CN110117359A - Poly- (gamma-butyrolacton) block copolymer of polyethers-b- and preparation method thereof - Google Patents

Abstract

The invention proposes a kind of compounds and preparation method thereof.The compound is stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate or the solvate of compound shown in formula (I) compound represented or formula (I).The present invention has obtained having poly- (gamma-butyrolacton) block copolymer of amphiphilic polyethers-b- for the first time, it is contemplated that has huge application prospect in biomedicine fields such as drug delivery, organizational project reparations.Compared with existing polyethers-b- polyester system, it is a kind of more ideal biomaterial for medical purpose that the degradation rate of poly- (gamma-butyrolacton) block copolymer of polyethers-b- in vivo is more suitable, while not easily causing the generation of internal inflammation.

Description

Polyether-b-poly(γ-butyrolactone) block copolymer and its preparation method

technical field

The invention relates to the field of chemical industry. Specifically, the present invention relates to polyether-b-poly(γ-butyrolactone) block copolymers and methods for their preparation.

Background technique

Amphiphilic block copolymers are an important class of polymer materials, which can self-assemble into micelles, vesicles or hydrogels in aqueous solution, and have important uses in biomedical fields, including drug delivery, gene transfection , tissue engineering restoration, 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 circulation time of drugs in the blood while reducing endocytosis by the immune system. On the other hand, aliphatic polyesters have good biocompatibility and biodegradability, low immunogenicity and good mechanical properties, making them ideal candidates for hydrophobic segments.

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

Contents 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 is based on the inventor's following findings:

Poly(γ-butyrolactone) is an important class of aliphatic polyesters, which has the following advantages: γ-butyrolactone can be prepared from succinic acid with wide sources and low price. Succinic acid can be obtained from biomass raw materials, such as corn, wheat and other crops, and is a renewable raw material. Poly(γ-butyrolactone) has a suitable degradation rate in vivo, which is between polyglycolide and polylactic acid, but unlike polyglycolide and polylactic acid, poly(γ-butyrolactone) degrades when It will not cause the accumulation of acidic substances in the tissue, and it is not easy to cause inflammation, so it is especially suitable for the field of biomedicine. Currently, poly(γ-butyrolactone) has been approved by the FDA and can be used clinically as surgical sutures and hernia mesh.

However, γ-butyrolactone has a five-membered ring structure, and the ring tension is small, so it is difficult to obtain high molecular weight poly(γ-butyrolactone) by ring-opening polymerization. Currently commercially used poly(γ-butyrolactone) is mainly obtained through biological fermentation, which makes it difficult to prepare copolymers of γ-butyrolactone with complex structures and other monomers by chemical modification.

In view of this, the inventors tried to use hydroxyl-terminated polyether as a macromolecular initiator, under the catalysis of a catalyst or an alkali metal or an alkali metal compound or an alkali metal alkoxy compound, by screening suitable reaction conditions, successfully A polyether-b-poly(γ-butyrolactone) block copolymer was obtained. In particular, low temperature conditions can effectively reduce the influence of the entropy effect of the system during the polymerization process, which is an important condition to ensure the success of the polymerization. It should be pointed out that the present invention has obtained amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer for the first time, 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 polyether-b-poly(γ-butyrolactone) block copolymer in vivo is more suitable, and at the same time, it is not easy to cause inflammation in vivo. 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 compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, or hydrate of a compound represented by formula (I) or solvates,

in,

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

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

R is selected from one of the following groups _:

_R and _R are independently selected from alkyl, alkenyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl,

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

The compounds of the present invention are block copolymers formed from polyether and poly(γ-butyrolactone). The block copolymer is initiated by a hydroxyl-terminated polyether. When the hydroxyl-terminated polyether is a single-terminal hydroxyl group, a polyether-b-poly(γ-butyrolactone) two-block copolymer is obtained; when the hydroxyl-terminated polyether is a double The hydroxyl groups at the terminals take the polyether as the axis to form poly(γ-butyrolactone)-b-polyether-b-poly(γ-butyrolactone) triblock copolymer symmetrically. The invention obtains the amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer for the first time, 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 polyether-b-poly(γ-butyrolactone) block copolymer in vivo is more suitable, and at the same time, it is not easy to cause inflammation in vivo. A more ideal medical biomaterial.

According to the embodiments of the present invention, the above compound may also have the following additional technical features:

According to an embodiment of the present invention, _R3 and _R4 are each independently selected from one of the following groups:

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

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

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

In another aspect of the present invention, the present invention provides a process for the preparation of the aforementioned compounds. According to an embodiment of the present invention, the method includes:

(1) Dissolving the catalyst or alkali metal or alkali metal compound or alkali metal alkoxy compound and hydroxyl-terminated polyether in an organic solvent to obtain a mixed solution;

(2) Mix γ-butyrolactone with the mixed solution and react, add a compound containing an active functional group to terminate the reaction, add the reaction mixture to methanol, and collect the precipitate to obtain the compound, wherein the reaction It is carried out at -70～-20°C.

The inventor tries to utilize the 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 alkoxy compound, by screening suitable reaction conditions, at low temperature (-70～- 20℃) successfully obtained polyether-b-poly(γ-butyrolactone) diblock copolymer. In particular, low temperature conditions can effectively reduce the influence of the entropy effect of the system during the polymerization process, which is an important condition to ensure 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 has obtained an amphiphilic polyether-b-poly(γ-butyrolactone) block copolymer for the first time, which is expected to have huge potential in biomedical fields such as drug delivery and tissue engineering repair. Application prospect. Compared with the existing polyether-b-polyester system, the degradation rate of polyether-b-poly(γ-butyrolactone) block copolymer in vivo is more suitable, and at the same time, it is not easy to cause inflammation in vivo. A more ideal medical biomaterial.

According to an embodiment of the present invention, the catalyst is selected from organic phosphazene base catalysts, preferably hexa[tri(dimethylamine)phosphazene]trimeric phosphazene, phosphazene ligand P4-tert-butyl or phosphazene ligand Body P2-tert-butyl. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the alkali metal is selected from sodium or potassium, and the alkali metal compound is selected from sodium hydride, potassium hydride, sodium naphthalene, potassium naphthalene, sodium biphenyl, sodium benzhydryl or benzhydryl potassium. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the alkali metal alkoxide is selected from potassium methoxide, sodium methoxide, sodium ethoxide or potassium ethoxide. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the hydroxyl-terminated polyether is selected from polyethylene oxide monomethyl ether, polypropylene oxide monomethyl ether, poly(1,2-butylene oxide) monomethyl ether, polyepoxide Ethylene, 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 a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the compound containing active functional groups is selected from acid, acid chloride, acid anhydride, thioisocyanate, isocyanate or halogenated hydrocarbon, preferably acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, butanediene Acid anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxyphenylthioisocyanate, 4-methoxyphenylisocyanate. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the method includes: (1-1) dissolving the hydroxyl-terminated polyether and the catalyst in an organic solvent, placing them in a low-temperature cooling bath and stirring; (1-2) adding γ-butyrolactone to the (1-1) In the obtained mixed solution, react, add a compound containing an active functional group to terminate the reaction, add the reaction mixture to methanol, collect the precipitate, so as to obtain the compound, wherein the catalyst and hydroxyl-terminated polyether The molar ratio is 1:3 to 2:1; the organic solvent is selected from tetrahydrofuran, dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, 1,1, At least one of 2,2-tetrachloroethane, acetonitrile and dioxane; the low-temperature cooling bath stirring is carried out at -70～-10°C for 10～30min. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the method includes: (2-1) dissolving the hydroxyl-terminated polyether and an alkali metal or an alkali metal compound in an organic solvent, reacting under nitrogen protection, and obtaining a polyether alkali metal salt after filtering solution; (2-2) dissolving the polyether alkali metal salt solution and γ-butyrolactone in an organic solvent, reacting, adding a compound containing an active functional group to terminate the reaction, adding the reaction mixture to methanol, 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 step (2-1), the reaction temperature is 25 to 70 °C, the time is 0.5-72h, the organic solvent is selected from tetrahydrofuran or dioxane; in step (2-2), the organic solvent is selected from tetrahydrofuran, dichloromethane, trichloromethane, 1,1-dioxane 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 a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the method includes: (3-1) dissolving the hydroxyl-terminated polyether and the alkali metal alkoxy compound in an organic solvent, placing them in a low-temperature cooling bath and stirring; (3-2) dissolving the γ- Add butyrolactone to the mixed solution obtained in step (3-1) to react, add a compound containing an active functional group to terminate the reaction, add the reaction mixture to methanol, and collect the precipitate to obtain the compound, wherein the base The molar ratio of the metal alkoxy compound to the hydroxyl-terminated polyether is 1:1 to 2:1; the organic solvent is selected from 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 stirring is carried out at -70 to -10° C. for 10 to 30 minutes. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

According to an embodiment of the present invention, the molecular weight of the hydroxyl-terminated polyether is 200-40000 g/mol, and the molar ratio of the hydroxyl-terminated polyether to γ-butyrolactone is 1:10-1:200; the γ- The molar concentration of butyrolactone in the system is 2 to 10 mol/L; the molar ratio of the active functional group-containing compound to the hydroxyl-terminated polyether is 1:1 to 10:1; the reaction is at -70 to -20°C Down for 0.5 ~ 12h. The inventors have found through a large number of experiments that the yield of the compound obtained under this condition is higher and the purity is better.

Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Description of drawings

The above and/or additional aspects and advantages of the present invention will become apparent and comprehensible from the description of the embodiments in conjunction with the following drawings, wherein:

Fig. 1 is the 1H NMR spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) that makes in embodiment 1;

Fig. 2 is the 1H NMR spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) that makes in embodiment 2;

Fig. 3 is the 1H NMR spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) that makes in embodiment 3;

Fig. 4 is the 13C NMR spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) that makes in embodiment 1;

Fig. 5 is the GPC spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) and PEG2000 that make in embodiment 1;

Fig. 6 is the GPC spectrogram of polyethylene oxide-b-poly(γ-butyrolactone) and PEG2000 prepared in embodiment 2;

Fig. 7 is the GPC spectrogram of polyethylene oxide-b-poly(γ-butyrolactone) and PEG5000 prepared in embodiment 3;

Fig. 8 is the GPC spectrogram of polyethylene oxide-b-poly(γ-butyrolactone) and PEG2000 prepared in embodiment 4;

Fig. 9 is the GPC spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) and PEG2000 that make in embodiment 5;

Fig. 10 is the infrared spectrogram of the polyethylene oxide-b-poly(γ-butyrolactone) that makes in embodiment 1;

Fig. 11 is the infrared spectrogram of polyethylene oxide-b-poly(γ-butyrolactone) prepared in Example 3.

Detailed ways

Embodiments of the present invention are described in detail below. The embodiments described below are exemplary only for explaining the present invention and should not be construed as limiting the present invention.

Definitions and General Terms

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

All the reaction steps of the present invention are reacted to a certain extent such as the consumption of raw materials is about greater than 70%, greater than 80%, greater than 90%, greater than 95%, or post-processing is carried out after the detection of reaction raw materials has been consumed, such as cooling, collecting, Extraction, filtration, separation, purification or a combination thereof. The degree of reaction can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and the like. The reaction solution can be post-treated by conventional methods, for example, the crude product is collected after vacuum evaporation or conventional distillation of the reaction solvent, and is directly put into the next step of reaction; or directly filtered to obtain the crude product, which is directly put into the next step of reaction; Finally, pour out the supernatant to obtain the crude product, which is directly put into the next reaction; or select an appropriate organic solvent or its combination to perform purification steps such as extraction, distillation, crystallization, column chromatography, rinsing, and beating.

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

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

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions 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, Its entire content is incorporated herein by reference.

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Wait.

The stereochemical definitions and rules used in the present invention generally follow S.P. 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 through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, 25 acetic acid, aminoethanol.

The "nitrogen oxide" in 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 N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).

The symbol "ran" in the structural formula of the present invention refers to a random copolymer (random copolymer), that is, the monomers M1 and M2 are randomly arranged on the macromolecular chain, and the two monomers are randomly distributed on the main chain. Monomers can form separate longer segments in the molecular chain.

The term "alkyl" as used herein includes saturated linear or branched monovalent hydrocarbon radicals, wherein the alkyl group may 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 carbon atoms, other embodiments are that the alkyl group contains 1-4 carbon atoms; other embodiments are that the alkyl group contains 1-3 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, n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains. Alkyl groups may be substituted with substituents described herein.

The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like. Alkoxy groups may be substituted with substituents described herein.

The term "cycloalkyl" or "carbocycle" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including monocyclic or 3 to 12 carbon atoms 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 by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, etc. . Depending on the structure, a cycloalkyl group can be a monovalent group or a divalent group, ie, a cycloalkylene group. C ₄ cycloalkyl refers to cyclobutyl, C ₅ cycloalkyl refers to cyclopentyl, and C ₇ cycloalkyl refers to cycloheptyl. Cycloalkyl groups may be substituted with substituents described herein.

The term "aryl" may refer to monocyclic, bicyclic and tricyclic carbocyclic ring systems, wherein at least one ring system is aromatic, wherein each ring system contains 6 to 8 atoms and has only one point of attachment to the molecule's The rest are connected. The term "aryl" may be used interchangeably with the term "aromatic ring", eg aromatic rings may include phenyl, naphthyl and anthracene. Depending on the structure, the aryl group can be a monovalent group or a divalent group, ie an arylene group. Aryl groups may be substituted with substituents described herein.

The terms "heteroaryl" and "heteroaromatic ring" 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 heteroaryl ring Aromatic ring systems are ringed in 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 replaced by heteroatoms. Heteroaryl systems can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. The heteroaromatic group can be a monocyclic ring consisting of 3-7 atoms.

In some other embodiments, the heteroaryl system (including heteroaryl, heteroaryl ring) includes the following examples, but is 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-methylisoxazol-5-yl, N -pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl, azinyl, thiazol-2-yl, tetrazolyl, triazolyl, etc. Heteroaryl groups may be substituted with substituents described herein.

"Heterocyclic group" may be carbon group or heteroatom group. "Heterocyclyl" also includes groups formed by combining a heterocyclic group with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxanyl, azetidinyl, thietanyl, piperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, oxazepinyl, diazepine Zynyl, Thiazepinyl, Pyrrolin-1-yl, 2-Pyrrolinyl, 3-Pyrrolinyl, Indolinyl, Indolinyl, Indorazinyl, Indolyl, Iso Benzotetrahydrofuranyl, isobenzotetrahydrothienyl.

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

The terms "spirocyclyl", "spirocycle", "spirobicyclyl", "spirobicyclyl" indicate that one ring is derived from a specific cyclic carbon on another ring. For example, as described below, a saturated bridged ring system (rings D and B') is called a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral". Each ring within a spirocycle is either carbocyclic or heteroalicyclic. Examples of such include, but are not limited to, spiro[2.4]heptan-5-yl, spiro[4.4]nonyl, and the like.

The term "spiroheterobicyclyl" means that one ring is derived from a specific cyclic carbon on another ring. For example, as described above, a saturated bridged ring system (rings D and B') is called a "fused bicyclic ring", whereas ring A' and ring D share a carbon atom in two saturated ring systems, It is called a "spiral". and at least one ring system contains one or more heteroatoms, such examples include, but are not limited to, 4-azaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, Spiro[2.4]heptyl, 2-azaspiro[4.5]decyl, 2-azaspiro[3.3]heptanyl, 1,7-diazaspiro[4.4]nonyl, 1,7 -Diazaspiro[4.4]nonan-6-one-yl, 2,9-diazaspiro[5.5]undecane-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]nonyl, 2-oxo-6-azaspiro[3.4]octyl, etc. Depending on the structure, the spiroheterobicyclyl can be a monovalent group or a divalent group, ie, a spiroheterobicyclyl group. Spiroheterocyclyl groups may be substituted with substituents described herein.

The terms "fused bicyclic", "fused ring", "fused bicyclyl" or "fused cycloyl" denote saturated or unsaturated fused ring systems, referring to non-aromatic bicyclic ring systems, at least one ring of which is non-aromatic of. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings. Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furanyl, 2,3,3a,4 ,7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptanyl, fused bicyclo[3.3.0]octyl, fused bicyclo[3.1.0]hexyl , 1,2,3,4,4a,5,8,8a-octahydronaphthyl, which are included in the fused bicyclic system.

The term "fused heterobicyclyl" means a saturated or unsaturated condensed ring system, involving non-aromatic bicyclic ring systems, at least one ring is non-aromatic. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics may serve as substituents thereon), and at least one ring system contains one or more heteroatoms.

Example 1

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

¹ H NMR (500MHz, CDCl ₃ ) δ (ppm): 4.11 (425H, t), 3.65 (180H, s), 3.38 (3H, s), 2.39 (426H, t), 1.96 (438H, m ). ¹³ C NMR (126MHz, 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 H NMR spectrum of the obtained block copolymer is shown in Figure 1, the carbon spectrum is shown in Figure 4, the GPC curve is shown in Figure 5, and the infrared spectrum is shown in Figure 10.

Example 2

(0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, average molecular weight M _n =2000g/mol) and (0.05mmol, 60mg) hexa[tris(dimethylamine)phosphazene]tripolyphosphorus Nitrile was added to the reaction tube, placed in a low-temperature cold bath at -40°C, added 0.6mL of dichloromethane, stirred for 10 minutes to mix the system evenly, placed in a low-temperature cold bath at -50°C, and 0.57mL of γ-butyrolactone was added with a syringe into the reaction tube. The reaction was carried out under nitrogen protection for 4h, acetic anhydride (0.3mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated to obtain polyethylene oxide-b-poly(γ-butyrolactone), the structure is as follows :

¹ H NMR (500MHz, 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 H NMR spectrum of the obtained block copolymer is shown in Figure 2, and the GPC curve is shown in Figure 6.

Example 3

(0.075mmol, 375mg) polyethylene oxide monomethyl ether (PEG5000, average molecular weight M _n =5000g/mol) and (0.05mmol, 60mg) hexa[tris(dimethylamine)phosphazene]tripolyphosphorus Nitrile was added to the reaction tube, placed in a low-temperature cooling bath at -50°C, 0.6 mL of dichloromethane was added, stirred for 10 min to mix the system evenly, and 0.57 mL of γ-butyrolactone was added to the reaction tube with a syringe. The reaction was carried out under the protection of nitrogen for 4h, acryloyl chloride (0.15mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated to obtain polyethylene oxide-b-poly(γ-butyrolactone), the structure is as follows :

¹ H NMR (500MHz, 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 H NMR spectrum of the obtained block copolymer is shown in FIG. 3 , the GPC curve is shown in FIG. 7 , and the infrared spectrum is shown in FIG. 11 .

Example 4

Add (0.075mmol, 152mg) polyethylene oxide monomethyl ether (PEG2000, average molecular weight M _n =2000g/mol) and (0.15mmol, 3.6mg) NaH into the reaction flask, add 5mL tetrahydrofuran, under nitrogen protection Reflux for 24 hours, filter the reaction mixture, and drain the filtrate to obtain sodium polyethylene oxide monomethyl ether. Add 0.2mL tetrahydrofuran to the obtained sodium polyethylene oxide monomethyl ether, stir for 10min, place it in a low-temperature cold bath at -50°C, add 0.4mL dichloromethane, stir for 10min to make the system evenly mixed, and inject 0.57mLγ - Butyrolactone was added to the reaction tube. The reaction was carried out under nitrogen protection for 4h, epichlorohydrin (7.5mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated to obtain polyethylene oxide-b-poly(γ-butyrolactone), the structure is as follows Shown:

The number average molecular weight measured by GPC was 12.4 kg/mol, and the molecular weight distribution was 1.48. The GPC curve of the obtained block copolymer is shown in FIG. 8 .

Example 5

Add (0.075mmol, 150mg) polyethylene oxide monomethyl ether (PEG2000, average molecular weight M _n =2000g/mol) and (0.15mmol, 10.5mg) potassium methoxide into the reaction tube, add 0.2mL tetrahydrofuran, and place in- In a cold bath at 50°C, add 0.4 mL of dichloromethane, stir for 10 minutes to mix the system evenly, and add 0.57 mL of γ-butyrolactone into the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, 4-methoxyphenyl isocyanate (0.6mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated 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 GPC curve of the obtained block copolymer is shown in FIG. 9 .

Example 6

Add (0.15mmol, 150mg) polyethylene oxide (PEG1000, average molecular weight M _n =1000g/mol) and (0.3mmol, 6.9mg) sodium into the reaction tube, add 0.2mL tetrahydrofuran, under nitrogen protection, 25°C Stir for 60 minutes, place in a low-temperature cooling bath at -50°C, add 0.4 mL of dichloromethane, stir for 10 minutes to make the system evenly mixed, and add 1.15 mL of γ-butyrolactone into the reaction tube. The reaction was carried out under nitrogen protection for 2h, succinic anhydride (0.45mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated 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

Add (0.1mmol, 250mg) polypropylene oxide monomethyl ether (PPG2500, average molecular weight M _n =2500g/mol) and (0.1mmol, 17.7mg) biphenyl sodium into the reaction tube, add 0.3mL tetrahydrofuran, and Stir at 25°C for 30min, place in a low-temperature cooling bath at -50°C, add 0.5mL of dichloromethane, stir for 10min to make the system evenly mixed, and add 0.77mL of γ-butyrolactone into the reaction tube. The reaction was carried out under the protection of nitrogen for 4h, 3-chloropropene (0.2mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated to obtain polypropylene oxide-b-poly(γ-butyrolactone), the structure is as follows Show:

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

Example 8

(0.1mmol, 200mg) polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide (PEG-b-PPG-b-PEG, average molecular weight M _n =2000g/mol) and (0.1 mmol, 63.4 mg) 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, Add 0.77 mL of γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, 4-methoxyphenyl thioisocyanate (0.3mmol) was added, the reaction mixture was poured into excess methanol, and centrifuged to obtain poly(γ-butyrolactone)-b-polycyclic Ethylene oxide-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

Add (0.075 mmol, 187.5 mg) poly(ethylene oxide-ran-propylene oxide) (PEG-ran-PPG, average molecular weight M _n =2500 g/mol) and (0.15 mmol, 3.6 mg) NaH to the reaction flask 5 mL of tetrahydrofuran was added, and the reaction was refluxed for 24 h under the protection of nitrogen, the reaction mixture was filtered, and the filtrate was drained to obtain poly(ethylene oxide-ran-propylene oxide) sodium. Add 0.2 mL of tetrahydrofuran to the obtained poly(ethylene oxide-ran-propylene oxide) sodium, stir for 10 min, place in a low-temperature cold bath at -50°C, add 0.4 mL of dichloromethane, and stir for 10 min to make the system evenly mixed. Add 0.57 mL of γ-butyrolactone to the reaction tube with a syringe. The reaction was carried out under nitrogen protection for 4h, maleimidobutyryl chloride (0.45mmol) was added, the reaction mixture was poured into excess methanol, centrifuged and precipitated 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

The compound was prepared according to the method of Example 1, except that acetic acid was replaced by the active functional group-containing compound shown in Table 1 to obtain the corresponding polyether-b-poly(γ-butyrolactone) block copolymer.

Table 1

Example 11

The compound was prepared according to the method of Example 6, except that succinic anhydride was replaced by the compound containing active functional groups shown in Table 2 to obtain the corresponding polyether-b-poly(γ-butyrolactone) block copolymer.

Table 2

Example 12

Prepare the compound according to the method of Example 7, the difference is that 3-chloropropene is replaced by the compound containing active functional groups shown in Table 3, thereby obtaining the corresponding polyether-b-poly(γ-butyrolactone) block copolymer .

table 3

Example 13

The compound is prepared according to the method of Example 8, the difference is that 4-methoxyphenyl thioisocyanate is replaced by the compound containing active functional groups shown in Table 4, so as to obtain the corresponding polyether-b-poly(γ-butyrol ester) block copolymers.

Table 4

Example 14

Prepare the compound according to the method of Example 9, the difference is that the maleimido butyryl chloride is replaced by the compound containing the active functional group shown in Table 5, thereby obtaining the corresponding polyether-b-poly(γ-butyrolactone) block copolymers.

table 5

Example 15

Prepare the compound according to the method of Example 6, the difference is that polyethylene oxide is replaced by polypropylene oxide, and succinic anhydride is replaced by the compound containing active functional groups shown in Table 6, thereby obtaining the corresponding polyether-b- Poly(γ-butyrolactone) block copolymer.

Table 6

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (10)

1. A compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, or a solvate of a compound of formula (I),

wherein,

r is selected from alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclic group, aryl, heteroaryl, fused bicyclic group, spiro bicyclic group, fused heterobicyclic group, spiro heterobicyclic group or a group shown in formula (II),

R₁a group selected from hydrogen or one of the following:

R₂a group selected from one of the following:

R₃and R₄Each independently selected from alkyl, alkenyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl,

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

2. A compound of claim 1, wherein R is₃And R₄Each independently selected from one of the following:

3. the compound of claim 1, having the structure of one of:

wherein each R is₅Each independently selected from hydrogen, methyl or ethyl.

4. The compound of claim 1, having the structure of one of:

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

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

(2) mixing gamma-butyrolactone with the mixed solution, carrying out a reaction, adding a compound containing an active functional group to terminate the reaction, adding the reaction mixture to methanol, and collecting the precipitate, so as to obtain the compound, wherein the reaction is carried out at-70 to-20 ℃.

6. A process according to claim 5, characterised in that the catalyst is selected from an organophosphazene base catalyst, preferably hexa [ tris (dimethylamine) phosphazene ] triphosphazene, phosphazene ligand P4-tert-butyl or phosphazene ligand P2-tert-butyl,

optionally, the alkali metal is selected from sodium or potassium, and the alkali metal compound is selected from sodium hydride, potassium hydride, sodium naphthalene, potassium naphthalene, sodium biphenyl, sodium diphenylmethyl, or potassium diphenylmethyl;

optionally, the alkali metal alkoxide is selected from potassium methoxide, sodium ethoxide or potassium ethoxide;

optionally, the hydroxyl-terminated polyether is selected from polyethylene oxide monomethyl ether, polypropylene oxide monomethyl ether, poly (1, 2-butylene oxide) monomethyl ether, polyethylene oxide, polypropylene oxide, poly (1, 2-butylene oxide), polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide, or poly (ethylene oxide-ran-propylene oxide);

optionally, the compound containing reactive functional group is selected from acid, acyl chloride, acid anhydride, thioisocyanate, isocyanate or halogenated hydrocarbon, preferably acetic acid, benzoic acid, acryloyl chloride, methacryloyl chloride, acetic anhydride, succinic anhydride, maleimidobutyryl chloride, epichlorohydrin, 3-chloropropene, 3-chloropropyne, 4-methoxyphenyl thioisocyanate, 4-methoxyphenyl isocyanate.

7. The method of claim 5, comprising:

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

(1-2) adding gamma-butyrolactone to the mixed solution obtained in the step (1-1), reacting, adding a compound having an active functional group to terminate the reaction, adding the reaction mixture to methanol, collecting the precipitate, to obtain the compound,

wherein,

the molar ratio of the catalyst to the hydroxyl-terminated polyether is 1: 3-2: 1;

the organic solvent is at least one selected from tetrahydrofuran, dichloromethane, trichloromethane, 1-dichloroethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, acetonitrile and dioxane;

the low-temperature cold bath stirring is carried out for 10-30 min at the temperature of-70 to-10 ℃.

8. The method of claim 5, comprising:

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

(2-2) dissolving the polyether alkali metal salt solution and gamma-butyrolactone in an organic solvent to effect a reaction, adding a compound having an active functional group to terminate the reaction, adding the reaction mixture to methanol, collecting the precipitate, to obtain the compound,

wherein,

the molar ratio of the hydroxyl-terminated polyether to the alkali metal or alkali metal compound is 1: 1-1: 10;

in the step (2-1), the reaction temperature is 25-70 ℃, the reaction time is 0.5-72 hours, and the organic solvent is selected from tetrahydrofuran or dioxane;

in the step (2-2), the organic solvent is at least one selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, 1-dichloroethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, acetonitrile and dioxane;

the molar ratio of the polyether alkali metal salt to the gamma-butyrolactone is 1: 10-1: 200.

9. the method of claim 5, comprising:

(3-1) dissolving hydroxyl-terminated polyether and alkali metal alkoxy compound in organic solvent, and stirring in low-temperature cold bath;

(3-2) adding gamma-butyrolactone to the mixed solution obtained in the step (3-1), reacting, adding a compound having an active functional group to terminate the reaction, adding the reaction mixture to methanol, collecting the precipitate, to obtain the compound,

wherein,

the molar ratio of the alkali metal alkoxy compound to the hydroxyl-terminated polyether is 1: 1-2: 1;

the organic solvent is at least one selected from tetrahydrofuran, dichloromethane, trichloromethane, 1-dichloroethane, 1, 2-dichloroethane, 1,2, 2-tetrachloroethane, acetonitrile and dioxane;

the low-temperature cold bath stirring is carried out for 10-30 min at the temperature of-70 to-10 ℃.

10. The method according to claim 5, wherein the hydroxyl-terminated polyether has a molecular weight of 200 to 40000g/mol, and the molar ratio of the hydroxyl-terminated polyether to γ -butyrolactone is 1: 10-1: 200 of a carrier; the molar concentration of the gamma-butyrolactone in the system is 2-10 mol/L; the molar ratio of the compound containing the active functional group to the hydroxyl-terminated polyether is 1: 1-10: 1;

the reaction is carried out at-70 to-20 ℃ for 0.5 to 12 hours.