醇(40mL)/水(8mL)，回流24小时，HPLC发现反应完全，过滤回收Pd/C，浓缩得粗品。柱纯化(流动相为3％MeOH/DCM)得到产品3.0g(产率82％)。Pd/C (0.4g) and TsOH (0.8g) were added to the above product (4g), methanol (40mL) / water (8mL) was added, and refluxed for 24 hours. The reaction was found to be complete by HPLC, and Pd/C was collected by filtration and concentrated. Crude. Column purification (mobile phase 3% MeOH / DCM) afforded product 3.0 g (yield 82%).
5、(N 3-EG 4) 2-EG 4-OTr的合成 5. Synthesis of (N 3 -EG 4 ) 2 -EG 4 -OTr
上步产物(1.5g)中加入甲苯(20mL)，冰水浴下加入NaH(60％，128mg)，室温反应2小时后，将TrO-EG 4-OMs(1.88g)的甲苯溶液(10mL)滴加至反应液中，70℃反应过夜，蒸干甲苯，加入DCM及水洗涤一次。蒸干DCM得到粗品。柱纯化(流动相为3％MeOH/DCM)得到产品2.08g(产率75.4％)。 To the above product (1.5 g), toluene (20 mL) was added, and NaH (60%, 128 mg) was added to an ice water bath. After reacting at room temperature for 2 hours, a solution of TrO-EG 4 -OMs (1.88 g) in toluene (10 mL) was added dropwise. It was added to the reaction liquid, and the reaction was carried out at 70 ° C overnight, and the toluene was evaporated to dryness, and washed once with DCM and water. The DCM was evaporated to dryness to give a crude material. Column purification (mobile phase 3% MeOH / DCM) furnished product 2.08 g (yield 75.4%).
6、(N 3-EG 4) 2-EG 4-OH(3)的合成 6. Synthesis of (N 3 -EG 4 ) 2 -EG 4 -OH(3)
将上步产物(1.5g)中加入DCM(15mL)及TFA(5mL)，室温反应过夜。蒸干溶剂，加入饱和盐水，用乙醚洗涤至水液点板无显色为止，然后用DCM抽提，蒸干有机相得到产物0.69g(产率62.3％)。The above product (1.5 g) was added to DCM (15 mL) andEtOAc. The solvent was evaporated to dryness. EtOAc EtOAc m.
NMR(CDCl 3)δ：3.1(m,4H,N 3-CH 2)；3.5-3.8(m,50H,其他氢)；ESI-MS：693.2(M+Na) +。 NMR (CDCl 3) δ: 3.1 (m, 4H, N 3 -CH 2); 3.5-3.8 (m, 50H, other hydrogen); ESI-MS: 693.2 ( M + Na) +.
实施例2 树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的合成 Example 2 Synthesis of dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH
其合成路线如图5所示。The synthetic route is shown in Figure 5.
1、(mEG 3) 2-N-C 3H 6-OMs的合成 1. Synthesis of (mEG 3 ) 2 -NC 3 H 6 -OMs
在(mEG 3) 2-N-C 3H 6-OH((1)，实施例1制得，3.1g)中加入TEA(1.4mL)及30mL DCM，置于冰水浴 中的反应瓶内。用DCM(5mL)溶解MsCl(0.72mL)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。用水(30mL)洗一遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约3g(产率79.8％)。 TEA (1.4 mL) and 30 mL of DCM were added to (mEG 3 ) 2 -NC 3 H 6 -OH ((1), obtained in Example 1, 3.1 g), and placed in a reaction flask in an ice water bath. MsCl (0.72 mL) was dissolved in DCM (5 mL), and dissolved, and then taken to a reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. Wash once with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave about 3 g of product (yield 79.8%).
2、树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的合成 2. Synthesis of dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH
氨基丙醇(0.18g)中加入由上述步骤1制得的(mEG 3) 2-N-C 3H 6-OMs(2.5g)及THF(30mL)。加热回流过夜后，倒出上层液，蒸干得粗品。柱纯化(流动相为MeOH/DCM体系，MeOH/DCM＝3-7％)，得到产品0.4g(11％)。 To the aminopropanol (0.18 g), (mEG 3 ) 2 -NC 3 H 6 -OMs (2.5 g) obtained in the above step 1 and THF (30 mL) were added. After heating to reflux overnight, the supernatant was poured and evaporated to dryness. Column purification (mobile phase in MeOH / DCM system, MeOH / DCM = 3-7%) afforded product 0.4 g (11%).
NMR(CDCl 3)δ：3.5-3.8(m,42H,OCH 2),3.37(s,12H,CH 3O),2.7-2.8(m,18H,N(CH 2) 3),1.6-1.7(m,6H,NCH 2CH 2CH 2)；ESI-MS：796.5(M+Na) +。 NMR (CDCl 3 ) δ: 3.5-3.8 (m, 42H, OCH 2 ), 3.37 (s, 12H, CH 3 O), 2.7-2.8 (m, 18H, N (CH 2 ) 3 ), 1.6-1.7 ( m, 6H, NCH 2 CH 2 CH 2); ESI-MS: 796.5 (m + Na) +.
实施例3 树状分子((mEG 3) 2-N-C 3H 6) 2-OH的合成 Example 3 Synthesis of dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -OH
其合成路线如图6所示。The synthetic route is shown in Figure 6.
3-丙烯氧基-1,2-丙二醇(0.52g,4mmol)中加入甲苯(20mL)，冰水浴下加入NaH(60％，0.5g)，室温反应2小时，滴加含(mEG 3) 2-N-C 3H 6-OMs(合成方式见实施例2，4.5g)的甲苯溶液(20mL)，60℃反应过夜，HPLC检测，蒸干甲苯，加入DCM及水各洗涤一次，蒸干DCM得到粗品。 Toluene (20 mL) was added to 3-propenyloxy-1,2-propanediol (0.52 g, 4 mmol), NaH (60%, 0.5 g) was added to the ice water bath, and the reaction was carried out for 2 hours at room temperature, and (mEG 3 ) 2 was added dropwise. -NC 3 H 6 -OMs (see Example 2, 4.5 g for the synthesis), a toluene solution (20 mL), reacted at 60 ° C overnight, HPLC, evaporated toluene, washed once with DCM and water, evaporated to dryness .
将上步反应粗品(5g)中加入Pd/C(0.5g)、TsOH(1.0g)，加入甲醇(50mL)/水(10mL)，回流24小时，过滤回收Pd/C，浓缩得粗品。柱纯化(2-7％MeOH/DCM)得到产品1.1g(产率35％)。Pd/C (0.5 g) and TsOH (1.0 g) were added to the crude reaction product (5 g), and methanol (50 mL) / water (10 mL) was added and refluxed for 24 hours, and Pd/C was collected by filtration and concentrated to give a crude product. Column purification (2-7% MeOH / DCM) gave product (1 g, 35%).
NMR(CDCl 3)δ：3.4-3.8(m,48H,OCH 2),3.37(s,12H,CH 3O),3.25(m,1H,OCH),2.5-2.7(m,12H,NCH 2),1.6-1.7(m,4H,NCH 2CH 2CH 2)；ESI-MS：791.3(M+H) +。 NMR (CDCl 3 ) δ: 3.4-3.8 (m, 48H, OCH 2 ), 3.37 (s, 12H, CH 3 O), 3.25 (m, 1H, OCH), 2.5-2.7 (m, 12H, NCH 2 ) , 1.6-1.7 (m, 4H, NCH 2 CH 2 CH 2 ); ESI-MS: 791.3 (M+H) + .
实施例4树状分子((mEG 3) 2-EG 4) 2-OH的合成 Example 4 Synthesis of Dendrimer ((mEG 3 ) 2 -EG 4 ) 2 -OH
其合成路线如图7所示。The synthetic route is shown in Figure 7.
1、((mEG 3) 2-EG 4)-OH的合成 Synthesis of ((mEG 3 ) 2 -EG 4 )-OH
(mEG 3) 2-OH(实施例1合成，7.7g)中加入甲苯(70mL)，冰水浴下加入NaH(60％，1.0g)，室温反应2小时后，将TrO-EG 4-OMs(实施例1合成，12.3g)的甲苯溶液(90mL)滴加至反应液中，70℃反应过夜，蒸干甲苯，加入DCM及水洗涤一次。蒸干DCM得到粗品。柱纯化(流动相为3％MeOH/DCM)得到中间体11g(产率69％)。 (mEG 3 ) 2 -OH (Synthesis of Example 1, 7.7 g), toluene (70 mL) was added, NaH (60%, 1.0 g) was added to the ice water bath, and TrO-EG 4 -OMs ( In the synthesis of Example 1, 12.3 g of a toluene solution (90 mL) was added dropwise to the reaction mixture, and the reaction was carried out at 70 ° C overnight, and the toluene was evaporated to dryness and washed with DCM and water. The DCM was evaporated to dryness to give a crude material. Column purification (mobile phase 3% MeOH / DCM) gave Intermediate 11 g (yield 69%).
将上步产物(10g)中加入DCM(100mL)及TFA(30mL)，室温反应过夜。蒸干溶剂，加入饱和盐水，用乙醚洗涤至水液点板无显色为止，然后用DCM抽提，蒸干有机相得到产物8.2g(产率78％)。The above product (10 g) was added to DCM (100 mL) and TFA (30 mL) The solvent was evaporated to dryness, and brine was evaporated, evaporated, evaporated, evaporated.
NMR(CDCl 3)δ：3.89-3.50(m,45H),3.38(s,6H)；ESI-MS：583.6(M+Na)。 NMR (CDCl 3 ) δ: 3.89 - 3.50 (m, 45H), 3.38 (s, 6H); ESI-MS: 583.6 (M+Na).
2、((mEG 3) 2-EG 4) 2-OMs的合成 2. Synthesis of ((mEG 3 ) 2 -EG 4 ) 2 -OMs
在上步反应产物(7.5g)中加入TEA(1.6g)及60mL DCM，置于冰水浴中的反应瓶内。用DCM(15mL)溶解MsCl(1.76g)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。用水洗一遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约8.1g(产率95％)。TEA (1.6 g) and 60 mL of DCM were placed in the reaction product of the above step (7.5 g), and placed in a reaction flask in an ice water bath. MsCl (1.76 g) was dissolved in DCM (15 mL), dissolved, and then taken to a reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. Wash it with water. The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave the product about 8.1 g (yield 95%).
3、((mEG 3) 2-EG 4) 2-OH的合成 3. Synthesis of ((mEG 3 ) 2 -EG 4 ) 2 -OH
3-丙烯氧基-1,2-丙二醇(0.63g)中加入甲苯(40mL)，冰水浴下加入NaH(60％，0.59g)，室温反应2小时，滴加含((mEG 3) 2-EG 4) 2-OMs(合成方式见实施例2，7.5g)的甲苯溶液(40mL)，60℃反应过夜，HPLC检测，蒸干甲苯，加入DCM及水各洗涤一次，蒸干DCM得到粗品。 Toluene (40 mL) was added to 3-propenyloxy-1,2-propanediol (0.63 g), and NaH (60%, 0.59 g) was added under ice-water bath, and reacted at room temperature for 2 hours, and ((mEG 3 ) 2 - was added dropwise. EG 4 ) 2 -OMs (see Example 2, 7.5 g of the synthesis method) in a toluene solution (40 mL), which was reacted overnight at 60 ° C, HPLC was carried out, and the toluene was evaporated to dryness, washed once with DCM and water, and evaporated to dryness.
将上步反应粗品(8g)中加入Pd/C(0.8g)、TsOH(1.6g)，加入甲醇(80mL)/水(16mL)，回流24小时，过滤回收Pd/C，浓缩得粗品。柱纯化(0-3％MeOH/DCM)得到产品3.7g(产率67％)。Pd/C (0.8 g) and TsOH (1.6 g) were added to the crude reaction product (8 g), and methanol (80 mL) / water (16 mL) was added and refluxed for 24 hours, and Pd/C was collected by filtration and concentrated to give a crude product. Column purification (0-3% MeOH/DCM) gave 3.7 g (yield 67%).
NMR(CDCl 3)δ：3.89-3.50(m,96H),3.35(s,12H)；ESI-MS：1199.2(M+Na)。 NMR (CDCl 3 ) δ: 3.89 - 3.50 (m, 96H), 3.35 (s, 12H); ESI-MS: 1199.2 (M+Na).
实施例5 树状分子((NH 2-EG 4) 2-EG 4) 2-N-C 3H 6-OH的合成 Example 5 Synthesis of dendrimer ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NC 3 H 6 -OH
其合成路线如图8所示。Its synthetic route is shown in Figure 8.
1、(N 3-EG 4) 2-EG 4-OMs的合成 1. Synthesis of (N 3 -EG 4 ) 2 -EG 4 -OMs
在(N 3-EG 4) 2-EG 4-OH((3)，实施例1制得，5g)中加入TEA(1.24mL)及40mL DCM，置于冰水浴中的反应瓶内。用DCM(5mL)溶解MsCl(0.63mL)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。用水(30mL)洗一遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约5.2g(产率93％)。 TEA (1.24 mL) and 40 mL of DCM were added to (N 3 -EG 4 ) 2 -EG 4 -OH ((3), 5 g), and placed in a reaction flask in an ice water bath. MsCl (0.63 mL) was dissolved in DCM (5 mL), and then dissolved, and then applied dropwise to a reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. Wash once with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave the product about 5.2 g (yield 93%).
2、((N 3-EG 4) 2-EG 4) 2-N-C 3H 6-OH的合成 2. Synthesis of ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NC 3 H 6 -OH
氨基丙醇(0.19g)中加入由上述步骤1制得的(N 3-EG 4) 2-EG 4-OMs(4.5g)及THF(50mL)。加热回流过夜后，倒出上层液，蒸干得粗品。冰乙醚重结晶2次，得到产品0.8g(23％)。 To the aminopropanol (0.19 g), (N 3 -EG 4 ) 2 -EG 4 -OMs (4.5 g) obtained in the above step 1 and THF (50 mL) were added. After heating to reflux overnight, the supernatant was poured and evaporated to dryness. The ice diethyl ether was recrystallized twice to give a product (yield: 0.8 g).
3、((NH 2-EG 4) 2-EG 4) 2-N-C 3H 6-OH的合成 Synthesis of ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NC 3 H 6 -OH
向上述步骤2制得的((N 3-EG 4) 2-EG 4) 2-N-C 3H 6-OH(400mg)中加入DMF(20mL)及三苯基膦(425mg)，室温反应过夜后，加入水(0.1mL)，反应过夜。蒸干DMF，加入水(50mL)，依次用乙酸乙酯(40mL)洗涤2次及DCM(30mL)洗涤2次，蒸干水分，冰乙醚重结晶两次得到产物315mg，产率：85％。 To ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NC 3 H 6 -OH (400 mg) obtained in the above step 2, DMF (20 mL) and triphenylphosphine (425 mg) were added and reacted at room temperature overnight. Water (0.1 mL) was added and the reaction was carried out overnight. The DMF was evaporated to dryness. EtOAc EtOAc EtOAc.
NMR(CDCl 3)δ：1.6-1.7(m,2H,NCH 2CH 2CH 2),2.7-2.8(m,14H,N(CH 2) 3&NH 2CH 2),3.5-3.8(m,96H,除活泼氢外其余氢)；ESI-MS：1299.7(M+Na) +。 NMR (CDCl 3 ) δ: 1.6-1.7 (m, 2H, NCH 2 CH 2 CH 2 ), 2.7-2.8 (m, 14H, N(CH 2 ) 3 &NH 2 CH 2 ), 3.5-3.8 (m, 96H) , hydrogen other than active hydrogen); ESI-MS: 1299.7 (M+Na) + .
实施例6 树状分子((HOOC-EG 4) 2N-C 3H 6) 2-OH的合成 Example 6 Synthesis of dendrimer ((HOOC-EG 4 ) 2 NC 3 H 6 ) 2 -OH
其合成路线如图9所示。Its synthetic route is shown in Figure 9.
1、(tBuO-EG 4) 2N-C 3H 6-OMs的合成 1. Synthesis of (tBuO-EG 4 ) 2 NC 3 H 6 -OMs
在(tBuO-EG 4) 2N-C 3H 6-OH((2)，实施例1制得，2.2g)中加入TEA(0.54mL)及30mL DCM，置于冰水浴中的反应瓶内。用DCM(5mL)溶解MsCl(0.27mL)，溶解完全后，滴加至冰水浴中的反应瓶内。室温反应3小时。用水(30mL)洗一遍。有机相用无水硫酸钠干燥，过滤除去硫酸钠。浓缩得到产物约1.7g(产率69％)。 TEA (0.54 mL) and 30 mL of DCM were added to (tBuO-EG 4 ) 2 NC 3 H 6 -OH ((2), obtained in Example 1, 2.2 g), and placed in a reaction flask in an ice water bath. MsCl (0.27 mL) was dissolved in DCM (5 mL), and dissolved, and then poured into a reaction flask in an ice water bath. The reaction was carried out for 3 hours at room temperature. Wash once with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. Concentration gave the product about 1.7 g (yield 69%).
2、((tBuO-EG 4) 2N-C 3H 6) 2-OAlly的合成 2. Synthesis of ((tBuO-EG 4 ) 2 NC 3 H 6 ) 2 -OAlly
3-丙烯氧基-1,2-丙二醇(68mg)中加入甲苯(20mL)，冰水浴下加入NaH(60％，72mg)，室温反应2小时，滴加含(tBuO-EG 4) 2N-C 3H 6-OMs(1.5g)的甲苯溶液(10mL)，60℃反应过夜，HPLC检测，蒸干甲苯，冰乙醚重结晶2次得到产品1.0g(84％)。 Toluene (20 mL) was added to 3-propenyloxy-1,2-propanediol (68 mg), and NaH (60%, 72 mg) was added under ice-water bath, and reacted at room temperature for 2 hours, and (tBuO-EG 4 ) 2 NC 3 was added dropwise. H 6 -OMs (1.5g) in toluene (10mL), 60 ℃ overnight, HPLC detection, toluene, evaporated to dryness, recrystallized twice from ether to ice to give the product 1.0g (84%).
3、((HOOC-EG 4) 2N-C 3H 6) 2-OH的合成 3. Synthesis of ((HOOC-EG 4 ) 2 NC 3 H 6 ) 2 -OH
上步产物(0.8g)中加入Pd/C(0.08g)、TsOH(0.16g)，加入甲醇(10mL)/水(2mL)，回流24小时，HPLC发现反应完全，过滤回收Pd/C，浓缩后冰乙醚重结晶2次得到产品0.56g(86％)。Pd/C (0.08g) and TsOH (0.16g) were added to the above product (0.8g), and methanol (10mL) / water (2mL) was added, and refluxed for 24 hours. The reaction was found to be complete by HPLC, and Pd/C was collected by filtration and concentrated. The product was recrystallized twice from ice to give 0.56 g (86%).
NMR(CDCl 3)δ：1.6-1.7(m,4H,NCH 2CH 2CH 2),2.5-2.8(m,20H,N(CH 2) 3&CH 2COOH),3.5-3.8(m,73H,除活泼氢外其余氢)；ESI-MS：1221.2(M+Na) +。 NMR (CDCl 3 ) δ: 1.6-1.7 (m, 4H, NCH 2 CH 2 CH 2 ), 2.5-2.8 (m, 20H, N(CH 2 ) 3 &CH 2 COOH), 3.5-3.8 (m, 73H, Except for active hydrogen, hydrogen; ESI-MS: 1221.2 (M+Na) + .
实施例7 树状分子((NH 2-EG 4) 2-EG 4) 2-NHCO-C 2H 4-COOH的合成 Example 7 Synthesis of dendrimer ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NHCO-C 2 H 4 -COOH
其合成路线如图10所示。Its synthetic route is shown in Figure 10.
1、((N 3-EG 4) 2-EG 4) 2-NH-tBoc的合成 1. Synthesis of ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NH-tBoc
3-Boc-NH-1,2-丙二醇(0.78g)中加入甲苯(60mL)，冰水浴下加入NaH(60％，0.36g)，室温反应2小时，滴加含(N 3-EG 4) 2-EG 4-OH((3)，实施例1制得，7.3g)的甲苯溶液(30mL)，60℃反应过夜，HPLC检测，蒸干甲苯，加入DCM及水各洗涤一次，蒸干DCM得到粗品。冰乙醚重结晶2次得到产品4.5g(73％)。 Add 3-Boc-NH-1,2-propanediol (0.78g) to toluene (60mL), add NaH (60%, 0.36g) under ice water bath, react at room temperature for 2 hours, add (N 3 -EG 4 ) dropwise 2 -EG 4 -OH ((3), 7.3 g obtained in Example 1) in toluene (30 mL), reacted at 60 ° C overnight, HPLC, evaporated toluene, washed once with DCM and water, evaporated to dry DCM Get the crude. The ice diethyl ether was recrystallized twice to give the product 4.5 g (73%).
2、((N 3-EG 4) 2-EG 4) 2-NHCO-C 2H 4-COOH的合成 2. Synthesis of ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NHCO-C 2 H 4 -COOH
((N 3-EG 4) 2-EG 4) 2-NH-tBoc(4g)中加入三氟乙酸(13mL)及二氯甲烷(27mL)，室温搅拌过夜，蒸干溶剂，乙醚重结晶2次得到中间体。然后加入二氯甲烷(35mL)及三乙胺(0.5mL)，搅拌均匀后加入琥珀酸酐(400mg)，室温反应过夜，用pH＝5的饱和盐水洗涤一次，冰乙醚重结晶2次得到产品3g(76％)。 ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NH-tBoc (4 g) was added with trifluoroacetic acid (13 mL) and dichloromethane (27 mL). An intermediate is obtained. Then, dichloromethane (35 mL) and triethylamine (0.5 mL) were added, and after stirring, succinic anhydride (400 mg) was added thereto, and the mixture was reacted at room temperature overnight, washed once with saturated brine of pH=5, and recrystallized twice from ice diethyl ether to give product 3 g. (76%).
3、((NH 2-EG 4) 2-EG 4) 2-NHCO-C 2H 4-COOH的合成 Synthesis of ((NH 2 -EG 4 ) 2 -EG 4 ) 2 -NHCO-C 2 H 4 -COOH
向上述步骤2制得的((N 3-EG 4) 2-EG 4) 2-NHCO-C 2H 4-COOH(2g)中加入DMF(20mL)及三苯基膦(1.96g)，室温反应过夜后，加入水(0.1mL)，反应过夜。蒸干DMF，加入水(50mL)，依次用乙酸乙酯(40mL)洗涤2次及DCM(30mL)洗涤2次，蒸干水分得到产物1.4g，产率：75％。 To ((N 3 -EG 4 ) 2 -EG 4 ) 2 -NHCO-C 2 H 4 -COOH (2 g) obtained in the above step 2, DMF (20 mL) and triphenylphosphine (1.96 g) were added at room temperature. After reacting overnight, water (0.1 mL) was added and the reaction was stood overnight. The DMF was evaporated to dryness. EtOAc (EtOAc m.
NMR(CDCl 3)δ：2.4-2.6(m,4H,CH 2COOH),2.8(m,8H,NH 2CH 2),3.5-3.8(m,103H,除活泼氢外其余氢)；ESI-MS：1415.1(M+Na) +。 NMR (CDCl 3 ) δ: 2.4-2.6 (m, 4H, CH 2 COOH), 2.8 (m, 8H, NH 2 CH 2 ), 3.5-3.8 (m, 103H, hydrogen other than active hydrogen); MS: 1415.1 (M+Na) + .
实施例8 树状分子衍生物((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH三种衍生物的合成 Example 8 Synthesis of three derivatives of dendrimer derivative ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH
分别制备((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的胆固醇、十六醇和薄荷醇衍生物。 Cholesterol, cetyl alcohol and menthol derivatives of ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH were prepared separately.
1、取实施例2制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH(0.4g)中加入DCM(5mL)及TEA(0.11mL)，然后将胆固醇氯甲酸酯(0.3g)溶于DCM(5mL)中，滴加至反应瓶中。室温搅拌过夜。水洗一遍，旋干得粗品。柱纯化(流动相为MeOH/DCM体系，MeOH/DCM＝0-7％)，得到产品190mg(产率31％)。 1. ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH (0.4 g) prepared in Example 2 was added DCM (5 mL) and TEA (0.11 mL), then cholesterol chloride The formate (0.3 g) was dissolved in DCM (5 mL) and added dropwise to a reaction mixture. Stir at room temperature overnight. Wash it once and spin it dry. Column purification (mobile phase in MeOH / DCM system, MeOH / DCM = 0 - 7%) afforded product 190 mg (yield 31%).
NMR(CDCl 3)δ：5.55-5.45(m,1H),4.65-4.50(m,1H),4.1-4.0(m,2H),3.5-3.8(m,40H),3.37(s,12H),2.7-2.8(m,12H),2.50-0.80(m,46H),0.65-0.60(m,3H)。 NMR (CDCl 3 ) δ: 5.55-5.45 (m, 1H), 4.65-4.50 (m, 1H), 4.1-4.0 (m, 2H), 3.5-3.8 (m, 40H), 3.37 (s, 12H), 2.7-2.8 (m, 12H), 2.50-0.80 (m, 46H), 0.65-0.60 (m, 3H).
2、取实施例2制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH(0.4g)中加入DCM(5mL)及TEA(0.11mL)，然后将十六醇氯甲酸酯(0.23g)溶于DCM(5mL)中，滴加至反应瓶中。室温搅拌过夜。TLC检测反应完全，水洗一遍，旋干得粗品，柱纯化(6％MeOH/DCM)得到十六醇衍生物150mg(产率28％)。 2. Add ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH (0.4 g) prepared in Example 2 to DCM (5 mL) and TEA (0.11 mL), then 16 The alcohol chloroformate (0.23 g) was dissolved in DCM (5 mL) and added dropwise to a reaction mixture. Stir at room temperature overnight. The reaction was completely detected by TLC, washed with water, and then evaporated to dryness, and purified by column (yield of 6% MeOH/DCM) to afford 150 mg (yield 28%) of the hexadecanol derivative.
NMR(CDCl 3)R：4.1-4.2(m,4H),3.5-3.8(m,40H),3.37(s,12H),2.7-2.8(m,18H),1.6-1.7(m,8H),1.2-1.3(m,26H),0.88(t,3H)。 NMR (CDCl 3 ) R: 4.1-4.2 (m, 4H), 3.5-3.8 (m, 40H), 3.37 (s, 12H), 2.7-2.8 (m, 18H), 1.6-1.7 (m, 8H), 1.2-1.3 (m, 26H), 0.88 (t, 3H).
3、取实施例2制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH(0.4g)中加入DCM(5mL)及吡啶(0.11mL)，然后将薄荷醇氯甲酸酯(0.17g)溶于DCM(5mL)中，滴加至反应瓶中。室温搅拌过夜。TLC检测反应完全，水洗一遍，旋干得粗品，柱纯化(2％MeOH/DCM)得到薄荷醇衍生物155mg(31％)。 3. (Mg 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH (0.4 g) was added to DCM (5 mL) and pyridine (0.11 mL), followed by menthol The chloroformate (0.17 g) was dissolved in DCM (5 mL) and added dropwise to a reaction mixture. Stir at room temperature overnight. The reaction was completed by TLC, washed with water, dried and evaporated to dryness, and purified by column (2% MeOH/DCM) to afford 155 mg (31%) of menthol.
NMR(CDCl 3)R：4.4(m,1H),4.0-4.2(m,2H),3.5-3.8(m,40H,OCH2),3.37(s,12H,CH3O),2.7-2.8(m,18H,N(CH2)3),2.0(m,1H),1.82(m,1H),1.6-1.7(m,9H),1.4(m,4H),1.0(m,9H)。 NMR (CDCl 3 ) R: 4.4 (m, 1H), 4.0-4.2 (m, 2H), 3.5-3.8 (m, 40H, OCH2), 3.37 (s, 12H, CH3O), 2.7-2.8 (m, 18H) , N(CH2)3), 2.0 (m, 1H), 1.82 (m, 1H), 1.6-1.7 (m, 9H), 1.4 (m, 4H), 1.0 (m, 9H).
实施例9 直链分子衍生物mEG 7-OH的三种衍生物的合成 Example 9 Synthesis of Three Derivatives of Linear Molecular Derivative mEG 7 -OH
取市售获得的mEG 7-OH，参照实施例8相同条件制备mEG 7-OH的三种衍生物。 Three derivatives of mEG 7 -OH were prepared under the same conditions as in Example 8 using commercially available mEG 7 -OH.
胆固醇衍生物：NMR(CDCl 3)δ：5.45-5.55(m,1H),4.50-4.65(m,1H),4.0-4.1(m,2H),3.5-3.8(m,26H),3.37(s,3H),0.80-2.50(m,40H),0.60-0.65(m,3H)。 Cholesterol Derivatives: NMR (CDCl 3 ) δ: 5.45-5.55 (m, 1H), 4.50-4.65 (m, 1H), 4.0-4.1 (m, 2H), 3.5-3.8 (m, 26H), 3.37 (s) , 3H), 0.80-2.50 (m, 40H), 0.60-0.65 (m, 3H).
十六醇衍生物：NMR(CDCl 3)δ：4.27(t,2H),4.12(t,2H),3.5-3.8(m,26H),3.38(s,3H),1.65(m,2H),1.25(m,26H),0.88(t,3H)。 Cetyl alcohol derivative: NMR (CDCl 3 ) δ: 4.27 (t, 2H), 4.12 (t, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.65 (m, 2H), 1.25 (m, 26H), 0.88 (t, 3H).
薄荷醇衍生物：NMR(CDCl 3)δ：4.4-4.6(m,1H),4.2-4.3(m,2H),3.5-3.8(m,26H),3.38(s,3H),1.9-2.1(m,2H),1.0-1.7(m,7H),0.7-0.9(m,9H)。 Menthol derivative: NMR (CDCl 3 ) δ: 4.4-4.6 (m, 1H), 4.2-4.3 (m, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.9-2.1 ( m, 2H), 1.0-1.7 (m, 7H), 0.7-0.9 (m, 9H).
实施例10 两种胆固醇衍生物在水中溶解度比较Example 10 Comparison of Solubility of Two Cholesterol Derivatives in Water
将实施例8制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的胆固醇衍生物50.0mg分散于50mL水中，从中取出5mL，加入1.5mL水，每隔5min剧烈震摇30s，30min后，溶液浑浊；又加入1.5mL水，每隔5min剧烈震摇30s，直至总共加入9mL水，溶液变澄清。 50.0 mg of the cholesterol derivative of ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH prepared in Example 8 was dispersed in 50 mL of water, 5 mL was taken out therefrom, and 1.5 mL of water was added every 5 min. After shaking for 30 s for 30 s, the solution was turbid after 30 min; 1.5 mL of water was added and shaken vigorously for 5 s every 5 min until a total of 9 mL of water was added, and the solution became clear.
将实施例9制备得到的mEG 7-OH的胆固醇衍生物24.2mg分散于50mL水中，从中取出5mL，加入5mL水，每隔5min剧烈震摇30s，30min后，溶液浑浊；又加入5mL水，每隔5min剧烈震摇30s，直至加入25mL水。再从稀释溶液中取出5mL溶液，同样操作直至加入10mL水，溶液变澄清。 24.2 mg of the cholesterol derivative of mEG 7 -OH prepared in Example 9 was dispersed in 50 mL of water, 5 mL was taken out therefrom, 5 mL of water was added, and the mixture was vigorously shaken for 30 s every 5 minutes. After 30 minutes, the solution was cloudy; 5 mL of water was added thereto, Shake vigorously for 30 s every 5 minutes until 25 mL of water was added. Then, 5 mL of the solution was taken out from the diluted solution, and the same operation was carried out until 10 mL of water was added, and the solution became clear.
结果如表1所示，由结果分析可知，树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的胆固醇衍生物溶解度为35.7mg/100g H 2O，是mEG 7-OH的胆固醇衍生物的溶解度2.69mg/100g H 2O的13.3倍，是胆固醇溶解度(<0.2mg/100g H 2O)的178倍。 The results are shown in Table 1. As a result of analysis, it was found that the solubility of the dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH in the cholesterol derivative was 35.7 mg / 100 g H 2 O, cholesterol solubility mEG 7 -OH derivative of 2.69mg / 100g 13.3 times in H 2 O, cholesterol solubility (<0.2mg / 100g H 2 O ) 178 times.
实施例11 两种十六醇衍生物在水中溶解度比较试验Example 11 Comparison Test of Solubility of Two Cetyl Alcohol Derivatives in Water
将实施例8制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的十六醇衍生物111.0mg分散于50μL水中，每隔5min剧烈震摇30s，30min后，溶液澄清；又加入50μL水，每隔5min剧烈震摇30s，直至加入1.025mL水，溶液仍然澄清。 111.0 mg of the cetyl alcohol derivative of ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH prepared in Example 8 was dispersed in 50 μL of water, shaken vigorously for 30 s every 5 min, after 30 min. The solution was clarified; 50 μL of water was added and shaken vigorously for 5 s every 5 minutes until 1.025 mL of water was added, and the solution remained clear.
将实施例9制备得到的mEG 7-OH的十六醇衍生物112.9mg分散于50μL水中，每隔5min剧烈震摇30s，30min后，溶液浑浊；又加入50μL水，每隔5min剧烈震摇30s，直至加入250μL水，溶液变澄清。 112.9 mg of the cetyl alcohol derivative of mEG 7 -OH prepared in Example 9 was dispersed in 50 μL of water, shaking vigorously for 30 s every 5 minutes. After 30 minutes, the solution was turbid; 50 μL of water was added, and shaking was vigorously every 30 minutes for 30 s. The solution became clear until 250 μL of water was added.
结果如表1所示，由结果分析可知，树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的十六醇衍生物室温下可以任何比例与水混溶，而mEG 7-OH的十六醇衍生物的溶解度为45.2g/100g H 2O，十六醇溶解度<1mg/100g H 2O。 The results are shown in Table 1. From the results analysis, it is known that the dendritic alcohol derivative of the dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH can be miscible with water at any ratio at room temperature. The solubility of the cetyl alcohol derivative of mEG 7 -OH is 45.2 g / 100 g H 2 O, and the solubility of cetyl alcohol is < 1 mg / 100 g H 2 O.
实施例12 两种薄荷醇衍生物在水中溶解度比较Example 12 Comparison of Solubility of Two Menthol Derivatives in Water
将实施例8制备得到的((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的薄荷醇衍生物106.7mg分散于50μL水中，每隔5min剧烈震摇30s，30min后，溶液澄清；又加入50μL水，每隔5min剧烈震摇30s，直至加入1.025mL水，溶液仍然澄清。 106.7 mg of the menthol derivative of ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH prepared in Example 8 was dispersed in 50 μL of water, shaken vigorously for 30 s every 5 min, after 30 min, The solution was clarified; 50 μL of water was added and shaken vigorously for 5 s every 5 minutes until 1.025 mL of water was added, and the solution remained clear.
将实施例9制备得到的mEG 7-OH的薄荷醇衍生物101.3mg分散于50μL水中，每隔5min剧烈震摇30s，30min后，溶液浑浊；又加入50μL水，每隔5min剧烈震摇30s，30min后，溶液变澄清。 101.3 mg of the menthol derivative of mEG 7 -OH prepared in Example 9 was dispersed in 50 μL of water, shaken vigorously for 30 s every 5 minutes, and after 30 minutes, the solution was cloudy; 50 μL of water was added, and shaking vigorously for 30 s every 5 minutes. After 30 min, the solution became clear.
结果如表1所示，树状分子((mEG 3) 2-N-C 3H 6) 2-N-C 3H 6-OH的薄荷醇衍生物室温下可以任何比例与水混溶，而mEG 7-OH的薄荷醇衍生物的溶解度为67.5g/100g H 2O，薄荷醇溶解度<100mg/100g H 2O。 The results are shown in Table 1. The menthol derivative of the dendrimer ((mEG 3 ) 2 -NC 3 H 6 ) 2 -NC 3 H 6 -OH can be miscible with water in any ratio at room temperature, while mEG 7 -OH The menthol derivative has a solubility of 67.5 g/100 g H 2 O and a menthol solubility of <100 mg/100 g H 2 O.
表1 三种衍生物的溶解度Table 1 Solubility of three derivatives
Figure PCTCN2018093134-appb-000054
Figure PCTCN2018093134-appb-000054
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., which are within the spirit and principles of the present invention, should be included in the scope of the present invention. within.

Claims (14)

  1. 一种树状多缩乙二醇衍生物，其具有式(Ⅰ)的结构：A dendritic polyglycol derivative having the structure of formula (I):
    Figure PCTCN2018093134-appb-100001
    Figure PCTCN2018093134-appb-100001
    其中，among them,
    A 1、A 2、D 1和D 2为相同或不同的Y-X-结构，或相同或不同的
    Figure PCTCN2018093134-appb-100002
    结构；J、K为相同或不同的Y-X-结构；     A 1 , A 2 , D 1 and D 2 are the same or different YX-structures, or the same or different
    Figure PCTCN2018093134-appb-100002
    Structure; J, K are the same or different YX-structures;
    R a1、R a2、R a3、R a4、R b1、R b2、R d1、R d2、R d3和R d4、R j和R k为连接基团，独立地选自：-(CH 2) r-、-(CR 1R 2) r-、-(CH 2) rNH-、-NHCO(CH 2) r-、-(CH 2) rCONH-和-CO(CH 2) r-中的一种或多种的组合，r为0-30的整数， R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R d1 , R d2 , R d3 and R d4 , R j and R k are linking groups independently selected from the group consisting of: —(CH 2 ) r -, -(CR 1 R 2 ) r -, -(CH 2 ) r NH-, -NHCO(CH 2 ) r -, -(CH 2 ) r CONH- and -CO(CH 2 ) r - a combination of one or more, r is an integer from 0 to 30,
    R 1和R 2独立地选自：-H、C1-C6的烷基、-OR'、-NHR'、-N(R') 2、-CN、-F、-Cl、-Br、-I、-COR'、-COOR'、-OCOR'、-CONHR'和-CON(R') 2中的一种或多种的组合， R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
    R'选自：-H、C1-C6的烷基、-F、-Cl、-Br和-I，R' is selected from the group consisting of: -H, C1-C6 alkyl, -F, -Cl, -Br and -I,
    B为A 1、A 2、D 1、D 2、J和K相同或不同的Y-X-结构； B is the same or different YX-structure of A 1 , A 2 , D 1 , D 2 , J and K;
    X为连接基团，选自：-(CH 2) i-、-(CH 2) iNH-、-CO(CH 2) i-、-(CH 2) iOCOO-、-(CH 2) iOCONH-、-(CH 2) iNHCONH-、-OC(CH 2) iCOO-、-(CH 2) iCOO-和-(CH 2) iCONH-中的一种或两种以上的组合，i为0-10的整数； X is a linking group selected from: -(CH 2 ) i -, -(CH 2 ) i NH-, -CO(CH 2 ) i -, -(CH 2 ) i OCOO-, -(CH 2 ) i One or a combination of two or more of OCONH-, -(CH 2 ) i NHCONH-, -OC(CH 2 ) i COO-, -(CH 2 ) i COO-, and -(CH 2 ) i CONH-, i is an integer from 0-10;
    Y为端基，选自：C1-C6的烷基、C1-C6的烷氧基、H、羟基、氨基、氨甲基、马来酰亚胺基、羧基、酯基、巯基、琥珀酰亚胺碳酸酯、琥珀酰亚胺乙酸酯、琥珀酰亚胺丙酸酯、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸酯基、叠氮基、戊二酸基、酰肼基、炔基、对硝基苯碳酸酯基、异氰酸基、硅烷基、羧甲基、乙烯砜基和维生素H残基中的一种；Y is a terminal group selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, H, hydroxy, amino, aminomethyl, maleimide, carboxyl, ester, decyl, succinyl Amine carbonate, succinimide acetate, succinimide propionate, succinimide succinate, succinimidyl, dithiopyridyl, propionic acid, aldehyde, oxime, Acrylate, acrylate, azide, glutaric acid, hydrazide, alkynyl, p-nitrophenyl carbonate, isocyanate, silane, carboxymethyl, vinylsulfone and vitamin H One of the bases;
    E 1-7、E j和E k为相同或不同的多缩乙二醇基团(OCH 2CH 2) m，m为0-100的整数； E 1-7 , E j and E k are the same or different polyglycol group (OCH 2 CH 2 ) m , m is an integer from 0-100;
    L 1-3和L n为支化点，独立地选自式(II)-(Ⅷ)的结构中的一种或两种以上的组合： L 1-3 and L n are branching points independently selected from one or a combination of two or more of the structures of the formulae (II) to (VIII):
    Figure PCTCN2018093134-appb-100003
    Figure PCTCN2018093134-appb-100003
    Z选自：O、S、NH、NHCO、CO、COO、OC(O)和(CH 2) s中的一种，s为0-10的整数； Z is selected from one of: O, S, NH, NHCO, CO, COO, OC(O), and (CH 2 ) s , and s is an integer from 0 to 10;
    p为0-10的整数；p is an integer from 0 to 10;
    W为O或S；W is O or S;
    V为O或NH。V is O or NH.
  2. 如权利要求1所述的衍生物，其特征在于，所述Z选自：O、NH、NHCO和(CH 2) s中的一种；和/或， The derivative according to claim 1, wherein said Z is selected from the group consisting of: O, NH, NHCO, and (CH 2 ) s ; and/or
    所述R a1、R a2、R a3、R a4、R b1、R b2、R d1、R d2、R d3、R d4、R j和R k为相同或不同的-(CH 2) r-，r选自0-10的整数。 The R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R d1 , R d2 , R d3 , R d4 , R j and R k are the same or different -(CH 2 ) r -, r is selected from an integer from 0-10.
  3. 如权利要求1或2所述的衍生物，其特征在于，所述L 1-3和L n独立地选自
    Figure PCTCN2018093134-appb-100004
    Figure PCTCN2018093134-appb-100005
    The derivative according to claim 1 or 2, wherein said L 1-3 and L n are independently selected from the group consisting of
    Figure PCTCN2018093134-appb-100004
    Figure PCTCN2018093134-appb-100005
  4. 如权利要求1-3任一项所述的衍生物，其特征在于，所述X为-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-或(CH 2) iCONH-，和/或，所述i为0、1、2、3或4；和/或， The derivative according to any one of claims 1 to 3, wherein X is -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 ) i NH- or ( CH 2 ) i CONH-, and/or, the i is 0, 1, 2, 3 or 4; and/or,
    所述Y选自：甲基、甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种。The Y is selected from one of a methyl group, a methoxy group, a hydroxyl group, an amino group, an azide group, a decyl group, a carboxyl group, an ester group, an aldehyde group, an acryl group, and a maleimide group.
  5. 如权利要求1-4任一项所述的衍生物，其特征在于，所述的A 1、A 2、D 1和D 2独立地选自：-H、-CH 3、-OCH 3、-OH、-NH 2、-CH 2NH 2、-CH 2CH 2NH 2、-N 3、-CH 2N 3、-CH 2CH 2N 3、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种；和/或， The derivative according to any one of claims 1 to 4, wherein the A 1 , A 2 , D 1 and D 2 are independently selected from the group consisting of: -H, -CH 3 , -OCH 3 , - OH, -NH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -N 3 , -CH 2 N 3 , -CH 2 CH 2 N 3 , -CH 2 COOH, -CH 2 CH 2 COOH, One of -SH, -CH 2 CH 2 CHO and -CH 2 CH 2 CH 2 CHO; and/or,
    所述的B选自：-H、-OH、-NH 2、-CH 2COOH、-CH 2CH 2COOH、-SH、-CH 2CH 2CHO和-CH 2CH 2CH 2CHO中的一种。 The B is selected from the group consisting of: -H, -OH, -NH 2 , -CH 2 COOH, -CH 2 CH 2 COOH, -SH, -CH 2 CH 2 CHO and -CH 2 CH 2 CH 2 CHO Kind.
  6. 如权利要求1-5任一项所述的衍生物，其特征在于，所述多缩乙二醇基团(OCH 2CH 2) m中m为0-20的整数，优选为0-12的整数，更优选为0、1、2、3、4、5、6、7或8。 The derivative according to any one of claims 1 to 5, wherein m in the polyglycol group (OCH 2 CH 2 ) m is an integer of 0-20, preferably 0-12 An integer is more preferably 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  7. 如权利要求1-6任一项所述的衍生物，其特征在于，所述树状多缩乙二醇衍生物选自如下式(Ⅸ)至式(Ⅻ)结构：The derivative according to any one of claims 1 to 6, wherein the dendritic polyglycol derivative is selected from the following structures of the formulae (IX) to (XII):
    Figure PCTCN2018093134-appb-100006
    Figure PCTCN2018093134-appb-100006
    Figure PCTCN2018093134-appb-100007
    Figure PCTCN2018093134-appb-100007
  8. 如权利要求1-7任一项所述的衍生物，其特征在于，所述树状多缩乙二醇衍生物选自如下式(ⅩⅢ)至式(ⅩⅥ)结构：The derivative according to any one of claims 1 to 7, wherein the dendritic polyglycol derivative is selected from the following structures of the formulae (XIII) to (XVI):
    Figure PCTCN2018093134-appb-100008
    Figure PCTCN2018093134-appb-100008
    Figure PCTCN2018093134-appb-100009
    Figure PCTCN2018093134-appb-100009
    优选地，m1-6独立地选自0-20的整数；更优选为0-12的整数，进一步优选为0、1、2、3、4、5、6、7或8；和/或，Preferably, m1-6 is independently selected from an integer from 0-20; more preferably an integer from 0 to 12, further preferably 0, 1, 2, 3, 4, 5, 6, 7, or 8; and/or,
    所述A 1、A 2、D 1、D 2和B中，所述X选自-(CH 2) i-、-CO(CH 2) i-、-(CH 2) iNH-和(CH 2) iCONH-中一种或多种的组合；和/或， In the A 1 , A 2 , D 1 , D 2 and B, the X is selected from the group consisting of -(CH 2 ) i -, -CO(CH 2 ) i -, -(CH 2 ) i NH- and (CH) 2 ) a combination of one or more of i CONH-; and/or,
    所述A 1、A 2、D 1、D 2和B中，所述Y选自：甲氧基、羟基、氨基、叠氮基、巯基、羧基、酯基、醛基、丙烯酸基和马来酰亚胺基中的一种；和/或， In the A 1 , A 2 , D 1 , D 2 and B, the Y is selected from the group consisting of: a methoxy group, a hydroxyl group, an amino group, an azide group, a fluorenyl group, a carboxyl group, an ester group, an aldehyde group, an acryl group, and a Malay. One of the imide groups; and/or,
    所述R a1、R b1和R d1为相同或不同的-(CH 2) r-，r选自0-10的整数；和/或， The R a1 , R b1 and R d1 are the same or different -(CH 2 ) r -, and r is selected from an integer of 0-10; and/or
    所述Z为O或NHCO。The Z is O or NHCO.
  9. 如权利要求8所述的衍生物，其特征在于，所述树状多缩乙二醇衍生物具有如下式结构：The derivative according to claim 8, wherein the dendritic polyglycol derivative has the following structure:
    Figure PCTCN2018093134-appb-100010
    Figure PCTCN2018093134-appb-100010
    Figure PCTCN2018093134-appb-100011
    Figure PCTCN2018093134-appb-100011
    Figure PCTCN2018093134-appb-100012
    Figure PCTCN2018093134-appb-100012
  10. 一种树状多缩乙二醇衍生物的制备方法，其采用收敛合成法，包括如下步骤：A method for preparing a dendritic polyglycol derivative, which adopts a convergence synthesis method, comprising the following steps:
    (1)将多缩乙二醇衍生物一端修饰后，与中心分子发生亲核取代反应或酰胺化反应连接；(1) after modifying one end of the polyglycolic acid derivative, a nucleophilic substitution reaction or an amidation reaction is carried out with the central molecule;
    (2)将步骤(1)的反应产物中中心分子部分的一端修饰后，与中心分子发生亲核取代反应或酰胺化反应连接，得到四臂树状多缩乙二醇衍生物；(2) modifying one end of the central molecular moiety in the reaction product of the step (1), and then performing a nucleophilic substitution reaction or an amidation reaction with the central molecule to obtain a four-arm dendritic polyglycol derivative;
    以此类推，可得到臂数呈指数增长的树状多缩乙二醇衍生物；By analogy, a dendritic polyglycol derivative having an exponential increase in the number of arms can be obtained;
    步骤(1)中所述的多缩乙二醇衍生物，其结构为R-X-E-R t-OH、R-X-E-R t-NH 2或R-X-E-R t-COOH； The polyglycol derivative described in the step (1), which has the structure RXER t -OH, RXER t -NH 2 or RXER t -COOH;
    其中，among them,
    R t选自：-(CH 2) t-、-(CR 1R 2) t-、-(CH 2) tNH-、-NHCO(CH 2) t-、-(CH 2) tCONH-和-CO(CH 2) t-中的一种或多种的组合，t为0-30的整数； R t is selected from: -(CH 2 ) t -, -(CR 1 R 2 ) t -, -(CH 2 ) t NH-, -NHCO(CH 2 ) t -, -(CH 2 ) t CONH- and a combination of one or more of -CO(CH 2 ) t -, t is an integer from 0 to 30;
    R 1和R 2独立地选自：-H、C1-C6的烷基、-OR'、-NHR'、-N(R') 2、-CN、-F、-Cl、-Br、-I、-COR'、-COOR'、-OCOR'、-CONHR'和-CON(R') 2中的一种或多种的组合， R 1 and R 2 are independently selected from: -H, C1-C6 alkyl, -OR', -NHR', -N(R') 2 , -CN, -F, -Cl, -Br, -I a combination of one or more of -COR', -COOR', -OCOR', -CONHR', and -CON(R') 2 ,
    R″选自：-H、C1-C6的烷基、-F、-Cl、-Br和-I，R" is selected from the group consisting of: -H, a C1-C6 alkyl group, -F, -Cl, -Br, and -I,
    X为连接基团，选自：-(CH 2) i-、-(CH 2) iNH-、-CO(CH 2) i-、-(CH 2) iOCOO-、-(CH 2) iOCONH-、-(CH 2) iNHCONH-、-OC(CH 2) iCOO-、-(CH 2) iCOO-和-(CH 2) iCONH-中的一种或两种以上的组合，i为0-10的整数； X is a linking group selected from: -(CH 2 ) i -, -(CH 2 ) i NH-, -CO(CH 2 ) i -, -(CH 2 ) i OCOO-, -(CH 2 ) i One or a combination of two or more of OCONH-, -(CH 2 ) i NHCONH-, -OC(CH 2 ) i COO-, -(CH 2 ) i COO-, and -(CH 2 ) i CONH-, i is an integer from 0-10;
    R选自：C1-C6的烷基、C1-C6的烷氧基、H、羟基、氨基、氨甲基、马来酰亚胺基、羧基、酯基、巯基、琥珀酰亚胺碳酸酯、琥珀酰亚胺乙酸酯、琥珀酰亚胺丙酸酯、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸酯基、叠氮基、戊二酸基、酰肼基、炔基、对硝基苯碳酸酯基、异氰酸基、硅烷基、羧甲基、乙烯砜基、维生素H残基、甲酯、乙酯、叔丁酯、缩醛基、苄氧基、叔丁氧基、亚胺基和卤素中的一种；R is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, H, hydroxy, amino, aminomethyl, maleimide, carboxyl, ester, decyl, succinimide carbonate, Succinimide acetate, succinimide propionate, succinimide succinate, succinimide, dithiopyridyl, propionate, aldehyde, oxime, acrylate, acrylic Ester, azide, glutaric acid, hydrazide, alkynyl, p-nitrophenyl carbonate, isocyanate, silane, carboxymethyl, vinylsulfone, vitamin H residue, methyl ester One of ethyl ester, tert-butyl ester, acetal, benzyloxy, tert-butoxy, imido and halogen;
    E为多缩乙二醇基团，其结构为：(OCH 2CH 2) m，m为0-100的整数； E is a polyglycol group having a structure of: (OCH 2 CH 2 ) m and m is an integer of 0-100;
    所述的修饰基团选自：-OTs、-OMs、-OBs、-OTf、-F、-Cl、-Br、-I、-NH 2和-COOH； The modifying group is selected from the group consisting of: -OTs, -OMs, -OBs, -OTf, -F, -Cl, -Br, -I, -NH 2 and -COOH;
    所述的中心分子含有如下结构：-NH 2、
    Figure PCTCN2018093134-appb-100013
    Figure PCTCN2018093134-appb-100014
    The central molecule has the following structure: -NH 2 ,
    Figure PCTCN2018093134-appb-100013
    Figure PCTCN2018093134-appb-100014
    Z选自：O、S、NH、NHCO、CO、COO、OC(O)和(CH 2) s中的一种，s为0-10的整数； Z is selected from one of: O, S, NH, NHCO, CO, COO, OC(O), and (CH 2 ) s , and s is an integer from 0 to 10;
    p为0-10的整数；p is an integer from 0 to 10;
    W为O或S；W is O or S;
    V为O或NH。V is O or NH.
  11. 一种权利要求1-9任一项所述的树状多缩乙二醇衍生物在超分子化学、生物医学、光化学或电化学或催化剂领域中的应用。Use of a dendritic polyethylene glycol derivative according to any one of claims 1 to 9 in the field of supramolecular chemistry, biomedicine, photochemistry or electrochemistry or catalysts.
  12. 如权利要求11所述的应用，其特征在于，所述应用为权利要求1-9任一项所述的树状多缩乙二醇衍生物在生物医学中的应用。The use according to claim 11, wherein the application is the use of the dendritic polyethylene glycol derivative according to any one of claims 1 to 9 in biomedicine.
  13. 如权利要求12所述的应用，其特征在于，所述的应用为权利要求1-9任一项所述的树状多 缩乙二醇衍生物在修饰药物中的应用，所述的药物优选为难溶性药物。The use according to claim 12, wherein the application is the use of the dendritic polyethylene glycol derivative according to any one of claims 1 to 9 in a modified drug, the drug preferably It is a poorly soluble drug.
  14. 一种共价结合物，其包含通过共价键连接的权利要求1-9任一项所述的树状多缩乙二醇衍生物和药物分子。A covalent conjugate comprising the dendritic polyglycol derivative of any of claims 1-9 and a drug molecule linked by a covalent bond.
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CN102367291A (en) * 2011-04-26 2012-03-07 刘超 Mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method
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Publication number Priority date Publication date Assignee Title
CN101389354A (en) * 2005-11-30 2009-03-18 遗传工程与生物技术中心 Four branched dendrimer-PEG for conjugation to proteins and peptides
CN102367291A (en) * 2011-04-26 2012-03-07 刘超 Mono-functional group-containing multilevel branched polyethylene glycol and its synthesis method
CN104387577A (en) * 2013-05-28 2015-03-04 厦门赛诺邦格生物科技有限公司 Single functionalized polyethylene glycol with nitrogen-atom branching center, preparation method and biologically-relevant substance thereof
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