Method for producing polylactic acid-glycolic acid copolymer, and polylactic acid-glycolic acid copolymer produced thereby

Abstract

The invention relates to a method for preparing a polylactic acid-glycolic acid copolymer and the polylactic acid-glycolic acid copolymer prepared by the method. The method comprises the step of carrying out condensation polymerization on a lactate monomer and a glycollate monomer which are used as raw materials to obtain the polylactic acid-glycollic acid copolymer.

Description

Technical Field

[0001] The present application relates to the technical field of biodegradable material synthesis. Specifically, the present application relates to a new method for manufacturing polylactic acid-glycolic acid copolymer, in particular, a method for preparing polylactic acid-glycolic acid copolymer from the polycondensation reaction of lactate and glycolate monomers. In addition, the present application also relates to the polylactic acid-glycolic acid copolymer manufactured by the method. Background Art

[0002] Poly(lactic-co-glycolic acid) (PLGA) is a polymer polymerized by the polymerization of lactic acid (LA) and glycolic acid (GA) or their derivatives. It combines the advantages of two different polyester materials, poly(lactic-co-glycolic acid) (PLA) and poly(glycolic acid) (PGA), and has high biodegradability and biocompatibility. The development of poly(lactic-co-glycolic acid) is of great significance to the sustainable development of mankind. On the one hand, since the degradation rate of PLGA is faster than that of PLA, and the degradation products are water and carbon dioxide, it can form a benign ecological cycle and has almost no pollution to the environment. On the other hand, after PLGA is decomposed in the human body, the generated water and carbon dioxide can be excreted from the body by the excretory system such as the kidneys, or can further participate in the body's metabolic cycle, which is non-toxic and harmless. Therefore, PLGA is a new type of polymer material with good biocompatibility and good biodegradability. PLGA has a wide range of uses, but is limited by factors such as cost. It is currently mainly used in biomedical engineering fields such as drug sustained-release systems, absorbable suture materials, orthopedic fixation and tissue repair materials.

[0003] At present, the main synthesis methods of polylactic acid-glycolic acid copolymers are ring-opening polymerization and direct polymerization, and both methods have their own advantages and disadvantages. The common ring-opening polymerization is to dehydrate and cyclize glycolic acid and lactic acid to synthesize glycolide and lactide monomers respectively, and then ring-opening polymerization of glycolide and lactide to obtain PLGA random copolymers. Another ring-opening polymerization route is to make six-membered cyclic lactide from two polymerization monomers of glycolic acid (chloroacetic acid is used in the experiment) and lactic acid, and then ring-opening polymerization to obtain an alternating copolymer of PLGA. The polymer has a regular structure, fixed composition, and relatively stable degradation performance. At present, PLGA materials are mostly synthesized by ring-opening polymerization, but due to the long process and cumbersome synthesis process, there are problems such as high cost and immature process, which limits the further development of polylactic acid-glycolic acid copolymers.

[0004] The direct polymerization method is to obtain polylactic acid-glycolic acid copolymer by direct dehydration condensation of lactic acid and glycolic acid. The direct polycondensation of PLGA is divided into two methods: solution polycondensation and melt polycondensation. The solution polymerization method generally uses a high boiling point solvent (such as dimethyl ether, toluene, xylene, etc.) to azeotropize with water to discharge water from the reaction system. The solvent can dissolve the polymer but does not participate in the reaction. The by-products glycolide and lactide are brought back to the reaction system through solvent reflux to avoid the decomposition of PLGA, and PLGA with low water content and high relative molecular weight is obtained. Therefore, this method is also called azeotropic distillation. Due to the insoluble characteristics of polymers, the solution polymerization method requires a large amount of solvent and is easy to pollute the environment. At the same time, the use of high boiling point organic solvents will complicate the process flow, increase the cost of equipment, and is not easy to industrialize. In addition, it is relatively difficult to purify the polymer, and the obtained product usually contains residual organic solvents that are difficult to remove.

[0005] Another direct polymerization method is melt polycondensation, which means that the oligomers formed by melt polycondensation are granulated and crystallized and dried, and then the oligomers are further polymerized under appropriate temperature conditions to connect small segments. Although the melt-solid phase polycondensation method can improve the crystallinity and relative molecular weight of PLGA, this method has high requirements for equipment. Generally, the reaction must be carried out under a very high vacuum degree to obtain high molecular weight PLGA, and it is still very difficult to popularize it in industry.

[0006] Prior art generally prepares the polylactic acid-glycolic acid copolymer obtained by direct polycondensation of lactic acid and glycolic acid and polycondensation of propane and glycolide ring opening. However, the polylactic acid-glycolic acid copolymer obtained by direct (dehydration) polycondensation of lactic acid and glycolic acid usually has the disadvantages of low molecular weight and very difficult further dehydration.

[0007] Therefore, there is still a need to develop a method for providing polylactic acid-glycolic acid copolymers, especially high molecular weight polylactic acid-glycolic acid copolymers, with low cost and relatively simple process. Summary of the invention

[0008] On the one hand, the present application provides a method for producing a polylactic acid-glycolic acid copolymer, comprising: using a lactate monomer and a glycolate monomer as raw materials to undergo a condensation reaction to obtain a polylactic acid-glycolic acid copolymer.

[0009] On the other hand, the present application provides a method for producing a polylactic acid-glycolic acid copolymer, comprising:

[0010] A polycondensation reaction is carried out with lactate monomer and glycolate monomer as raw materials to obtain a polycondensation product;

[0011] A step of subjecting the polycondensation product to transesterification or esterification with a reagent selected from any one of diols and dicarboxylic acids or their anhydrides to form an intermediate polymer having both terminal groups being hydroxyl groups or both terminal groups being carboxyl groups; and

[0012] The intermediate polymer and the chain extender are subjected to a chain extension reaction to obtain the polylactic acid-glycolic acid copolymer.

[0013] In yet another aspect, the present application provides a polylactic acid-glycolic acid copolymer produced by any of the above methods. DETAILED DESCRIPTION

[0014] In order to be able to understand the technical characteristics and content of the application in detail, the exemplary embodiments of the application will be described in more detail below. Although the exemplary embodiments of the application are described in the embodiment, it should be understood that the application can be realized in other various forms based on the disclosure and should not be limited by the embodiments set forth herein. If the manufacturer is not indicated for reagents used or instruments, they are all conventional products that can be obtained by commercial purchase.

[0015] definition

[0016] The following definitions and methods are provided to better define the present application and guide those of ordinary skill in the art in the practice of the present application. Unless otherwise specified, terms are understood according to conventional usage by those of ordinary skill in the relevant art.

[0017] As used herein, the terms "include" and "comprising" should be construed in an inclusive and open, non-exclusive sense, ie, "including, but not limited to."

[0018] References throughout this specification to "one embodiment" or "some embodiments" mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in at least one embodiment of the present application. Thus, the phrases "in one embodiment" or "in some embodiments" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0019] The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms on the same carbon atom are replaced by oxygen atoms. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0020] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted with halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely replaced (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group comprising one or more substituents, no substitution or substitution pattern will be introduced that is sterically impossible to exist and / or cannot be synthesized.

[0021] The terms "optionally substituted", "optionally substituted by", "optionally substituted by" mean that the hydrogen at the substitutable position of the group is not substituted or is substituted by one or more substituents (e.g., 1 to 4, 1 to 3 or 1 to 2). The substituents may be selected from: C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 3 -C 10 One or more of cycloalkyl, sulfhydryl, halogen, cyano, carbonyl and amino. When substituted, the substituent group is separate and independent. When a group is substituted by more than one substituent, the substituent group may be the same or different, and any substituted functional group herein may be substituted at one or more (e.g. 1 to 4) different positions, and those one or more (e.g. 1 to 4) substituent groups can be substituted at one or more (e.g. 1 to 4) positions independently of one another.

[0022] The numerical ranges herein indicating the number of carbon atoms refer to each integer in the given range, for example, "C 1 -C 20 " or "C 1-20 ” means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0023] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0024] "Mercapto" refers to a -SH group.

[0025] "Amino" refers to -NH 2 Group.

[0026] "Carboxy" refers to a -COOH group.

[0027] "Cyano" refers to a -CN group.

[0028] "Hydroxy" refers to an -OH group.

[0029] "Halogen" and "halo" refer to F, Cl, Br, and I.

[0030] "Carbonyl" refers to a functional group containing a carbon-oxygen double bond, and its general formula is RC(O)-, wherein R is hydrogen or a hydrocarbon group as defined below. The number of carbon atoms in the carbonyl group is not particularly limited, but the number of carbon atoms may be 1 to 20, 1 to 10, or 1 to 6. For example, the carbonyl group may have the following structure, but is not limited thereto:

[0031]

[0032] The term "hydrocarbyl" refers to a monovalent group consisting only of hydrogen and carbon. Hydrocarbyl includes aliphatic hydrocarbon groups and aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl (such as phenyl or benzyl), etc. 1 -C 20 The hydrocarbyl group refers to a hydrocarbyl group as defined above having 1 to 20 (eg, 1 to 15, 1 to 10, 1 to 6, or 1 to 3) carbon atoms.

[0033] The term "heteroalkyl" refers to an alkyl group in which at least one carbon (but not all carbons) is replaced by one or more heteroatoms. 1 -C 20 The heteroalkyl group refers to a heteroalkyl group as defined above having 1 to 20 (eg, 1 to 15, 1 to 10, 1 to 6, or 1 to 3) carbon atoms.

[0034] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, for example, a straight or branched chain group containing 1 to 20 carbon atoms, for example, a group containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), containing 1-8 carbon atoms (C 1-8 Alkyl), containing 1-6 carbon atoms (i.e. C 1-6 Alkyl) or 1-4 carbon atoms (i.e. C 1-4 Alkyl) or 2-4 carbon atoms (i.e. C 2-4 Alkyl), such as "C 1-6"Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0035] The term "alkoxy" refers to -O-alkyl, wherein "alkyl" is as defined above, examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy. "Optionally substituted alkoxy" means that the alkyl in the group is substituted or unsubstituted.

[0036] The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, such as C 2 -C 20 Alkenyl, C 2 -C 10 Alkenyl, C 2-6 Alkenyl, C 2-4 Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The term includes cis and trans isomers or mixtures of these isomers.

[0037] The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond, such as C 2 -C 20 Alkynyl, C 2 -C 10 Alkynyl, C 2-6 Alkynyl, C 2-4 Alkynyl, C 2-3 Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), 1-propynyl (—C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡CC≡CH), etc.

[0038] The term "cycloalkyl" refers to a fully saturated non-aromatic ring composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. Non-limiting examples of cycloalkyl include, but are not limited to, C 3-20 Cycloalkyl, C 3-18 Cycloalkyl, C 3-16 Cycloalkyl, C3-12 Cycloalkyl, C 3-10 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[3.3]heptyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like.

[0039] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a single ring, a fused ring, a bridged ring, or a spiro ring. Non-limiting examples of heterocycloalkyl include, but are not limited to, C 3-20 Heterocycloalkyl, C 3-18 Heterocycloalkyl, C 3-16 Heterocycloalkyl, C 3-12 Heterocycloalkyl, C 3-10 Heterocycloalkyl, C 3-8 Heterocycloalkyl, C 3-7 Heterocycloalkyl, C 3-6 Unless otherwise indicated, the heterocycle is generally a ring containing 1 or more heteroatoms.

[0040] The term "cycloalkenyl" refers to a non-aromatic mono- or polycyclic ring system containing at least one carbon-carbon double bond. In some embodiments, the cycloalkenyl ring contains, for example, 3-20 ring atoms, 3-10 ring atoms, 5-10 ring atoms, or 5-7 ring atoms. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, etc. Non-limiting examples of suitable polycyclic cycloalkenyls are norbornyl.

[0041] The term "heterocycloalkenyl" refers to a monovalent cyclic group of 1 to 20 carbon atoms (wherein the number of carbon atoms may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20) further comprising at least one heteroatom other than carbon atoms as a ring-forming atom in its ring and having at least one double bond. Examples of heterocycloalkenyl groups may include 4,5-dihydro-1,2,3,4-oxatriazolyl groups, 2,3-dihydrofuranyl groups, 2,3-dihydrothienyl groups, and the like.

[0042] The term "cycloalkynyl" refers to a non-aromatic monocyclic or polycyclic ring having at least one carbon-carbon triple bond and consisting only of carbon and hydrogen atoms, such as 4-15, 5-15, 6-10, 7-10 or 8-10 rings, such as 8- to 10-membered monocyclic or 12- to 15-membered bicyclic rings. It may include one or more fused or bridged rings. Unless otherwise indicated, the cycloalkynyl ring may be connected at any carbon atom, which produces a stable structure, and, if substituted, may be substituted at any suitable carbon atom, which produces a stable structure. Exemplary cycloalkynyl groups include cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, etc.

[0043] The term "heterocycloalkynyl" refers to a heterocycloalkyl group in which at least one carbon-carbon single bond is replaced by a carbon-carbon triple bond.

[0044] The term "aryl" refers to an aromatic ring or an aromatic or partially aromatic ring system consisting of carbon atoms and hydrogen atoms. It can be a single ring or a polycyclic ring (such as a bicyclic ring or more than two rings) fused together or covalently linked. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0045] The term "C 6 -C 20 "Aryl" refers to an aryl group as defined above having 6 to 20 carbon atoms, for example 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.

[0046] The term "heteroaryl" refers to an aromatic ring group consisting of carbon atoms and at least one heteroatom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can contain fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, thienyl, furanone, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, 2,3-naphthyridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

[0047] The term "C 3 -C 20 The term "heteroaryl" refers to an aromatic ring group having at least one heteroatom as a ring-forming atom in addition to 3 to 20 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 20 carbon atoms).

[0048] As used herein, the term "heteroatom" refers to any atom other than a carbon atom. Examples of heteroatoms include O, S, N, P, Si, B, Ge, Se, or any combination thereof, preferably O, S, N, P, or any combination thereof. The number of heteroatoms is, for example, 1 to 15, 1 to 10, 1 to 5, or 1 to 3.

[0049] The term "C 6 -C 20 "Monohydric alcohol" refers to a compound with a general formula of R-OH having 6 to 20 carbon atoms, wherein R represents a hydrocarbon group as defined above, including saturated alcohols and unsaturated alcohols.

[0050] The "atmospheric pressure" used in this article refers to 1 standard atmosphere, which has a value of approximately 101.325 kPa.

[0051] The term "low molecular weight polyfunctional alcohol or amine compound containing hydroxyl groups or amino groups" refers to a polyfunctional alcohol or amine compound containing hydroxyl groups or amino groups having a molecular weight of 300 or less.

[0052] In this article, "polylactic acid-glycolic acid copolymer" refers to a polyester polymer having a repeating unit with the following structure as the main chain. In this article, the (weight average) molecular weight of polylactic acid-glycolic acid copolymer is at least 900 (g / mol), and generally can reach more than 2000. It is understood that there may be a very small amount of other end groups or linking groups in polylactic acid-glycolic acid copolymer due to the specific process used, but it does not affect the representation of the main chain structure of polylactic acid-glycolic acid copolymer.

[0053]

[0054] On the one hand, the present application provides a method for producing a polylactic acid-glycolic acid copolymer, comprising: using a lactate monomer and a glycolate monomer as raw materials to undergo a condensation reaction to obtain a polylactic acid-glycolic acid copolymer.

[0055] On the other hand, the present application provides a method for producing a polylactic acid-glycolic acid copolymer, comprising:

[0056] A polycondensation reaction is carried out with lactate monomer and glycolate monomer as raw materials to obtain a polycondensation product;

[0057] A step of subjecting the polycondensation product to transesterification or esterification with a reagent selected from any one of diols and dicarboxylic acids or their anhydrides to form an intermediate polymer having both terminal groups being hydroxyl groups or both terminal groups being carboxyl groups; and

[0058] The intermediate polymer and the chain extender are subjected to a chain extension reaction to obtain the polylactic acid-glycolic acid copolymer.

[0059] In some embodiments of the manufacturing method of any of the above aspects, the condensation polymerization reaction using lactate monomers and glycolate monomers as raw materials includes: allowing the lactate monomers and glycolate monomers to undergo self-polymerization reactions to form their own self-polymerization products, and then allowing the two self-polymerization products to undergo a condensation polymerization reaction.

[0060] In some embodiments of the manufacturing method of any of the above aspects, in the polycondensation reaction using lactate monomers and glycolate monomers as raw materials, there may still be a small amount of lactate monomers and glycolate monomers that directly undergo polycondensation reaction, but the polycondensation reaction using lactate monomers and glycolate monomers as raw materials includes the following reaction as the main reaction: allowing the lactate monomers and glycolate monomers to undergo self-polymerization reaction to form their own self-polymerization products, and then allowing the two self-polymerization products to undergo a condensation reaction.

[0061] In some embodiments, the polycondensation product is subjected to an ester exchange reaction with a diol to form an intermediate polymer having hydroxyl groups at both ends. In some embodiments, the polycondensation product is subjected to an esterification reaction and an ester exchange reaction with a dicarboxylic acid or an anhydride thereof to form an intermediate polymer having carboxyl groups at both ends.

[0062] In some embodiments of the manufacturing method of any of the above aspects, the polycondensation reaction is carried out at a temperature of 0°C to 350°C (e.g., 0°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C, 300°C, 310°C, 320°C, 330°C, 340°C, or 350°C, etc.), preferably 50°C to 300°C, more preferably 100°C to 250°C, and even more preferably 100°C to 200°C.

[0063] In some embodiments of the manufacturing method of any of the above aspects, the polycondensation reaction is carried out at a pressure of 1 Pa to 20 MPa (e.g., 1 Pa, 10 Pa, 50 Pa, 100 Pa, 500 Pa, 1 kPa, 10 kPa, 20 kPa, 0.05 MPa, 0.08 MPa, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa, 1.0 MPa, The process may be carried out under an absolute pressure of 0.2 MPa to 10 MPa, more preferably 0.1 kPa to 1 MPa, and still more preferably 0.01 MPa to 1 MPa.

[0064] In some embodiments of the manufacturing method of any of the above aspects, the reaction time of the condensation polymerization reaction is 0.1 hour to 500 hours (e.g., 0.1 hour, 1 hour, 2 hours, 3 hours, 5 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, 40 hours, 45 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, 100 hours, 110 hours, 120 hours, 130 hours, 140 hours, 150 hours, 160 hours, 170 hours, 180 hours, 190 hours, 200 hours, 250 hours, 300 hours, 350 hours, 400 hours, 450 hours or 500 hours, etc.), 0.1 hour to 200 hours, or 1 hour to 150 hours.

[0065] In some embodiments of the production method of any of the above aspects, the polycondensation reaction is performed in steps.

[0066] In some embodiments of the production method of any of the above aspects, the polycondensation reaction is performed in two or more steps.

[0067] In some embodiments of the manufacturing method of any of the above aspects, the polycondensation reaction is carried out in three steps or more than three steps. In some embodiments, the polycondensation reaction is carried out in four steps.

[0068] In some embodiments, the absolute pressure in the first step of the polycondensation reaction is greater than or equal to atmospheric pressure. In some embodiments, the absolute pressure in the first step is atmospheric pressure to 20MPa (e.g., atmospheric pressure, 0.2MPa, 0.3MPa, 0.4MPa, 0.5MPa, 0.6MPa, 0.7MPa, 0.8MPa, 0.9MPa, 1.0MPa, 1.0MPa, 2.0MPa, 3.0MPa, 4.0MPa, 5.0MPa, 6.0MPa, 7.0MPa, 8.0MPa, 9.0MPa, 10MPa, 11MPa, 12MPa, 13MPa, 14MPa, 15MPa, 16MPa, 17MPa, 18MPa, 19MPa or 20MPa, etc.), preferably the absolute pressure in the first step is greater than atmospheric pressure, such as atmospheric pressure to 10MPa or atmospheric pressure to 5MPa.

[0069] In some embodiments, the absolute pressure in the second step and optional subsequent steps of the polycondensation reaction is less than atmospheric pressure. In some embodiments, the absolute pressure in the second step and optional subsequent steps is 0.1 kPa to less than 0.1 MPa (e.g., 0.1 kPa, 0.2 kPa, 0.3 kPa, 0.4 kPa, 0.5 kPa, 0.6 kPa, 0.7 kPa, 0.8 kPa, 0.9 kPa, 1 kPa, 2 kPa, 3 kPa, 4 kPa, 5 kPa, 6 kPa, 7 kPa, 8 kPa, 9 kPa, 0.01 MPa, 0.02 MPa, 0.03 MPa, 0.04 MPa, 0.05 MPa, 0.05 MPa, 0.06 MPa, 0.07 MPa, 0.08 MPa, or 0.09 MPa, etc.).

[0070] In some embodiments, the temperature in the second step and optional subsequent steps is greater than or equal to the temperature in the first step.

[0071] In some embodiments, the absolute pressure of the third step of the polycondensation reaction is less than or equal to the absolute pressure of the second step, preferably less than the absolute pressure of the second step.

[0072] In some embodiments, the temperature in the third step is greater than or equal to the temperature in the second step, preferably greater than the temperature in the second step.

[0073] In some embodiments, the reaction temperature of the first step is 50°C to 200°C (e.g., 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C, etc.) or 80-180°C.

[0074] In some embodiments, the reaction temperature in the second step and optional subsequent steps is 50°C to 200°C (e.g., 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C or 200°C, etc.) or 80-200°C.

[0075] In some embodiments, the reaction temperature in the third step is 80°C to 300°C (e.g., 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C or 300°C, etc.) or 100°C-300°C.

[0076] In some embodiments, for example, the polycondensation reaction can be continued for the first time at the first pressure and the first temperature, and then the second time can be carried out at the second pressure and the second temperature after changing the vacuum degree and / or changing the temperature. Preferably, the polycondensation reaction can also be carried out for the third time at the third pressure and the third temperature after further changing the vacuum degree and / or changing the temperature. Here, the absolute pressure in the first step, i.e. the first pressure, generally needs to be greater than or equal to atmospheric pressure, for example, from atmospheric pressure to 20MPa, for example, from atmospheric pressure to 10MPa or from atmospheric pressure to 5MPa. In a preferred embodiment, the absolute pressure in the second step and subsequent steps, i.e. the second pressure and the third pressure if present, etc., is generally less than atmospheric pressure, for example, from 0.1kPa to less than 0.1MPa. In a preferred embodiment, the temperature in the second step and the optional subsequent steps, i.e. the second temperature and the third temperature if present, etc., can be greater than or equal to, preferably greater than the temperature in the first step.

[0077] In some embodiments, the polycondensation reaction is carried out in three steps. In some embodiments, the absolute pressure in the third step, i.e., the third pressure, can be greater than or equal to, preferably greater than, the absolute pressure in the second step (i.e., the second pressure). In some embodiments, the third temperature can be greater than or equal to, preferably greater than the second temperature.

[0078] Without intending to be bound by theory, the step-by-step manufacturing method of the present disclosure advantageously promotes the initiation of the polymerization reaction and the formation of the polymer, and can advantageously promote the discharge of the small molecule product (i.e., monohydric alcohol) of the polycondensation reaction, thereby further promoting the polymerization. In addition, the discharged small molecule product, i.e., monohydric alcohol, can even be recycled and reused. For example, the discharged monohydric alcohol can also be recycled to react with lactic acid or glycolic acid to prepare lactic acid ester and glycolic acid ester, which is obviously very environmentally friendly.

[0079] In some embodiments of the manufacturing method of any of the above aspects, the lactate has the following structural formula:

[0080]

[0081] In some embodiments of the manufacturing method of any of the above aspects, the glycolate has the following structural formula:

[0082]

[0083] in:

[0084] R 1 and R 2 Each independently selected from: optionally substituted C 1 -C 20 Hydrocarbyl or optionally substituted C 1 -C20 Heteroalkyl.

[0085] In some embodiments, R 1 and R 2 Each independently selected from: Each independently selected from C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 3 -C 10 The C substituted group is optionally substituted with one or more substituents selected from cycloalkyl, mercapto, halogen, cyano, carbonyl and amino. 1 -C 20 Alkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Alkynyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Cycloalkenyl, C 6 -C 20 Aryl, C 3 -C 20 Heteroaryl, C 3 -C 20 Heterocycloalkyl, C 3 -C 20 Heterocycloalkenyl or C 4 -C 20 Heteroaralkyl.

[0086] In some embodiments, R 1 and R 2 Each independently selected from: C 1 -C 20 Alkyl, C 1 -C 12 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl.

[0087] In some embodiments, R 1 and R 2 Each is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers, dodecyl and its isomers. In a particularly preferred embodiment, R 1 C 1 -C 4Alkyl, especially methyl.

[0088] The method for producing the polylactic acid-glycolic acid copolymer according to the present application may directly use lactate monomers and glycolate monomers, or may include a step of preparing lactate monomers and glycolate monomers through an esterification reaction before the polycondensation reaction step.

[0089] In some embodiments of the manufacturing method of any of the above aspects, the lactate is a lactic acid ester 1 OH is represented by the esterification reaction of a monohydric alcohol, wherein R 1 As defined above.

[0090] In some embodiments of the manufacturing method of any of the above aspects, the glycolate is a glycolic acid ester and a 2 OH is represented by the esterification reaction of a monohydric alcohol, wherein R 2 As defined above.

[0091] In some embodiments, the monohydric alcohol can be selected from methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, cyclohexane methanol, octanol, nonanol, decanol, undecanol, dodecanol, tetradecanol, hexadecanol, heptadecanol, octadecanol, cyclopentanol, cyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, benzyl alcohol, phenylethyl alcohol, benzhydrol, naphthalene methanol, furfuryl alcohol, tetrahydrofurfuryl alcohol, 1-methoxy-2-propanol, 1-ethoxy-2-propanol, propanol, 3-methoxybutanol, vinyl alcohol, 2-aminoethyl alcohol, 1 ... alcohol, 2-(ethylamino)ethanol, 2-(dimethylamino)ethanol, isopropanol, isobutanol, sec-butanol, tert-butanol, 2-methyl-1-butanol, isopentanol, sec-pentanol, 3-pentanol, tert-pentanol, sec-isopentanol, 4-methyl-2-pentanol, 2-hexanol, 2-ethylbutanol, 2-methylpentanol, 2-methyl-2-pentanol, 2-methyl-3-pentanol, 3-ethyl-3-pentanol, 2-heptanol, 3-heptanol, 2-octanol, 2-ethylhexanol, 3,5,5-trimethylhexanol, 2,6-dimethyl-4-heptanol, etc.

[0092] In some preferred embodiments, the lactic acid ester can be selected from methyl lactate, ethyl lactate, propyl lactate, isopropyl lactate, butyl lactate, isobutyl lactate, sec-butyl lactate, tert-butyl lactate, amyl lactate, isopentyl lactate, and lactic acid and C 6 -C 20One or any combination of the esters formed by monohydric alcohols. In the method of the present disclosure, particularly preferred lactic acid esters are methyl lactate, ethyl lactate, propyl lactate, isopropyl lactate, butyl lactate, isobutyl lactate, sec-butyl lactate, tert-butyl lactate, amyl lactate and isopentyl lactate. Although the present disclosure is intended to include all lactic acid esters suitable for polycondensation, it is preferred to use those lactic acid esters that are easy to obtain and store and transport, such as methyl lactate, ethyl lactate, etc., so that the cost of obtaining lactic acid esters can be significantly reduced.

[0093] In some preferred embodiments, the glycolic acid ester can be selected from methyl glycolate, ethyl glycolate, propyl glycolate, isopropyl glycolate, butyl glycolate, isobutyl glycolate, sec-butyl glycolate, tert-butyl glycolate, amyl glycolate, isopentyl glycolate, and glycolic acid and C 6 -C 20 One or any combination of esters formed from monohydric alcohols. In the method according to the present disclosure, particularly preferred glycolic acid esters are methyl glycolate, ethyl glycolate, propyl glycolate, isopropyl glycolate, butyl glycolate, isobutyl glycolate, sec-butyl glycolate, tert-butyl glycolate, amyl glycolate, and isoamyl glycolate. Although the present disclosure is intended to include all glycolic acid esters suitable for polycondensation, it is preferred to use those glycolic acid esters that are easy to obtain and store and transport, such as methyl glycolate, ethyl glycolate, etc., which can significantly reduce the cost of obtaining glycolic acid esters.

[0094] In some embodiments of the production method of any of the above aspects, the polycondensation reaction is performed in the presence of a catalyst.

[0095] In some embodiments, the catalyst is an acidic or basic substance.

[0096] In some embodiments, the catalyst is selected from one of Lewis acids, acid salts, basic salts, inorganic bases, organic bases, sulfonic acids, halides, tin salts, stannous salts, zinc salts, calcium salts, metal oxides, rare earth compounds, heteropoly acids and sodium alkyl sulfonates, or any combination thereof.

[0097] In some preferred embodiments, the catalyst is selected from one of zinc acetate, phosphotungstic heteropoly acid, stannous chloride and stannous octoate or any combination thereof.

[0098] In some embodiments, the catalyst is used in an amount of 0.01 wt% to 50 wt% (e.g., 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1.0 wt%, 1.2 wt%, 1.5 wt%, 1.8 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 7.0 wt%, 8.0 wt%, 9.0 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt% or 50 wt%, etc.), 0.5 wt% to 10 wt%, or 1 wt% to 5 wt%, based on the total amount of lactate and glycolate.

[0099] In some embodiments, the transesterification reaction or esterification reaction can be carried out at a temperature of greater than 0°C to 300°C (e.g., 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C or 300°C, etc.), 50°C to 200°C, or 100°C to 200°C.

[0100] In some embodiments, the reaction time of the transesterification reaction or the esterification reaction can be 0.01 hour to 500 hours (e.g., 0.01 hour, 0.1 hour, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, 40 hours, 45 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours, 100 hours, 110 hours, 120 hours, 130 hours, 140 hours, 150 hours, 160 hours, 170 hours, 180 hours, 190 hours, 200 hours, 250 hours, 300 hours, 350 hours, 400 hours, 450 hours or 500 hours, etc.), 1 hour to 100 hours, or 1 hour to 10 hours.

[0101] In some embodiments, the transesterification reaction or esterification reaction can be carried out under an appropriate pressure, such as an absolute pressure of 0.1 kPa-10 MPa (e.g., 0.1 kPa, 0.5 Pa, 1 kPa, 10 kPa, 20 kPa, 0.05 MPa, 0.08 MPa, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa, 1.0 MPa, 2.0 MPa, 3.0 MPa, 4.0 MPa, 5.0 MPa, 6.0 MPa, 7.0 MPa, 8.0 MPa, 9.0 MPa or 10 MPa, etc.).

[0102] In some embodiments, the diol may be selected from one of ethylene glycol, propylene glycol, butylene glycol, pentanediol and hexanediol or any combination thereof, with ethylene glycol being particularly preferred.

[0103] In some embodiments, the dicarboxylic acid may be selected from one of terephthalic acid, phthalic acid, malonic acid, succinic acid, butenedioic acid, glutaric acid, adipic acid and suberic acid, or any combination thereof.

[0104] In the step of preparing the intermediate polymer using transesterification and esterification, there is no particular restriction on the amount of transesterification agent and esterification agent. Generally, the diol or dicarboxylic acid may be slightly excessive relative to the chain end groups of the polylactic acid-glycolic acid copolymer. After the reaction, the excess diol or dicarboxylic acid may be removed by distillation.

[0105] In some embodiments, the chain extender is selected from: one or any combination of low molecular weight multifunctional alcohols or amine compounds containing hydroxyl or amino groups, diisocyanates and epoxy resins. In some embodiments, the chain extender is selected from diisocyanates, dioxazolines and epoxy resins. In some embodiments, the chain extender is selected from diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), hexamethylene diisocyanate (HDI), dicyclohexyl diisocyanate (HMDI) and isophorone diisocyanate (IPDI) One or any combination thereof. In a preferred embodiment, the chain extender is diphenylmethane diisocyanate.

[0106] In some embodiments, for intermediate polymers with both ends being carboxyl groups, an oxazoline chain extender is used. In some embodiments, for intermediate polymers with both ends being hydroxyl groups, a diisocyanate chain extender is used.

[0107] In some embodiments, the amount of the chain extender used should not be excessive relative to the end groups of the intermediate polymer, and the amount can be appropriately reduced.

[0108] In some embodiments, the chain extension reaction is carried out at a temperature of greater than 0°C to 300°C (e.g., 5°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C or 300°C, etc.), 100°C to 200°C.

[0109] In some embodiments, the reaction time of the chain extension reaction is 0.01 hour to 100 hours (e.g., 0.01 hour, 0.1 hour, 1 hour, 2 hours, 3 hours, 5 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 36 hours, 40 hours, 45 hours, 50 hours, 60 hours, 70 hours, 80 hours, 90 hours or 100 hours, etc.), 1 to 100 hours, or 1 hour to 24 hours.

[0110] In some embodiments, the chain extension reaction can be carried out at an absolute pressure of, for example, 0.1 kPa-10 MPa (e.g., 0.1 kPa, 0.5 Pa, 1 kPa, 10 kPa, 20 kPa, 0.05 MPa, 0.08 MPa, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 0.9 MPa, 1.0 MPa, 1.0 MPa, 2.0 MPa, 3.0 MPa, 4.0 MPa, 5.0 MPa, 6.0 MPa, 7.0 MPa, 8.0 MPa, 9.0 MPa, or 10 MPa, etc.).

[0111] In some embodiments of the manufacturing method of any of the above aspects, the weight ratio of lactate monomers to glycolate monomers is 9:1 to 1:9, for example 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, or 1:9.

[0112] The manufacturing method further comprises purifying the polycondensation product.

[0113] In some embodiments, the manufacturing method further comprises purifying the product obtained from the reaction after the polycondensation reaction is completely completed. The purification can be performed by methods known in the art.

[0114] In yet another aspect, the present application also provides a polylactic acid-glycolic acid copolymer prepared by any of the above-mentioned manufacturing methods.

[0115] In some embodiments, the weight average molecular weight of the poly(lactic acid-glycolic acid) copolymer is greater than 900 (e.g., greater than 900, greater than 950, greater than 1000, greater than 1100, greater than 1200, greater than 1300, greater than 1400, greater than 1500, greater than 1600, greater than 1700, greater than 1800, greater than 1900, greater than 2000, greater than 3000, greater than 4000, greater than 5000, greater than 6000, greater than 7000, greater than 8000, greater than 9000, greater than 10000, greater than 11000, greater than 12000, greater than 13000, greater than 1400, greater than 1500, greater than 1600, greater than 000, greater than 7000, greater than 8000, greater than 9000, greater than 10000, greater than 20000, greater than 30000, greater than 40000, greater than 50000, greater than 60000, greater than 70000, greater than 80000, greater than 90000 or greater than 100000), greater than 1000, greater than 3000, greater than 5000, greater than 8000, greater than 10000, greater than 50000 or greater than 100000.

[0116] The weight average molecular weight of the polylactic acid-glycolic acid copolymer product thus prepared can be at least greater than 1000, greater than 3000, or even greater than 5000 or 8000. In a preferred case, the weight average molecular weight of the polylactic acid-glycolic acid copolymer product thus prepared can be even greater than 10,000, or even greater than 100,000.

[0117] The various inventions of the present disclosure provide one or more of the following advantages:

[0118] The method for producing the polylactic acid-glycolic acid copolymer disclosed herein uses lactate and glycolate as monomer raw materials, and polycondensation occurs under the action of a catalyst to synthesize a polylactic acid-glycolic acid copolymer product with a high molecular weight.

[0119] The method for producing the polylactic acid-glycolic acid copolymer disclosed in the present invention is easy to remove reaction byproducts, and the reaction efficiency is higher than the reaction efficiency of the conventional lactic acid and glycolic acid dehydration preparation process. The polylactic acid-glycolic acid copolymer obtained by the conventional direct (dehydration) polycondensation method of lactic acid and glycolic acid usually has the disadvantage that further dehydration is very difficult.

[0120] The method for producing the polylactic acid-glycolic acid copolymer disclosed in the present invention improves the degree of polymerization of the reaction, increases the molecular weight and / or yield, thereby improving the quality of the final polylactic acid-glycolic acid copolymer product and the overall production efficiency.

[0121] The method for producing the polylactic acid-glycolic acid copolymer disclosed in the present invention can effectively improve the synthetic molecular weight of the polylactic acid-glycolic acid copolymer while reducing the cost.

[0122] The method for producing the polylactic acid-glycolic acid copolymer disclosed in the present invention can not only improve the reaction efficiency but also significantly reduce the production cost of the polylactic acid-glycolic acid copolymer. It is a new industrial production process route with very important significance and broad development prospects.

[0123] The method for preparing the polylactic acid-glycolic acid copolymer disclosed in the present invention has low cost, simple process, can obtain a high molecular weight polylactic acid-glycolic acid copolymer, and has good economic benefits.

[0124] The method for producing the polylactic acid-glycolic acid copolymer disclosed herein uses lactic acid ester and glycolic acid ester as monomers to undergo polycondensation reaction and dealcoholization condensation, which can conveniently obtain a polylactic acid-glycolic acid copolymer with high molecular weight and high yield.

[0125] Example

[0126] Below in conjunction with embodiment, the specific embodiment of the present disclosure is described in further detail.The following examples are only for illustrative purposes, but not for limiting the scope of the present application.The raw materials and catalysts used in each embodiment can all be obtained from the market or directly obtained according to a general synthetic method.In addition, when not clearly indicated in each embodiment, the reaction pressure used is about atmospheric pressure.

[0127] For the convenience of explanation, the synthesis route of preparing polylactic acid-glycolic acid copolymer using methyl lactate and methyl glycolate as raw materials is illustrated as follows. The polylactic acid-glycolic acid copolymer in each embodiment and other polylactic acid-glycolic acid copolymers other than the embodiments can also be synthesized by referring to the following synthesis route:

[0128] Step a): Prepolymerization:

[0129]

[0130] Step b): Transesterification reaction:

[0131]

[0132] Step c): Chain extension reaction:

[0133]

[0134] Example 1

[0135] 50 g of methyl lactate, 43.27 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer (condensation product).

[0136] Then the pressure was changed, and the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 1196 and a yield of 72.7%.

[0137] Example 2

[0138] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0139] Then the pressure was changed, and the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 1305 and a yield of 70.4%.

[0140] Example 3

[0141] 50 g of methyl lactate, 10.82 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0142] Then the pressure was changed, and the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 1614 and a yield of 68.9%.

[0143] Example 4

[0144] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of stannous chloride were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0145] Then the pressure was changed, and the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 936 and a yield of 77.2%.

[0146] Example 5

[0147] 50 g of methyl lactate, 43.27 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0148] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0149] The temperature of the first polymer obtained in the above step was raised to 170° C. and vacuumed for 60 hours at 0.1 MPa to obtain a polylactic acid-glycolic acid copolymer with a weight average molecular weight of 7512 and a yield of 48.6%.

[0150] Example 6

[0151] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0152] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0153] The temperature of the first polymer obtained in the above step was raised to 170° C., and vacuumed for reaction for 36 hours at a vacuum degree of 0.1 MPa to obtain a polylactic acid-glycolic acid copolymer with a weight average molecular weight of 9375 and a yield of 42.3%.

[0154] Example 7

[0155] 50 g of methyl lactate, 10.82 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0156] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0157] The temperature of the first polymer obtained in the above step was raised to 170° C. and vacuumed for reaction for 18 hours at a vacuum degree of 0.1 MPa to obtain a polylactic acid-glycolic acid copolymer with a weight average molecular weight of 6481 and a yield of 56%.

[0158] Example 8

[0159] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 24 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0160] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0161] The temperature of the first polymer obtained in the above step was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 24 hours to obtain a polylactic acid-glycolic acid copolymer polymer with a molecular weight of 7481 and a yield of 48.5%.

[0162] Example 9

[0163] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of stannous chloride were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0164] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0165] The temperature of the first polymer obtained in the above step was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 36 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 8413 and a yield of 43.5%.

[0166] Example 10

[0167] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of stannous octoate were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0168] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0169] The temperature of the first polymer obtained in the above step was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 36 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 8032 and a yield of 44.1%.

[0170] Embodiment 11

[0171] 50g of methyl lactate, 28.85g of methyl glycolate and 2.5wt% (based on the total amount of lactate and glycolate) of phosphotungstic acid were placed in a stirred reactor with reflux, and reacted at atmospheric pressure and 140°C for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0172] Then, the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a first polymer.

[0173] The temperature of the first polymer obtained in the above step was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 36 hours to obtain a polylactic acid-glycolic acid copolymer polymer with a molecular weight of 8204 and a yield of 43.8%.

[0174] Example 12

[0175] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a prepolymer.

[0176] The reaction was carried out at a temperature of 140°C and a vacuum degree of 0.05-0.1 MPa for 12 hours.

[0177] Then the temperature was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 36 hours to obtain the first polymer.

[0178] Ethylene glycol was added to the first polymer obtained in the above step, and an ester exchange reaction was carried out at 160° C. for 3 hours to obtain an ester exchange product.

[0179] Chain extender MDI was added to the ester exchange product obtained in the above step, and a chain extension reaction was carried out at 160° C. for 1 hour to obtain a polylactic acid-glycolic acid copolymer product with a molecular weight of 25325 and a yield of 42.1%.

[0180] Embodiment 13

[0181] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of zinc acetate were placed in a stirred reactor with reflux and reacted at atmospheric pressure and 140° C. for 32 hours to obtain a prepolymer.

[0182] The reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours.

[0183] Then the temperature was raised to 170° C., and the reaction was carried out under a vacuum degree of 0.1 MPa for 36 hours to obtain the first polymer.

[0184] Ethylene glycol was added to the first polymer obtained in the above step, and an ester exchange reaction was carried out at 160° C. for 3 hours to obtain an ester exchange product.

[0185] Chain extender HDI was added to the transesterification product obtained in the above step, and a chain extension reaction was carried out at 160° C. for 1 hour to obtain a polylactic acid-glycolic acid copolymer product with a molecular weight of 38905 and a yield of 41.7%.

[0186] Embodiment 14

[0187] 50 g of methyl lactate, 28.85 g of methyl glycolate and 2.5 wt % (based on the total amount of lactate and glycolate) of stannous chloride were placed in a stirred reactor with reflux, and reacted at 0.5 MPa and 140° C. for 32 hours to obtain a polylactic acid-glycolic acid copolymer prepolymer.

[0188] Then the pressure was changed, and the reaction was carried out at a temperature of 140° C. and a vacuum degree of 0.05-0.1 MPa for 12 hours to obtain a polylactic acid-glycolic acid copolymer with a molecular weight of 958 and a yield of 79.5%.

[0189] The present invention has been described in detail above with general descriptions and specific embodiments, but it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, these modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A method for producing a polylactic acid-glycolic acid copolymer, comprising: The polylactic acid-glycolic acid copolymer is obtained by polycondensation reaction of lactate monomer and glycolate monomer as raw materials.

2. A method for producing a polylactic acid-glycolic acid copolymer, comprising: A polycondensation reaction is carried out with lactate monomer and glycolate monomer as raw materials to obtain a polycondensation product; A step of subjecting the polycondensation product to transesterification or esterification with a reagent selected from any one of diols and dicarboxylic acids or their anhydrides to form an intermediate polymer having both terminal groups being hydroxyl groups or both terminal groups being carboxyl groups; and The intermediate polymer and the chain extender are subjected to a chain extension reaction to obtain the polylactic acid-glycolic acid copolymer.

3. The method according to claim 1 or 2, wherein: The polycondensation reaction using lactate monomers and glycolate monomers as raw materials comprises: allowing lactate monomers and glycolate monomers to undergo self-polymerization reactions to form respective self-polymerization products, and then allowing the two self-polymerization products to undergo a polycondensation reaction; or The polycondensation reaction using lactate monomer and glycolate monomer as raw materials includes the following reaction as the main reaction: allowing lactate monomer and glycolate monomer to undergo self-polymerization reaction to form their own self-polymerization products, and then allowing the two self-polymerization products to undergo a polycondensation reaction.

4. The method according to any one of claims 1 to 3, wherein: The polycondensation reaction is carried out at a temperature of 0°C to 350°C, 50°C to 300°C, 100°C to 250°C, or 100°C to 200°C; and / or The polycondensation reaction is carried out at an absolute pressure of 1 Pa to 20 MPa, 10 Pa to 10 MPa, or 0.1 kPa to 1 MPa; and / or The reaction time of the polycondensation reaction is 0.1 hour to 500 hours, 0.1 hour to 200 hours, or 1 hour to 150 hours.

5. The method according to any one of claims 1 to 4, wherein: The polycondensation reaction is carried out step by step; or The polycondensation reaction is carried out in two or more steps; or The polycondensation reaction is carried out in three or more steps; Preferably, the absolute pressure in the first step of the polycondensation reaction is greater than or equal to atmospheric pressure, or the absolute pressure in the first step is from atmospheric pressure to 20 MPa, preferably the absolute pressure in the first step is greater than atmospheric pressure; Preferably, the absolute pressure in the second step and optional subsequent steps of the polycondensation reaction is less than atmospheric pressure, or the absolute pressure in the second step and optional subsequent steps is 0.1 kPa to less than 0.1 MPa; and / or the temperature in the second step and optional subsequent steps is greater than or equal to the temperature in the first step; Preferably, the absolute pressure of the third step of the polycondensation reaction is less than or equal to, preferably less than the absolute pressure of the second step; and / or the temperature in the third step is greater than or equal to, preferably greater than the temperature in the second step; Preferably, the reaction temperature of the first step is 50°C to 200°C or 80-180°C; Preferably, the reaction temperature in the second step and optional subsequent steps is 50°C to 200°C or 80-200°C; Preferably, the reaction temperature in the third step is 80°C to 300°C or 100°C-300°C.

6. The method according to any one of claims 1 to 5, wherein: The lactate has the following structural formula: and / or The glycolate has the following structural formula: in: R1 and R2 are each independently selected from: optionally substituted C1-C 20 Hydrocarbyl or optionally substituted C1-C 20 heteroalkyl; or R1 and R2 are each independently selected from: each independently selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 A C1-C12-substituted alkyl radical optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, mercapto, halogen, cyano, carbonyl and amino 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C3-C 20 Cycloalkyl, C3-C 20 Cycloalkenyl, C6-C 20 Aryl, C3-C 20 Heteroaryl, C3-C 20 Heterocycloalkyl, C3-C 20 Heterocycloalkenyl or C4-C 20 heteroarylalkyl; or R1 and R2 are each independently selected from: C1-C 20 Alkyl, C1-C 12 Alkyl, C1-C6 alkyl or C1-C4 alkyl; or R1 and R2 are each independently selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers, dodecyl and its isomers.

7. The method according to any one of claims 1 to 6, wherein: The lactic acid ester is formed by the esterification reaction of lactic acid with a monohydric alcohol represented by R1OH, wherein R1 is as defined in claim 3; and / or The glycolate is formed by the esterification reaction of glycolic acid with a monohydric alcohol represented by R2OH, wherein R2 is as defined in claim 4; and / or The lactic acid ester is selected from methyl lactate, ethyl lactate, propyl lactate, isopropyl lactate, butyl lactate, isobutyl lactate, sec-butyl lactate, tert-butyl lactate, amyl lactate, isopentyl lactate and lactic acid and C6-C 20 One or any combination of esters formed from monohydric alcohols; and / or The glycolic acid ester is selected from methyl glycolate, ethyl glycolate, propyl glycolate, isopropyl glycolate, butyl glycolate, isobutyl glycolate, sec-butyl glycolate, tert-butyl glycolate, amyl glycolate, isopentyl glycolate, and glycolic acid and C6-C 20 One or any combination of esters formed from monohydric alcohols.

8. The method according to any one of claims 1 to 7, wherein: The polycondensation reaction is carried out in the presence of a catalyst; Optionally, the catalyst is an acidic or alkaline substance; Optionally, the catalyst is selected from one of Lewis acids, acid salts, basic salts, inorganic bases, organic bases, sulfonic acids, halides, tin salts, stannous salts, zinc salts, calcium salts, metal oxides, rare earth compounds, heteropoly acids and sodium alkyl sulfonates or any combination thereof; Preferably, the catalyst is selected from one of zinc acetate, phosphotungstic heteropoly acid, stannous chloride and stannous octoate or any combination thereof; Preferably, the catalyst is used in an amount of 0.01 wt % to 50 wt %, 0.5 wt % to 10 wt % or 1 wt % to 5 wt % based on the sum of the amounts of lactic acid ester and glycolic acid ester.

9. The method according to any one of claims 1 to 7, wherein: The transesterification reaction or esterification reaction is carried out at a temperature of greater than 0°C to 300°C, 50°C to 200°C, or 100°C to 200°C; and / or The reaction time of the transesterification reaction or the esterification reaction is 0.01 hours to 500 hours, 1 hour to 100 hours, or 1 hour to 10 hours; and / or The diol is selected from one of ethylene glycol, propylene glycol, butylene glycol, pentanediol and hexanediol or any combination thereof; and / or The dicarboxylic acid is selected from one of terephthalic acid, phthalic acid, malonic acid, succinic acid, butenedioic acid, glutaric acid, adipic acid and suberic acid or any combination thereof; and / or The chain extender is selected from: one or any combination of low molecular weight multifunctional alcohols or amine compounds containing hydroxyl or amino groups, diisocyanates and epoxy resins; or the chain extender is selected from diisocyanates, dioxazolines and epoxy resins; or the chain extender is selected from one or any combination of diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), hexamethylene diisocyanate (HDI), dicyclohexyl diisocyanate (HMDI) and isophorone diisocyanate (IPDI); and / or The chain extension reaction is carried out at a temperature of greater than 0°C to 300°C, 100°C to 200°C; and / or The reaction time of the chain extension reaction is 0.01 hours to 100 hours, 1 to 50 hours, or 1 hour to 24 hours.

10. A poly(lactic acid-co-glycolic acid) produced by the method of any one of claims 1 to 9, Preferably, the weight average molecular weight of the polylactic acid-glycolic acid copolymer is greater than 900, greater than 1000, greater than 3000, greater than 5000, greater than 8000, greater than 10000, greater than 50000 or greater than 100000.

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