WO2019149086A1 - POLYETHER-B-POLY (γ-BUTYROLACTONE) BLOCK COPOLYMER AND PREPARATION METHOD THEREFOR - Google Patents

Abstract

Provided by the present invention are a compound and a preparation method therefor. The compound is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate or a solvate of the compound of the formula (I). (I)

Description

Polyether-b-poly(γ-butyrolactone) block copolymer and preparation method thereof Technical field

The invention relates to the field of chemical engineering. In particular, the present invention relates to polyether-b-poly(?-butyrolactone) block copolymers and processes for their preparation.

Background technique

Amphiphilic block copolymers are an important class of polymeric materials that can self-assemble into micelles, vesicles or hydrogels in aqueous solutions and have important applications in biomedical applications, including drug delivery, gene transfection. , tissue engineering repair, etc. Among them, polyethylene oxide (PEG) is often used as the hydrophilic segment therein. PEG has been approved by the US Food and Drug Administration (FDA) for clinical use. PEG-encapsulated drugs can significantly prolong the cycle time of the drug in the blood while reducing the endocytosis of the immune system. The aliphatic polyester has good biocompatibility and biodegradability, low immunogenicity and good mechanical properties, and is an ideal choice for hydrophobic segments.

However, polyethylene oxide-aliphatic polyester block copolymers are still to be developed.

Summary of the invention

The present invention aims to solve at least one of the problems of the prior art at least to some extent.

It should be noted that the present invention has been completed based on the following findings of the inventors:

Poly(γ-butyrolactone) is an important class of aliphatic polyesters with the following advantages: γ-butyrolactone can be prepared from succinic acid, with a wide range of sources and low cost. Succinic acid can be obtained from biomass materials such as corn, wheat and other crops and is a renewable raw material. Poly(γ-butyrolactone) has a suitable degradation rate in vivo, between polyglycolide and polylactic acid, but unlike polyglycolide and polylactic acid, poly(γ-butyrolactone) is degraded. It does not cause accumulation of acidic substances in tissues and is not easy to cause inflammation, so it is particularly suitable for use in the biomedical field. Currently, poly(γ-butyrolactone) has been approved by the FDA and can be used clinically as a surgical suture and hernia patch. The above properties have been reported in related literature (Biochem. Eng. J. 2003, 16, 97-105; Biomed. Tech. (Berl) 2013, 58, 439-452; Angew. Chem. Int. Ed. 2016, 55, 4188 -4193; Nat. Chem. 2016, 8, 42-49).

However, γ-butyrolactone has a five-membered ring structure and a small ring tension, and it is difficult to obtain a high molecular weight poly(γ-butyrolactone) by a ring-opening polymerization method. The poly(?-butyrolactone) currently used commercially is mainly obtained by a biological fermentation method, which makes it difficult to prepare a copolymer having a complicated structure of γ-butyrolactone and other monomers by a chemical modification method.

In view of this, the inventors attempted to use the hydroxyl terminated polyether as a macroinitiator to successfully succeed at low temperatures by screening suitable reaction conditions under the catalysis of a catalyst or an alkali metal or an alkali metal compound or an alkali metal alkoxide. A polyether-b-poly(?-butyrolactone) block copolymer was obtained. In particular, the low temperature condition can effectively reduce the influence of the entropy effect of the system during the polymerization process, and is an important condition for ensuring the success of the polymerization. It should be noted that the present invention is the first to obtain an amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer, which is expected to have great application prospects in biomedical fields such as drug delivery and tissue engineering repair. . Compared with the existing polyether-b-polyester system, the degradation rate of the polyether-b-poly(γ-butyrolactone) block copolymer is more suitable in vivo, and it is not easy to cause inflammation in the body. A more ideal medical biomaterial.

To this end, in one aspect of the invention, the invention proposes a compound. According to an embodiment of the present invention, the compound is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate of a compound represented by the formula (I) or a compound of the formula (I). Or solvate,

among them,

R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused bicyclic, spirobicyclo, fused heterobicyclic, spiro a heterobicyclic group or a group represented by the formula (II),

R _{1 is} selected from hydrogen or a group of one of the following:

R _{2 is} selected from the group consisting of one of the following:

R ₃ and R ₄ are each independently selected from alkyl, alkenyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl.

x, y and n are each independently selected from a natural number of not less than 5.

The compound of the present invention is a block copolymer formed of a polyether and poly(?-butyrolactone). The block copolymer is initiated by a hydroxyl terminated polyether, and when the terminal hydroxyl polyether is a single terminal hydroxyl group, a polyether-b-poly(γ-butyrolactone) two-block copolymer is obtained; when the terminal hydroxyl polyether is double The terminal hydroxyl group is symmetrical with a polyether as a poly(γ-butyrolactone)-b-polyether-b-poly(γ-butyrolactone) triblock copolymer. The present invention is the first to obtain an amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer, which is expected to have great application prospects in biomedical fields such as drug delivery and tissue engineering repair. Compared with the existing polyether-b-polyester system, the degradation rate of the polyether-b-poly(γ-butyrolactone) block copolymer is more suitable in vivo, and it is not easy to cause inflammation in the body. A more ideal medical biomaterial.

According to an embodiment of the invention, the above compounds may also have the following additional technical features:

According to an embodiment of the invention, R ₃ and R ₄ are each independently selected from the group consisting of one of the following:

According to an embodiment of the invention, the compound has the structure of one of the following:

Wherein each R _{5 is} independently selected from hydrogen, methyl or ethyl.

According to an embodiment of the invention, the compound has the structure of one of the following:

In another aspect of the invention, the invention provides a method of preparing a compound as described above. According to an embodiment of the invention, the method comprises:

(1) dissolving a catalyst or an alkali metal or alkali metal compound or an alkali metal alkoxide compound and a hydroxyl terminated polyether in an organic solvent to obtain a mixed solution;

(2) mixing γ-butyrolactone with the mixed solution, and reacting, adding a compound having a reactive functional group to terminate the reaction, adding the reaction mixture to methanol, collecting a precipitate to obtain the compound, wherein the reaction It is carried out at -70 to -20 °C.

The inventors attempted to utilize a hydroxyl terminated polyether as a macroinitiator, under the catalysis of a catalyst or an alkali metal or an alkali metal compound or an alkali metal alkoxide, by screening suitable reaction conditions at a low temperature (-70~- A polyether-b-poly(?-butyrolactone) diblock copolymer was successfully obtained at 20 °C. In particular, the low temperature condition can effectively reduce the influence of the entropy effect of the system during the polymerization process, and is an important condition for ensuring the success of the polymerization. The method has high yield, good product purity, simple operation and is suitable for large-scale production. At the same time, it should be pointed out that the present invention is the first to obtain an amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer, which is expected to have a huge biomedical field such as drug delivery, tissue engineering repair, and the like. Application prospects. Compared with the existing polyether-b-polyester system, the degradation rate of the polyether-b-poly(γ-butyrolactone) block copolymer is more suitable in vivo, and it is not easy to cause inflammation in the body. A more ideal medical biomaterial.

According to an embodiment of the present invention, the step (1) further comprises: dissolving the catalyst or the alkali metal or alkali metal compound or the alkali metal alkoxide with the terminal hydroxyl polyether and urea in an organic solvent to obtain a mixed liquid. By further adding a co-catalyst urea to the reaction system, the controllability of the polymerization reaction can be improved, and the molecular weight of the block copolymer can be effectively controlled.

According to an embodiment of the present invention, the urea is a compound of the formula (III), and R ₆ and R ₇ are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclohexyl, phenyl, 4-chloro Phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxy Phenyl.

According to an embodiment of the invention, the urea has a structure of one of the following:

According to an embodiment of the invention, the molar ratio of the catalyst or alkali metal or alkali metal compound or alkali metal alkoxide to urea is 1: (1 to 10). Thereby, the controllability of the polymerization reaction can be improved, and the molecular weight of the block copolymer can be effectively controlled.

According to an embodiment of the invention, the catalyst is selected from the group consisting of organophosphazene base catalysts, preferably hexa[tris(dimethylamine)phosphazene]tripolyphosphazene, phosphazene ligand P4-tert-butyl or phosphazene P2-tert-butyl. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the invention, the alkali metal is selected from the group consisting of sodium or potassium, and the alkali metal compound is selected from the group consisting of sodium hydride, potassium hydride, sodium naphthalene, potassium naphthalate, sodium biphenyl, sodium diphenylmethyl or diphenylmethyl Potassium. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the invention, the alkali metal alkoxide is selected from the group consisting of potassium methoxide, sodium methoxide, sodium ethoxide or potassium ethoxide. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the invention, the hydroxyl terminated polyether is selected from the group consisting of polyethylene oxide monomethyl ether, polypropylene oxide monomethyl ether, poly(1,2-butylene oxide) monomethyl ether, polyepoxy Ethane, polypropylene oxide, poly(1,2-butylene oxide), polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide or poly(ethylene oxide-ran- Propylene oxide). The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the present invention, the reactive functional group-containing compound is selected from the group consisting of an acid, an acid chloride, an acid anhydride, a thioisocyanate, an isocyanate or a halogenated hydrocarbon, preferably acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, and dibutyl Anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxyphenylthioisocyanate, 4-methoxyphenyl isocyanate. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the present invention, the method comprises: (1-1) dissolving the hydroxyl terminated polyether and the catalyst in an organic solvent, and stirring in a low temperature cold bath; (1-2) adding the γ-butyrolactone step (1-1) In the obtained mixed solution, the reaction is carried out, the reaction is terminated by adding a compound having a reactive functional group, the reaction mixture is added to methanol, and a precipitate is collected to obtain the compound, wherein the catalyst and the terminal hydroxyl polyether are obtained. The molar ratio is 1:3 to 2:1; the organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, 1,1. At least one of 2,2-tetrachloroethane, acetonitrile and dioxane; the low temperature cold bath agitation is carried out at -70 to -10 ° C for 10 to 30 minutes. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the present invention, the step (1-1) further comprises: dissolving the hydroxyl terminated polyether, the catalyst and the urea in an organic solvent, and stirring in a low temperature cold bath. Thus, by adding a co-catalyst urea to the reaction system to increase the controllability of the polymerization reaction, the molecular weight of the block copolymer is effectively controlled.

According to an embodiment of the present invention, the method comprises: (2-1) dissolving a hydroxyl terminated polyether and an alkali metal or an alkali metal compound in an organic solvent, performing a reaction under a nitrogen atmosphere, and filtering to obtain a polyether alkali metal salt. (2-2) dissolving the polyether alkali metal salt solution and γ-butyrolactone in an organic solvent, performing a reaction, adding a compound having a reactive functional group to terminate the reaction, adding the reaction mixture to methanol, and collecting the precipitate. In order to obtain the compound, wherein the molar ratio of the hydroxyl terminated polyether to the alkali metal or alkali metal compound is 1:1 to 1:10; in the step (2-1), the temperature of the reaction is 25 to 70. °C, the time is 0.5-72h, the organic solvent is selected from tetrahydrofuran or dioxane; in the step (2-2), the organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-di At least one of ethyl chloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile and dioxane; the polyether alkali metal salt and γ-butyrolactone The molar ratio is 1:10 to 1:200. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the present invention, the step (2-1) further comprises: dissolving the hydroxyl terminated polyether and the alkali metal or alkali metal compound and urea in an organic solvent, performing the reaction under the protection of nitrogen, and filtering to obtain a polyether alkali. Metal salt solution and urea. Thus, by adding a co-catalyst urea to the reaction system to increase the controllability of the polymerization reaction, the molecular weight of the block copolymer is effectively controlled.

According to an embodiment of the present invention, the method comprises: (3-1) dissolving a hydroxyl terminated polyether and an alkali metal alkoxide in an organic solvent, and stirring in a low temperature cold bath; (3-2) γ- The butyrolactone is added to the mixed solution obtained in the step (3-1), the reaction is carried out, the reaction is terminated by adding a compound having a reactive functional group, the reaction mixture is added to methanol, and a precipitate is collected to obtain the compound, wherein the base is obtained. The molar ratio of the metal alkoxide to the terminal hydroxyl polyether is 1:1 to 2:1; the organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2 - at least one of dichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile and dioxane; the low temperature cold bath agitation is carried out at -70 to -10 °C for 10 to 30 minutes. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

According to an embodiment of the present invention, the step (3-1) further comprises: dissolving the hydroxyl terminated polyether, the alkali metal alkoxide, and urea in an organic solvent, and stirring in a low temperature cold bath. Thus, by adding a co-catalyst urea to the reaction system to increase the controllability of the polymerization reaction, the molecular weight of the block copolymer is effectively controlled.

According to an embodiment of the present invention, the terminal hydroxyl polyether has a molecular weight of 200 to 40,000 g/mol, and the molar ratio of the hydroxyl terminated polyether to the γ-butyrolactone is 1:10 to 1:200; The molar concentration of butyrolactone in the system is 2-10 mol/L; the molar ratio of the reactive functional group-containing compound to the terminal hydroxyl polyether is 1:1 to 10:1; and the reaction is at -70 to -20 °C. The next 0.5 to 12h. The inventors have found through extensive experiments that the yield of the compound obtained under these conditions is high and the purity is good.

The additional aspects and advantages of the invention will be set forth in part in the description which follows.

DRAWINGS

The above and/or additional aspects and advantages of the present invention will become apparent and readily understood from

1 is a 1H NMR spectrum of polyethylene oxide-b-poly(γ-butyrolactone) obtained in Example 1;

2 is a 13C NMR spectrum of polyethylene oxide-b-poly(γ-butyrolactone) obtained in Example 1;

3 is a GPC spectrum of polyethylene oxide-b-poly(γ-butyrolactone) and PEG2000 prepared in Example 1;

4 is an infrared spectrum of polyethylene oxide-b-poly(γ-butyrolactone) obtained in Example 1;

Figure 5 is a transmission electron micrograph of an assembly of polyethylene oxide-b-poly(?-butyrolactone) obtained in Example 1 in water, wherein (a) is a vesicle, and (b) is Micellar

6 is a release curve of DOX/mPEG-PBL amphiphilic block copolymer drug-loaded micelles in a buffer solution of pH=7.4 in Example 1;

7 is a result of toxicity test of mPEG-PBL (a), DOX/mPEG-PBL drug-loaded micelles (b) and DOX (c) on Hela cells in Example 1;

Figure 8 is a 1H NMR spectrum of polyethylene oxide-b-poly(?-butyrolactone) obtained in Example 2;

Figure 9 is a GPC chart of polyethylene oxide-b-poly(?-butyrolactone) and PEG2000 prepared in Example 2;

Figure 10 is a 1H NMR spectrum of polyethylene oxide-b-poly(?-butyrolactone) obtained in Example 3;

Figure 11 is a GPC chart of polyethylene oxide-b-poly(?-butyrolactone) and PEG5000 prepared in Example 3;

Figure 12 is an infrared spectrum of polyethylene oxide-b-poly(?-butyrolactone) obtained in Example 3;

Figure 13 is a GPC chart of polyethylene oxide-b-poly(?-butyrolactone) and PEG2000 prepared in Example 4;

Figure 14 is a GPC chart of polyethylene oxide-b-poly(?-butyrolactone) and PEG2000 prepared in Example 5.

Detailed ways

Embodiments of the present invention are described in detail below. The embodiments described below are illustrative only and are not to be construed as limiting the invention.

Definitions and general terms

In the context of the present invention, all numbers disclosed herein are approximate. The value of each number may vary by 1%, 2%, 5%, 7%, 8% or 10%. Whenever a number with an N value is disclosed, any has N +/- 1%, N +/- 2%, N +/- 3%, N +/- 5%, N +/- 7%, N +/- 8% or N+ A number within the /-10% value will be explicitly disclosed, where "+/-" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, when a value range is disclosed, any value within the disclosed range will be explicitly disclosed.

All the reaction steps described in the present invention are reacted to a certain extent, such as raw material consumption of more than 70%, greater than 80%, greater than 90%, greater than 95%, or post-treatment after detection of the reaction raw materials have been consumed, such as cooling, collection, Extraction, filtration, separation, purification treatment, or a combination thereof. The degree of the reaction can be detected by a conventional method such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) or the like. The reaction solution may be post-treated by a conventional method, for example, by vacuum evaporation or conventional distillation to collect the crude product, and directly input to the next reaction; or directly filtered to obtain a crude product, which is directly added to the next reaction; or left to stand. Thereafter, the supernatant liquid is decanted to obtain a crude product, which is directly fed to the next reaction; or a suitable organic solvent or a combination thereof is selected for purification steps such as extraction, distillation, crystallization, column chromatography, rinsing, and beating.

Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. , the entire contents of which is incorporated herein by reference.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

"Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis 20/trans) isomers, atropisomers, etc. Wait.

The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, 25 acetic acid, aminoethanol.

The "nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).

The symbol "ran" in the structural formula of the present invention means a random copolymer, that is, the monomers M1, M2 are randomly arranged on a macromolecular chain, and the two monomers are randomly distributed in the main chain, and none of them Monomers can form separate longer segments on the molecular chain.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups wherein the alkyl group can be independently and optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms; in other embodiments, the alkyl group contains 1-6 A further carbon atom, in other embodiments, the alkyl group contains from 1 to 4 carbon atoms; in other embodiments, the alkyl group contains from 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl or isobutyl, 1-methylpropyl Or sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1- Butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2 -pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, Positive heptyl, n-octyl, and so on. The term "alkyl" and its prefix "alk" are used herein to encompass both straight-chain and branched saturated carbon chains. The alkyl group may be substituted with a substituent as described herein.

The term "alkoxy" as used in the present invention relates to an alkyl group, as defined in the present invention, attached to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like. The alkoxy group may be substituted with a substituent as described herein.

The term "cycloalkyl" or "carbocyclic" refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring and does not contain a heteroatom, including a single ring of 3 to 12 carbon atoms or 3 to A bicyclic or tricyclic ring of 12 carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1 -cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, etc. . Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group, ie, a cycloalkylene group. The C ₄ cycloalkyl group means a cyclobutyl group, the C ₅ cycloalkyl group means a cyclopentyl group, and the C ₇ cycloalkyl group means a cycloheptyl group. The cycloalkyl group may be substituted with a substituent as described herein.

The term "aryl" may be a monocyclic, bicyclic, and tricyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system contains from 6 to 8 atoms and has only one point of attachment to the molecule The rest are connected. The term "aryl" may be used interchangeably with the term "aromatic ring", such as an aromatic ring which may include phenyl, naphthyl and anthracene. Depending on the structure, the aryl group may be a monovalent group or a divalent group, ie, an arylene group. The aryl group may be substituted with a substituent as described herein.

The terms "heteroaryl" and "heteroaryl" are used interchangeably herein to refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein a bicyclic heteroaryl ring, a tricyclic heteroaryl ring or a tetracyclic ring is used. The aromatic ring system is fused in a fused form. Wherein at least one ring system of the heteroaromatic ring system is aromatic, and one or more atoms on the ring are independently and optionally substituted by a hetero atom. The heteroaryl system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. The heteroaryl system group may be a single ring composed of 3-7 atoms.

In other embodiments, heteroaromatic systems (including heteroaryl, heteroaryl) include the following examples, but are not limited to these examples: furan-2-yl, furan-3-yl, N-imidazolyl, imidazole-2 -yl, imidazol-4-yl, imidazol-5-yl, isoxazol-3-yl, oxazol-4-yl, oxazol-5-yl, 4-methylisoxazole-5-yl, N - pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl, xylyl, thiazol-2-yl, tetrazolyl, triazolyl and the like. The heteroaryl group can be substituted with a substituent as described herein.

The "heterocyclic group" may be a carbon group or a hetero atom group. "Heterocyclyl" also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxazyl, azetidinyl, thioheterobutyl, piperidinyl, epoxypropyl, azepanyl, oxetanyl, thietyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, oxazepine, diaza Zhuoji, thiazepine, pyrrolin-1-yl, 2-pyrolinyl, 3-pyrrolyl, indanyl, indanyl, pyridazinyl, fluorenyl, iso Benzotetrahydrofuranyl, isobenzotetrahydrothiol.

In some embodiments, a heterocyclic group is a heterocyclic group consisting of 1 to 12 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 1 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen and sulfur. And oxygen atoms. Examples of the heterocyclic group consisting of 1 to 12 atoms include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, 2-pyrroline, pyrazolinyl, pyrazolidinyl, Imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydrogen Pyranyl, tetrahydrothiopyranyl, piperidinyl, and the like.

The terms "spirocyclyl", "spirocyclic", "spirobicyclo", and "spirobicyclic" mean that one ring originates from a particular cyclic carbon on the other ring. For example, as described below, a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring." Each ring in the spiral ring is either a carbon ring or a heteroalicyclic ring. Such examples include, but are not limited to, spiro[2.4]heptane-5-yl, spiro[4.4]decylalkyl, and the like.

The term "spirobicyclo" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, a saturated bridged ring system (rings D and B') is referred to as a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring." And at least one ring system comprises one or more heteroatoms, examples of which include, but are not limited to, 4-azaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptyl, 5-aza Spiro[2.4]heptyl, 2-azaspiro[4.5]decyl, 2-azaspiro[3.3]heptyl, 1,7-diazaspiro[4.4]decyl, 1,7 -diazaspiro[4.4]decane-6-one-yl, 2,9-diazaspiro[5.5]undec-1-one-yl, 1-oxo-3,8-diazaspiro [4.5] decane-2-one-yl, 1-oxo-3,7-diazaspiro[4.5]decane-2-one-yl, 2,6-diazaspiro[3.3]heptyl , 2-oxo-7-azaspiro[3.5]decylalkyl, 2-oxo-6-azaspiro[3.4]octyl and the like. Depending on the structure, the spirobicyclic group may be a monovalent group or a divalent group, that is, a spirobicyclo group. The spiroheterocyclyl can be substituted with a substituent as described herein.

The term "fused bicyclic", "fused ring", "fused bicyclic" or "fused ring" means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic of. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring. Each of the fused bicyclic rings is either a carbocyclic ring or a heteroalicyclic group, and such examples include, but are not limited to, hexahydro-furan [3,2-b]furanyl, 2,3,3a,4 , 7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0] hexane 1,2,3,4,4a,5,8,8a-octahydronaphthyl, these are all contained within the fused bicyclic system.

The term "fused heterobicyclic" means a saturated or unsaturated fused ring system involving a non-aromatic bicyclic system, at least one of which is non-aromatic. Such a system may comprise an independent or conjugated unsaturated state, but the core structure does not comprise an aromatic ring or an aromatic heterocyclic ring (but an aromatic may serve as a substituent thereon), and at least one ring system comprises one or more Hetero atom.

Example 1

The (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.05mmol, 60mg) hexa [tris (dimethylamino) phosphazene] phosphate trimer Nitrile was added to the reaction tube, placed in a -40 ° C low temperature cold bath, 1.2 mL of dichloromethane was added, stirred for 10 min to make the system evenly mixed, placed in a low temperature cold bath of -50 ° C, and 1.15 mL of γ-butyrolactone was added by syringe. Into the reaction tube. The reaction was carried out under nitrogen for 4 h, acetic acid (0.15 mmol) was added, and the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). The structure is as follows:

Nuclear magnetic resonance spectrum ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.11 (425H, t), 3.65 (180H, s), 3.38 (3H, s), 2.39 (426H, t), 1.96 (438H, m ). Nuclear magnetic carbon spectrum ¹³ C NMR (126 MHz, CDCl ₃ ) δ (ppm): 172.6, 70.48, 63.44, 30.56, 23.89. The number average molecular weight measured by GPC was 16.5 kg/mol, and the molecular weight distribution was 1.33. The obtained magnetic resonance spectrum of the block copolymer is shown in Fig. 1, the carbon spectrum is shown in Fig. 2, the GPC curve is shown in Fig. 3, and the infrared spectrum is shown in Fig. 4.

The polyether-b-poly(?-butyrolactone) block copolymer can self-assemble in aqueous solution to form micelles or vesicles (Fig. 5) for use as a drug carrier. Figure 6 shows the release profile of polyether-b-poly(γ-butyrolactone) block copolymer loaded with doxorubicin (DOX) in a pH=7.4 buffer solution, indicating polyether-b-poly(γ - Butyrolactone) block copolymer has a good controlled release effect on doxorubicin. In addition, Figure 7 shows the toxicity test of Hela cells after loading polyether-b-poly(γ-butyrolactone) block copolymer with doxorubicin (DOX). The results show that polyether-b-poly(γ- The butyrolactone block copolymer itself is not cytotoxic, and can effectively kill cancer cells after loading doxorubicin.

Example 2

The (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.05mmol, 60mg) hexa [tris (dimethylamino) phosphazene] phosphate trimer Nitrile was added to the reaction tube, placed in a -40 ° C low temperature cold bath, added 0.6 mL of dichloromethane, stirred for 10 min to mix the system, placed in a low temperature cold bath of -50 ° C, 0.57mL γ-butyrolactone was added by syringe Into the reaction tube. The reaction was carried out under nitrogen for 4 h, acetic anhydride (0.3 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). The structure is shown below. :

Nuclear magnetic resonance spectrum ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.11 (160H, t), 3.65 (180H, s), 3.38 (3H, s), 2.39 (163H, t), 1.96 (180H, m ). The number average molecular weight measured by GPC was 11.7 kg/mol, and the molecular weight distribution was 1.93. The resulting nuclear copolymer hydrogen spectroscopy of the block copolymer is shown in Fig. 8, and the GPC curve is shown in Fig. 9.

Example 3

The (0.075mmol, 375mg) polyethylene oxide monomethyl ether (PEG5000, an average molecular weight M _n = 5000g / mol) and (0.05mmol, 60mg) hexa [tris (dimethylamino) phosphazene] phosphate trimer Nitrile was added to the reaction tube, placed in a low temperature cold bath at -50 ° C, 0.6 mL of dichloromethane was added, and the system was uniformly stirred for 10 minutes, and 0.57 mL of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen for 4 h, acryloyl chloride (0.15 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). The structure is shown below. :

Nuclear magnetic resonance spectrum ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.11 (312H, t), 3.65 (450H, s), 3.38 (3H, s), 2.39 (309H, t), 1.96 (314H, m ). The number average molecular weight measured by GPC was 10.9 kg/mol, and the molecular weight distribution was 2.50. The resulting nuclear copolymer hydrogen spectroscopy of the block copolymer is shown in Fig. 10, the GPC curve is shown in Fig. 11, and the infrared spectrum is shown in Fig. 12.

Example 4

The (0.075mmol, 152mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.15mmol, 3.6mg) NaH was added to the reaction flask, was added 5mL of tetrahydrofuran, under nitrogen at The reaction was refluxed for 24 h, the reaction mixture was filtered, and the filtrate was evaporated to dryness. Add 0.2 mL of tetrahydrofuran to the obtained sodium polyethoxide monomethyl ether, stir for 10 min, place in a low temperature cold bath at -50 ° C, add 0.4 mL of dichloromethane, stir for 10 min to mix the system uniformly, and 0.57 mL γ with a syringe. - Butyrolactone is added to the reaction tube. The reaction was carried out under nitrogen for 4 h, and epichlorohydrin (7.5 mmol) was added. The reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). Shown as follows:

The number average molecular weight measured by GPC was 12.4 kg/mol, and the molecular weight distribution was 1.48. The resulting block copolymer GPC curve is shown in FIG.

Example 5

In the (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.15mmol, 10.5mg) was added potassium methoxide reaction tube, was added 0.2mL of tetrahydrofuran, placed - In a 50 ° C low temperature cold bath, 0.4 mL of dichloromethane was added, and the system was uniformly stirred for 10 minutes, and 0.57 mL of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen for 4 h, 4-methoxyphenyl isocyanate (0.6 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). ), the structure is as follows:

The number average molecular weight measured by GPC was 4.5 kg/mol, and the molecular weight distribution was 1.66. The resulting block copolymer GPC curve is shown in Fig. 14.

Example 6

The (0.15mmol, 150mg) polyethylene oxide (of PEG1000, an average molecular weight M _n = 1000g / mol) and (0.3mmol, 6.9mg) was added sodium reaction tube, was added 0.2mL of tetrahydrofuran, under nitrogen, 25 ℃ After stirring for 60 min, it was placed in a low temperature cold bath of -50 ° C, 0.4 mL of dichloromethane was added, and the system was uniformly stirred for 10 min, and 1.15 mL of γ-butyrolactone was added to the reaction tube. The reaction was carried out under nitrogen for 2 h, succinic anhydride (0.45 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain poly(γ-butyrolactone)-b-polyethylene oxide-b-poly. (γ-butyrolactone), the structure is as follows:

The number average molecular weight measured by GPC was 6.1 kg/mol, and the molecular weight distribution was 1.45.

Example 7

The (0.1mmol, 250mg) polypropylene oxide monomethyl ether (PPG2500, an average molecular weight M _n = 2500g / mol) and (0.1mmol, 17.7mg) was added sodium -biphenyl reaction tube, was added 0.3mL of tetrahydrofuran, under nitrogen protection The mixture was stirred at 25 ° C for 30 min, placed in a low temperature cold bath at -50 ° C, added with 0.5 mL of dichloromethane, stirred for 10 min to uniformly mix the system, and 0.77 mL of γ-butyrolactone was added to the reaction tube. The reaction was carried out under nitrogen for 4 h, 3-chloropropene (0.2 mmol) was added, and the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polypropylene oxide-b-poly(γ-butyrolactone). Show:

The number average molecular weight measured by GPC was 4.4 kg/mol, and the molecular weight distribution was 1.35.

Example 8

The (0.1mmol, 200mg) -b- polyethylene oxide polypropylene oxide polyethylene oxide -b- (PEG-b-PPG-b -PEG, average molecular weight M _n = 2000g / mol), and (0.1 Methyl, 63.4mg) phosphazene ligand P4-tert-butyl (tert-Bu-P ₄ ) was added to the reaction tube, placed in a low temperature cold bath at -50 ° C, added 1 mL of dichloromethane, stirred for 10 min to make the system evenly mixed, 0.77 mL of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen for 4 h, 4-methoxyphenylthioisocyanate (0.3 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain a poly(gamma-butyrolactone)-b-polycyclic ring. Oxyethane-b-polypropylene oxide-b-polyethylene oxide-b-poly(γ-butyrolactone), the structure is as follows:

The number average molecular weight measured by GPC was 6.5 kg/mol, and the molecular weight distribution was 1.56.

Example 9

The (0.075mmol, 187.5mg) poly (ethylene oxide -ran- propylene oxide) (PEG-ran-PPG, an average molecular weight M _n = 2500g / mol) and (0.15mmol, 3.6mg) NaH was added to the reaction flask Into, 5 mL of tetrahydrofuran was added, and the reaction was refluxed under a nitrogen atmosphere for 24 hours, and the reaction mixture was filtered, and the filtrate was dried to give a poly(ethylene oxide-ran- propylene oxide) sodium. 0.2 mL of tetrahydrofuran was added to the obtained poly(ethylene oxide-ran-propylene oxide) sodium, stirred for 10 min, placed in a low temperature cold bath of -50 ° C, 0.4 mL of dichloromethane was added, and the mixture was stirred for 10 min to make the system uniformly mixed. 0.57 mL of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen for 4 h, maleimidobutyryl chloride (0.45 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain poly(γ-butyrolactone)-b-poly(epoxy). Ethane-ran-propylene oxide)-b-poly(γ-butyrolactone), the structure is as follows:

The number average molecular weight measured by GPC was 10.4 kg/mol, and the molecular weight distribution was 1.41.

Example 10

A compound was prepared according to the method of Example 1, except that acetic acid was replaced with the active functional group-containing compound shown in Table 1, thereby obtaining the corresponding polyether-b-poly(?-butyrolactone) block copolymer.

Table 1

Example 11

A compound was prepared according to the method of Example 6 except that succinic anhydride was replaced with the active functional group-containing compound shown in Table 2 to give the corresponding polyether-b-poly(?-butyrolactone) block copolymer.

Table 2

Example 12

A compound was prepared according to the method of Example 7, except that 3-chloropropene was replaced with the active functional group-containing compound shown in Table 3, thereby obtaining the corresponding polyether-b-poly(γ-butyrolactone) block copolymer. .

table 3

Example 13

A compound was prepared according to the method of Example 8, except that 4-methoxyphenylthioisocyanate was replaced with the active functional group-containing compound shown in Table 4, thereby obtaining the corresponding polyether-b-poly(γ-butane). Ester) block copolymer.

Table 4

Example 14

A compound was prepared according to the method of Example 9, except that the maleimidobutyryl chloride was replaced with the active functional group-containing compound shown in Table 5, thereby obtaining the corresponding polyether-b-poly(γ-butyrolactone). Block copolymer.

table 5

Example 15

A compound was prepared according to the method of Example 6 except that the polyethylene oxide was replaced with polypropylene oxide, and the succinic anhydride was replaced with the active functional group-containing compound shown in Table 6, thereby obtaining the corresponding polyether-b- Poly(γ-butyrolactone) block copolymer.

Table 6

Example 16

The (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.05mmol, 60mg) hexa [tris (dimethylamino) phosphazene] phosphate trimer Nitrile and (0.15mmol, 32.7mg) 1-cyclohexyl 3-phenylurea were added to the reaction tube, placed in a -40 ° C low temperature cold bath, added 1.2 mL of dichloromethane, stirred for 10 min, the system was mixed evenly, placed at -50 In a low temperature cold bath, (15 mmol, 1.15 mL) of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under nitrogen for 4 h, acetic acid (0.15 mmol) was added, and the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). The structure is as follows:

The number average molecular weight measured by GPC was 19.0 kg/mol, and the molecular weight distribution was 1.13. The molecular weight of the block copolymer obtained after the addition of 1-cyclohexyl 3-phenylurea is close to the designed molecular weight, and the molecular weight distribution is narrowed.

Example 17

The (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.15mmol, 3.6mg) NaH and (0.3mmol, 74.4) 1- cyclohexyl-3- ( 4-methoxyphenyl)urea was added to the reaction flask, 5 mL of tetrahydrofuran was added, and the reaction was refluxed at 25 ° C for 24 h under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was drained to obtain a mixture of sodium polyethoxide monomethyl ether and urea. . 0.2 mL of tetrahydrofuran was added to the mixture, stirred for 10 min, placed in a low temperature cold bath at -50 ° C, 0.4 mL of dichloromethane was added, and the mixture was stirred for 10 min to homogenize the system, and (7.5 mmol, 0.57 mL) of γ-butyrolactone was syringed. Add to the reaction tube. The reaction was carried out under nitrogen for 4 h, and epichlorohydrin (7.5 mmol) was added. The reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). Shown as follows:

The number average molecular weight measured by GPC was 10.6 kg/mol, and the molecular weight distribution was 1.08. The molecular weight of the block copolymer obtained after the addition of 1-cyclohexyl 3-(4-methoxyphenyl)urea is close to the designed molecular weight, and the molecular weight distribution is narrowed.

Example 18

The (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, an average molecular weight M _n = 2000g / mol) and (0.15mmol, 10.5mg) and potassium methoxide (0.45mmol, 125.2mg) 1- cyclohexyl - 3-(2,6-Dimethoxyphenyl)urea was added to the reaction tube, 0.2 mL of tetrahydrofuran was added, placed in a low temperature cold bath at -50 ° C, 0.4 mL of dichloromethane was added, and the mixture was stirred for 10 min to homogenize the system. A syringe (7.5 mmol, 0.57 mL) of γ-butyrolactone was added to the reaction tube. The reaction was carried out under nitrogen for 4 h, 4-methoxyphenyl isocyanate (0.6 mmol) was added, the reaction mixture was poured into excess methanol, and the precipitate was separated by centrifugation to obtain polyethylene oxide-b-poly(γ-butyrolactone). ), the structure is as follows:

The number average molecular weight measured by GPC was 10.5 kg/mol, and the molecular weight distribution was 1.06. The molecular weight of the block copolymer obtained after the addition of 1-cyclohexyl-3-(2,6-dimethoxyphenyl)urea is close to the designed molecular weight, and the molecular weight distribution is narrowed.

In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means a specific feature described in connection with the embodiment or example. A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (31)

1. A compound characterized by being a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate of a compound of formula (I). Or solvate,

   

   among them,

   R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused bicyclic, spirobicyclo, fused heterobicyclic, spiro a heterobicyclic group or a group represented by the formula (II),

   

   R _{1 is} selected from hydrogen or a group of one of the following:

   

   R _{2 is} selected from the group consisting of one of the following:

   

   R ₃ and R ₄ are each independently selected from alkyl, alkenyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl.

   x, y and n are each independently selected from a natural number of not less than 5.
2. The compound according to claim 1, wherein R ₃ and R ₄ are each independently selected from the group consisting of one of the following:

   
3. The compound according to claim 1, which has a structure of one of the following:

   

   Wherein each R _{5 is} independently selected from hydrogen, methyl or ethyl.
4. The compound according to claim 1, which has a structure of one of the following:

   

   

   

   

   

   
5. A method of preparing a compound according to any one of claims 1 to 4, comprising:

   (1) dissolving a catalyst or an alkali metal or alkali metal compound or an alkali metal alkoxide compound and a hydroxyl terminated polyether in an organic solvent to obtain a mixed solution;

   (2) mixing γ-butyrolactone with the mixed solution, and reacting, adding a compound having a reactive functional group to terminate the reaction, adding the reaction mixture to methanol, collecting a precipitate to obtain the compound, wherein the reaction It is carried out at -70 to -20 °C.
6. The method according to claim 5, wherein the catalyst is selected from the group consisting of organophosphazene base catalysts, preferably hexa[tris(dimethylamine)phosphazene]tripolyphosphazene, phosphazene ligand P4-tertiary Butyl or phosphazene ligand P2-tert-butyl.
7. The method according to claim 5, wherein the alkali metal is selected from sodium or potassium, and the alkali metal compound is selected from the group consisting of sodium hydride, potassium hydride, sodium naphthalene, potassium naphthalate, sodium biphenyl, and diphenylmethyl. Sodium or diphenylmethyl potassium.
8. The method according to claim 5, wherein the alkali metal alkoxide is selected from the group consisting of potassium methoxide, sodium methoxide, sodium ethoxide or potassium ethoxide.
9. The method according to claim 5, wherein said hydroxyl terminated polyether is selected from the group consisting of polyethylene oxide monomethyl ether, polypropylene oxide monomethyl ether, and poly(1,2-butylene oxide) single. Methyl ether, polyethylene oxide, polypropylene oxide, poly(1,2-butylene oxide), polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide or poly(ring) Oxyethane-ran-propylene oxide).
10. The method according to claim 5, wherein the reactive functional group-containing compound is selected from the group consisting of an acid, an acid chloride, an acid anhydride, a thioisocyanate, an isocyanate or a halogenated hydrocarbon, preferably acetic acid, benzoic acid, acryloyl chloride or methacryloyl chloride. , acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxyphenyl thioisocyanate, 4-methoxyphenyl Isocyanate.
11. The method according to claim 5, wherein the step (1) further comprises: dissolving the catalyst or the alkali metal or alkali metal compound or the alkali metal alkoxide with the hydroxyl terminated polyether and urea in an organic solvent, In order to get a mixture.
12. The method according to claim 11, wherein said urea is a compound of formula (III), and R ₆ and R ₇ are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclohexyl, Phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4 ,6-trimethoxyphenyl,

    
13. The method of claim 11 wherein said urea has a structure of one of the following:

    
14. The method according to claim 11, wherein the catalyst or the molar ratio of the alkali metal or alkali metal compound or alkali metal alkoxide to urea is 1: (1 to 10).
15. The method according to any one of claims 5 to 14, comprising:

    (1-1) dissolving the hydroxyl terminated polyether and the catalyst in an organic solvent, and stirring in a low temperature cold bath;

    (1-2) γ-butyrolactone is added to the mixed solution obtained in the step (1-1), the reaction is carried out, the reaction is terminated by adding a compound having a reactive functional group, the reaction mixture is added to methanol, and the precipitate is collected to obtain a solution. Said compound.
16. The method of claim 15 wherein the molar ratio of said catalyst to hydroxyl terminated polyether is from 1:3 to 2:1.
17. The method according to claim 15, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, 1,1. At least one of 2,2-tetrachloroethane, acetonitrile and dioxane.
18. The method according to claim 15, wherein said low temperature cold bath agitation is carried out at -70 to -10 ° C for 10 to 30 minutes.
19. The method according to claim 15, wherein the step (1-1) further comprises: dissolving the terminal hydroxyl polyether, the catalyst and the urea in an organic solvent, and stirring in a low temperature cold bath.
20. The method according to any one of claims 5 to 14, comprising:

    (2-1) dissolving the hydroxyl terminated polyether and the alkali metal or alkali metal compound in an organic solvent, performing the reaction under a nitrogen atmosphere, and filtering to obtain a polyether alkali metal salt solution;

    (2-2) dissolving the polyether alkali metal salt solution and γ-butyrolactone in an organic solvent, performing a reaction, adding a compound having a reactive functional group to terminate the reaction, adding the reaction mixture to methanol, and collecting the precipitate to obtain Said compound.
21. The method according to claim 20, wherein the molar ratio of the hydroxyl terminated polyether to the alkali metal or alkali metal compound is from 1:1 to 1:10.
22. The method according to claim 20, wherein in the step (2-1), the reaction temperature is 25 to 70 ° C and the time is 0.5 to 72 h, and the organic solvent is selected from tetrahydrofuran or dioxane. .
23. The method according to claim 20, wherein in the step (2-2), the organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2- At least one of dichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile and dioxane.
24. The method according to claim 20, wherein the molar ratio of the polyether alkali metal salt to γ-butyrolactone is from 1:10 to 1:200.
25. The method according to claim 20, wherein the step (2-1) further comprises: dissolving the hydroxyl terminated polyether and the alkali metal or alkali metal compound and urea in an organic solvent, and performing the reaction under the protection of nitrogen. After filtration, a polyether alkali metal salt solution and urea were obtained.
26. The method according to any one of claims 5 to 14, comprising:

    (3-1) dissolving the hydroxyl terminated polyether and the alkali metal alkoxide in an organic solvent, and stirring in a low temperature cold bath;

    (3-2) γ-butyrolactone is added to the mixed solution obtained in the step (3-1), the reaction is carried out, the reaction is terminated by adding a compound having a reactive functional group, the reaction mixture is added to methanol, and the precipitate is collected to obtain a solution. Compound,
27. The method according to claim 26, wherein the molar ratio of the alkali metal alkoxide to the terminal hydroxyl polyether is from 1:1 to 2:1.
28. The method according to claim 26, wherein said organic solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, 1,1 At least one of 2,2-tetrachloroethane, acetonitrile and dioxane.
29. The method according to claim 26, wherein said low temperature cold bath agitation is carried out at -70 to -10 ° C for 10 to 30 minutes.
30. The method according to claim 26, wherein the step (3-1) further comprises: dissolving the hydroxyl terminated polyether, the alkali metal alkoxide, and urea in an organic solvent, and stirring in a low temperature cold bath.
31. The method according to claim 5, wherein the hydroxyl terminated polyether has a molecular weight of 200 to 40,000 g/mol, and the molar ratio of the terminal hydroxyl polyether to the γ-butyrolactone is 1:10 to 1: 200; The molar concentration of the γ-butyrolactone in the system is 2 to 10 mol / L; the molar ratio of the reactive functional group-containing compound to the terminal hydroxyl polyether is 1:1 to 10:1;

    The reaction is carried out at -70 to -20 ° C for 0.5 to 12 hours.

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