KR20200035195A - Block copolymer of lactone and poly (propylene fumarate) - Google Patents

Abstract

In various embodiments, the present invention provides maleic anhydride (MAn) from ROP of cyclic esters using magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg (BHT) ₂ (THF) ₂ ). ) And a new 1-port, expandable ring-opening block-sequence copolymerization (ROBOCOP) to produce a PPF-based block copolymer for application to additive processing and patient-specific regenerative medicine by "switching" with ROCOP of propylene oxide (PO). Provided are well-defined biodegradable poly (lactone- b -propylene fumarate) diblock and triblock polymers formed using techniques. These block copolymers can be fully reabsorbed and photochemically crosslinked in many applications, including 3D printing. By adding the lactone block to the PPF polymer, the viscosity of the block copolymer obtained at working temperature can be precisely controlled and the amount of reactive diluent in the printable resin can be reduced or eliminated.

Description

Block copolymer of lactone and poly (propylene fumarate)

Cross reference of related applications

This application is filed on February 2, 2017, United States Provisional Patent Application Serial No. 62 / 543,786 entitled "Block copolymer of lactone and poly (propylene fumarate)", filed February 2, 2017 United States Provisional Patent Application No. 62 / 453,724 entitled "Method for Copolymerization with Action Initiators of Propylene Oxide and Maleic Anhydride Using Mg Catalyst," filed May 3, 2017, "3D printing for improved bioactivity U.S. Provisional Patent Serial No. 62 / 500,777 entitled Post-functionalized polymer scaffold, "Functionalized poly (propylene fumarate) polymer filed May 22, 2017 and method for manufacturing same" United States Provisional Patent Application Serial No. 62 / 509,340, titled "Synthesis and Characterization of Well-Defined Poly (propylene Fumarate) and Poly (ethylene Glycol) Block Copolymers," filed August 7, 2017 US Provisional Patent Serial Number 62/5 No. 41,889, US Provisional Patent Serial No. 62 / 561,722 entitled "Mg Catalyzed Production of Poly (propylene Fumarate) in Hexane," filed September 22, 2017, and February 2, 2018 Claims the benefit of the US patent application entitled "Functionalized poly (propylene fumarate) polymers prepared by ring-opening polymerization using magnesium catalyst" filed by the applicant with the present application, all of which are incorporated herein in their entirety. This is incorporated by reference.

Group name about joint research contract

This application is based on Akron University, Akron, Ohio and 21st Century Medical Technologies, Inc., Akron, Ohio. Belongs to the joint research agreement between.

Field of invention

One or more embodiments of the present invention relate to novel block copolymers and methods for synthesizing various poly (lactone) and poly (propylene fumarate) (PPF) polymers. In certain embodiments, the present invention relates to well-defined biodegradable poly (lactone- b -propylene fumarate) polymers and scalable methods for making and functionalizing them.

Background of invention

Aliphatic polyesters are the only class of materials that have been intensively studied as sustainable replacements for specialized materials for petroleum products and biomedical devices as a result of their easy hydrolytic decomposition, biocompatibility, and renewable precursors. . One of the most common synthetic methods for obtaining aliphatic polyesters is ring-opening polymerization (ROP) of lactones, which provides easy control of molecular weight and molecular weight distribution, and that small-molecule byproducts are not produced. It is an economical atom in that respect. However, limited functional diversity in the lactone monomer family and few options for post-polymerization modifications have been limited to commercial use for small examples in packaging and passive biomedical devices. An alternative chain-growth route to aliphatic polyesters that has attracted substantial interest in the past few years is the ring-opening copolymerization of epoxides and anhydrides. The introduction of two distinct monomeric species allowed tuning of properties and functionality not accessible by ROP of lactones.

To further extend the range of accessible polymers and their related properties, the synthesis of aliphatic terpolyesters has been of particular interest in recent years. The use of mixed monomer feeds has the potential to expand the range of polymer properties, but it also introduces the need for sequence selectivity. In particular, block copolymers of polyesters have been found to be applied in medicine, nanotechnology, lithography, photonics, and electronics. Block copolymers have been produced from lactones using a number of one-pot ROP systems based on empirical reactivity ratios, and several 1-port ring-opening copolymerization (ROCOP) systems that rely on mechanical control, in particular, It has been reported to obtain block sequencing using epoxides, anhydrides, and carbonates. Other methods of producing block copolyesters include linking ROP and ROCOP, and the technology typically relies on sequential addition and tandem catalysis. For example, metal salen catalysts have been used for ROCOP of epoxides using CO ₂ before chain transfer by addition of organo-catalysts to water and lactide ROP in a 1-port process. (See, e.g. Wu, GP ,; Darensbourg, DJ; Mechanistic Insights into Water-Mediated Tandem Catalysis of Metal-Coordination CO ₂ / Epoxide copolymerization and Organocatalytic Ring-Opening Polymerization: One-Pot, Two Steps, and Three Catalysis Cycles for Triblock Copolymers Synthesis. Macromolecules, 2016, 49 (3), pp 807-814, the disclosure thereof is incorporated by reference its entirety herein). However, despite the chemical complexity obtained by linking two distinct polymerization cycles, the need for two separate catalysts increases the cost and limits industrial viability.

Focusing on this, "switch" catalyst trials have been developed to produce ordered block copolymers that are combined in a 1-port system using a di-zinc catalyst with a homogeneous ROP and ROCOP. Did. Unlike standard ternary copolymerization, these “switch” methods involve a mechanical switch between the apparent polymerization cycles using a single catalyst. Using this method, a polymer composed of alternating polycarbonate blocks and lactone homopolymer blocks was produced from a mixture of cyclohexane oxide (CHO), ε -caprolactone ( ε CL), and CO ₂ . Subsequently, a small library of order-defined block copolymers was developed using several different combinations of epoxide, anhydride, and lactone monomers with CO ₂ , the method being a polyester from the copolymerization of epoxide and anhydride. It has been used to produce unique examples of higher dimensional block copolymers containing. Another example of a “switch” catalyst system has been reported recently, where the block copolymer of CHO, CO ₂ , and β-butyrolactone (βBL) using a di-zinc catalyst coordinated by a β-diiminate ligand. It was synthesized from the mixture. In these systems, selective ROCOP of CHO and CO ₂ occurs prior to ROP of βBL, but the order is dependent on very high CO ₂ pressure (40 atm) and random incorporation occurs at lower pressure. However, non- "switch" systems have been successfully developed for the production of polyesters in applications in additional manufacturing and recycling machines.

Advances in additional fabrication techniques enable the development of patient-specific scaffolds and devices. However, this progress will depend heavily on the availability of printable materials that meet the chemical, mechanical and biological requirements of special applications. Various forms of additional fabrication, more commonly known as 3D printing, have been demonstrated in the literature. Fused deposition modeling (FDM) is a self-assembly method of extruded solid filaments such as poly (urethane) (PU), poly ( l -lactic acid) (PLLA) or poly (ester urea) (PEU) layer -by-layer method). The polymeric resin can also be printed using continuous digital light processing (cDLP), where photo-crosslinking in a specific region is achieved through high resolution stereolithography. Stereolithography methods, such as cDLP, have been demonstrated to exhibit much higher resolution compared to FDM technology, such as those restricted by the light source of the printer rather than the materials used. This allows the 3D scaffold to be printed with controlled porosity that can be adjusted to match the physiological state. Inkjet methods have also been demonstrated in 3D printing and can be used with powders or resins.

However, patient-specific devices will require highly specified polymers that can be easily functionalized and widely tuned for both mechanical and decomposition properties. Polyesters such as poly ( ε -caprolactone) (PCL), poly ( l -lactic acid) (PLLA), and poly (propylene fumarate) (PPF) have all been tested as tissue processing scaffolds, but each of them is recycled It requires the tuning of thermal, mechanical, rheological, and decomposition properties before it can be used extensively for applications. Moreover, in order to be used to produce 3D scaffolds that are compatible with biological systems, the polymer must be non-toxic, implantable without rejection and fully resorbable upon degradation. The first two criteria are achieved in a number of polymer systems, but there are also relatively few bioresorbable examples: polylactide, poly ( ε -caprolactone) (PCL) and poly (propylene fumarate). (PPF).

Since each of these examples is a polyester, it can be degraded in vivo enzymatically or through hydrolysis. However, as a result of the rapid degradation of PLLA, acidosis and inflammation of surrounding tissues are generally observed. Conversely, slow degradation of PCL in the human body limits its use in relation to tissue repair, particularly regeneration of vascular tissue. In addition, both PLLA and PCL can be extruded through FDM to produce 3D scaffolds that can be degraded in vitro , but these materials exhibit only moderate mechanical and tensile properties, and most of the defects in the material It is observed at the interface between the deposited layers. And, as a result of the achievable width of the extrusion nozzle in FDM, the resolution of 3D printed scaffolds made using these polymers is limited.

PPF can be formed by ring-opening (co) polymerization (ROCOP) of propylene oxide (PO) and maleic anhydride (MAn), which have been reported to produce PPF cis -alkene isomer poly (propylene maleate) (PPM). It is an unsaturated polyester, which can be converted to PPF using a weak acid at low (60 ° C) temperature. Advantageously, ROCOP allows a high degree of control over molecular weight distribution and terminal group fidelity through the diversity of ratios of monomer (s) to alcohol initiator. A recent study of PPF synthesis via ROP, including contact cytotoxicity assays and cell culture results, demonstrated that the PPF polymer produced by ROP is non-toxic and cells adhere to its thin film and proliferate well. .

In addition, PPF decomposes in vivo to form fumaric acid and propylene glycol, which is naturally released, and does not cause acidosis and inflammation of surrounding tissue sites that are regularly observed using PLLA. PPF has been used for a variety of medical applications such as vascular stents, neurotransplantation, cartilage, drug release vehicles, vascular engineering, and bone tissue engineering. As a result of the unsaturated alkels in the polymer backbone, intermolecular crosslinking can be achieved to enhance the mechanical properties of the material to provide better tunable mechanical properties than those observed in conventional PLLA and PCL.

Conventional PPF polymers have not been liquid at room temperature and have been formed into printable PPF resins by dissolving them into reactive diluent diethyl fumarate (DEF), which acts as both a solvent and a crosslinking agent. These resins have been researched and proven to be capable of producing 3D scaffolds with compressive modulus comparable to bone. The main drawback to the use of PPF polymer in these systems is that any excess DEF (ie, no DEF actually crosslinks the PPF polymer chain) must be removed before the printed structure can be used in biological systems.

Thus, what is needed in the art is additional fabrication and patient specific regeneration by "switching" from catalyzing the ROP of cyclic esters to catalyzing ROCOP of maleic anhydride (MAn) and propylene oxide (PO). One-port, scalable, open-open bulk order copolymerization using a catalyst capable of producing lower viscosity PPF-based block copolymers that require little solvent for application in medicine and avoid the limitations of prior art systems ring-opening block-order copolymerization (ROBOCOP).

Summary of the invention

In one or more embodiments, the present invention provides maleic anhydride from ROP of cyclic esters using magnesium 2,6- di - tert -butyl-4-methylphenoxide (Mg (BHT) ₂ (THF) ₂ ). MAn) and a novel 1-port, expandable ring-opening bulk order copolymerization (ROBOCOP) that produces PPF-based block copolymers for application to additional manufacturing and patient-specific regenerative medicines by "switching" to ROCOP of propylene oxide (PO). ) Technology to provide a well-defined biodegradable poly (lactone- b -propylene fumarate) polymer. These block copolymers are completely resorbable and PPF based materials are unique in that they can be crosslinked photochemicals in many applications, including 3D printing. The unique type and composition of lactone blocks confers the ability to tune physical, chemical and decomposition properties for specific applications. In particular, by adding a lactone block to the PPF polymer, the viscosity of the block copolymer obtained at working temperature can be precisely controlled and used as a solvent and a crosslinking agent used to form a printable resin, a reactive diluent di. The amount of ethyl fumarate (DEF) can be reduced and can be removed in some cases.

In a first aspect, the present invention relates to block copolymers comprising poly (lactone) segments and poly (propylene fumarate) segments. In one or more of these embodiments, the poly (lactone) segment is δ-valerolactone, ε-caprolactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl -ε-caprolactone (mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxephanone (dihydrocarbide), 7- (pro P-2-ynyl) oxepan-2-one, alkyl-substituted lactone, γ -methyl- ε -caprolactone, ε -heptalactone, ε -decalactone macrolactone, ω-pentadecaractone (PDL), functional lactone, θ- propargyl - ε - no hell tone (θp ε NL), α - propargyl - ε - caprolactone (CL ε α p), and includes a residue of a lactone selected from the group consisting of a combination thereof do.

In one or more embodiments, the block co-polymers of the invention are benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenziocyclooctin group, cyclooctin group, ketone group, aldehyde group, 3 Any one or more of the above-referenced embodiments of the first aspect of the present invention further comprising a functional end group selected from the group consisting of tertiary halogen groups and poly (ethylene glycol) groups, and combinations thereof. do.

In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the first aspect of the present invention, wherein the poly (propylene fumarate) segment is from about 0.1 mole percent to about 99 Mole percent terminal functionalized block co-polymer. In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the first aspect of the present invention, wherein the poly (lactone) segment is from about 0.1 mole percent to about 99 mole percent. Block functionalized block co-polymers.

In one or more embodiments, the block co-polymers of the present invention are the above-mentioned embodiments of the first aspect of the present invention having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa as measured by proton NMR. Any one or more of these. In one or more embodiments, the block co-polymers of the present invention are among the above-mentioned embodiments of the first aspect of the present invention having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa as measured by GPC. It includes any one or more. In one or more embodiments, the present invention comprises any one or more of the above-mentioned embodiments of the first aspect of the present invention, wherein the block co-polymer has a polydispersity index ( Ð _m ) from about 1.1 to about 2.3.

In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the first aspect of the present invention having the formula:

In the above formula,

n is an integer from about 1 to about 500; m is an integer from about 1 to about 500; x is an integer from about 1 to about 20; R is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group, poly (ethylene glycol) group, and A terminal functional group selected from the group consisting of combinations thereof; R ₁ is a hydrogen atom, a propargyl group, or a C ₁ -C ₁₀ alkyl group; R ₂ is a hydrogen atom, a methyl group, a butyl group, a propargyl group or a C ₁ -C ₁₀ alkyl group. In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the first aspect of the present invention having the formula:

,

,

,

,

또는

,

,

,

,

or

In the above formula,

n is an integer from about 1 to about 500; m is an integer from about 1 to about; k is an integer from about 1 to about 500; R is an end functional group.

In a second aspect, the present invention relates to a block co-polymer comprising a reaction product of poly (lactone), maleic anhydride, and propylene oxide. In one or more of these embodiments, the poly (lactone) is a terminal functionalized poly (lactone). In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the second aspect of the present invention, wherein the terminal functionalized poly (lactone) is a benzyl group, an alkyne Group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group and poly (ethylene glycol) group, and combinations thereof Selected terminal functional groups. In one or more embodiments, the block co-polymers of the present invention include any one or more of the above-mentioned embodiments of the second aspect of the present invention, wherein the poly (lactone) is δ-valerolactone, ε-capro. Lactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε-caprolactone (mented), 2,5-oxepanedione (OPD), 7 -Methyl-4- (1-methylethenyl) -2-oxepanone (dihydrocarbide), 7- (prop-2-ynyl) oxepan-2-one, alkyl-substituted lactone, γ -methyl - ε - caprolactone, ε - heptyl fallen tone, ε - deca-lactone macro lactone, ω- penta deca-lactone (PDL), functional lactone, θ- propargyl - ε - no hell tone (ε θp NL), α -Propargyl- ε -caprolactone ( α p ε CL), and combinations thereof.

In one or more embodiments, the block co-polymer of the present invention comprises from about 0.1 mole percent to about 99 mole percent of the terminally functionalized poly (lactone) residue of the above-mentioned embodiment of the second aspect of the invention. It includes any one or more. In one or more embodiments, the block co-polymers of the invention have any of the above-mentioned embodiments of the second aspect of the invention having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa, as measured by NMR. It contains one or more. In one or more embodiments, the block co-polymers of the present invention are any of the above-mentioned embodiments of the second aspect of the present invention having a number average molecular weight ( M _n ) of about 0.5 kDa to about 100 kDa as measured by GPC. Includes above. In one or more embodiments, the block co-polymers of the present invention comprise any one or more of the above-mentioned embodiments of the second aspect of the present invention having a polydispersity index ( Ð _m ) of about 1.1 to about 2.3.

In a third aspect, the present invention provides a method for preparing a starting alcohol; Combining the starting alcohol, magnesium catalyst, and lactone in a suitable reaction vessel; Dissolving the contents of the reaction vessel with a suitable solvent; Heating the solution after sealing to induce or maintain ring-opening polymerization of the lactone initiated by the starting alcohol, thereby forming a poly (lactone) polymer; Dissolving maleic anhydride and propylene oxide in a suitable solvent and adding them to the reaction vessel; Heating the solution to form a block co-polymer comprising poly (lactone) segments and poly (propylene maleate) segments; And isomerizing the poly (propylene maleate) segment to form a poly (lactone-b-propylene fumarate) polymer. In one or more of these embodiments, the starting alcohol is benzyl alcohol, propargyl alcohol, allyl alcohol, 4-dibenzylcyclooctinol, 4-hydroxybutan-2-one, 3-hydroxypropane-2- ON, 5-hydroxypentan-2-one, 6-hydroxyhexan-2-one, 6-hardidoxyhexan-2-one, 7-hydroxyheptan-2-one, 8-hydroxyoctan-2- On, 5-norbornene-2-ol, PEG diol, α-bromoisobutyryl 4-methanol benzylmethanoate, and combinations thereof.

In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the starting alcohol is end functionalized, and the formed poly The (lactone) polymer is a terminal functionalized lactone polymer, and a block co-polymer comprising poly (lactone) fragments and poly (propylene maleate) fragments is terminal functionalized and produced poly (lactone-b-propylene fumarate) The polymer is a terminal functionalized poly (lactone-b-propylene fumarate) polymer. In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the terminal functionalized poly (lactone-b- Propylene fumarate) polymers include benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group and poly (ethylene glycol) ) Groups and combinations thereof. In one or more embodiments, the method of making a block co-polymer of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the lactone is δ-valerolactone, ε- Caprolactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε-caprolactone (mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxepanone (dihydrocarbide), 7- (prop-2-ynyl) oxepan-2-one, alkyl-substituted lactone, γ- Methyl- ε -caprolactone, ε -heptalactone, ε -decaractone macrolactone, ω-pentadecaractone (PDL), functional lactone, θ-propargyl- ε -nonaractone (θp ε NL), α -propargyl- ε -caprolactone ( α p ε CL), and combinations thereof.

In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the magnesium catalyst is Mg (BHT) ₂ (THF ) ₂ . In one or more embodiments, the method for preparing the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the concentration of lactone in solution is from about 0.5M to It is about 10M. In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the total of maleic anhydride and propylene oxide in solution The concentration is about 0.5M to about 10M. In one or more embodiments, the method of making a block co-polymer of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the lactone solution is from about 40 ° C to about 100 ° C. It is heated to the temperature. In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the lactone solution thereof is from about 1 hour to about 96 Heat for an hour.

In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the poly (lactone) polymer, maleic anhydride, The propylene oxide solution is heated to a temperature of about 40 ° C to about 100 ° C. In one or more embodiments, the method of making the block co-polymers of the present invention comprises any one or more of the above-mentioned embodiments of the third aspect of the present invention, wherein the poly (lactone) polymer, maleic anhydride, The propylene oxide solution is heated for about 1 hour to about 96 hours.

상기식에서,
n은 약 1 내지 약 500의 정수이고; m은 약 1 내지 약 500의 정수이며; x는 약 1 내지 약 20의 정수이고; R은 개시 알콜의 잔기를 포함하는 말단 그룹이며 바람직하게는 말단 작용성 그룹을 포함하고; R₁은 수소 원자, 프로파르길 그룹, 또는 C₁-C₁₀ 알킬 그룹이며; R₂는 수소 원자, 메틸 그룹, 부틸 그룹, 프로파르길 그룹 또는 C₁-C₁₀ 알칸이다.
이들 구현예들 중 하나 이상에서, R은 벤질 그룹, 알킨 그룹, 프로파르길 그룹, 알릴 그룹, 알켄 그룹, 4-디벤지오사이클로옥틴 그룹, 사이클로옥틴 그룹, 케톤 그룹, 알데하이드 그룹, 3차 할로겐 그룹 및 폴리(에틸렌 글리콜) 그룹, 및 이의 조합일 수 있다. 이들 구현예들 중 일부에서, n은 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 500 내지 약 500, 다른 구현예에서, 약 150 내지 약 500, 다른 구현예에서, 약 250 내지 약 500, 및 다른 구현예에서, 약 350 내지 약 500의 정수이다. 이들 구현예들 중 일부에서, m은 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 500 내지 약 500, 다른 구현예에서, 약 150 내지 약 500, 다른 구현예에서, 약 250 내지 약 500, 및 다른 구현예에서, 약 350 내지 약 500의 정수이다.
이들 구현예들 중 일부에서, x는 약 1 내지 약 20, 다른 구현예에서, 약 1 내지 약 15, 다른 구현예에서, 약 1 내지 약 10, 다른 구현예에서, 약 1 내지 약 5, 다른 구현예에서, 약 1 내지 약 3의 정수이다. 이들 구현예들 중 일부에서, R₁은 수소 원자, 프로파르길 그룹 또는 C₁-C₁₀ 알킬 그룹일 수 있다. 이들 구현예들 중 일부에서, R₂는 수소 원자, 메틸 그룹, 부틸 그룹, 프로파르길 그룹 또는 C₁-C₁₀ 알킬 그룹일 수 있다.
일부 구현예에서, 본 발명의 블록 공-중합체는 다음 식을 가질 수 있다:

,

,

,

,

또는

상기식에서,
n은 약 1 내지 약 500의 정수이고; m은 약 1 내지 약 500의 정수이며; k는 약 1 내지 약 500의 정수이고; R은 개시 알코올의 잔기를 포함하는 말단 그룹이고, 바람직하게는 상술한 바와 같이, 말단 작용성 그룹을 포함한다.
이들 구현예들 중 하나 이상에서, R은 벤질 그룹, 알킨 그룹, 프로파르길 그룹, 알릴 그룹, 알켄 그룹, 4-디벤지오사이클로옥틴 그룹, 사이클로옥틴 그룹, 케톤 그룹, 알데하이드 그룹, 3차 할로겐 그룹 및 폴리(에틸렌 글리콜) 그룹, 또는 이의 조합일 수 있다. 이들 구현예들 중 일부에서, n은 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 500 내지 약 500, 다른 구현예에서, 약 150 내지 약 500, 다른 구현예에서, 약 250 내지 약 500, 및 다른 구현예에서, 약 350 내지 약 500의 정수이다. 이들 구현예들 중 일부에서, m은 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 500 내지 약 500, 다른 구현예에서, 약 150 내지 약 500, 다른 구현예에서, 약 250 내지 약 500, 및 다른 구현예에서, 약 350 내지 약 500의 정수이다. 이들 구현예들 중 일부에서, k는 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 500 내지 약 500, 다른 구현예에서, 약 150 내지 약 500, 다른 구현예에서, 약 250 내지 약 500, 및 다른 구현예에서, 약 350 내지 약 500의 정수이다.
일부 구현예에서, 본 발명의 블록 공중합체는 ¹H NMR 분광 분석을 사용하는 말단-그룹 분석으로 측정하는 경우 약 0.5 kDa 내지 약 500 kDa의 수 평균 분자량(M _n )을 갖는다. 일부 구현예에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 ¹H NMR 분광 분석을 사용한 말단-그룹 분석으로 측정하는 경우 약 0.5 kDa 내지 약 400 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 300 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 200 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 100 kDa, 다른 구현예에서, 약 50 kDa 내지 약 500 kDa, 다른 구현예에서, 약 150 kDa 내지 약 500 kDa, 및 다른 구현예에서, 약 250 kDa 내지 약 500 kDa의 수 평균 분자량(M _n )을 갖는다.
일부 구현예에서, 본 발명의 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 크기 배제 크로마토그래피(SEC)로 측정하는 경우 약 0.5 kDa 내지 약 500 kDa의 수 평균 분자량(M _n )을 가질 수 있다. 일부 구현예에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 크기 배제 크로마토그래피(SEC)로 측정하는 경우 약 0.5 kDa 내지 약 400 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 300 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 200 kDa, 다른 구현예에서, 약 0.5 kDa 내지 약 100 kDa, 다른 구현예에서, 약 50 kDa 내지 약 500 kDa, 다른 구현예에서, 약 150 kDa 내지 약 500 kDa, 및 다른 구현예에서, 약 250 kDa 내지 약 500 kDa의 수 평균 분자량(M _n )을 갖는다.
일부 구현예에서, 본 발명의 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 SEC로 측정하는 경우 약 2 kDa 내지 약 500 kDa의 중량 평균 분자량(M _w )을 갖는다. 일부 구현예에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 크기 배제 크로마토그래피(SEC)로 측정하는 경우 약 2 kDa 내지 약 250 kDa, 다른 구현예에서, 약 2 kDa 내지 약 100 kDa, 다른 구현예에서, 약 2 kDa 내지 약 50 kDa, 다른 구현예에서, 약 2 kDa 내지 약 25 kDa, 다른 구현예에서, 약 2 kDa 내지 약 10 kDa의 중량 평균 분자량(M _w )을 가질 것이다.
다양한 구현예에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 SEC로 측정하는 경우 약 1.1 내지 약 2.3의 다분산성(Ð _M)을 가질 수 있다. 일부 구현예에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 폴리(스티렌) 표준물에 대한 THF 속에서 SEC로 측정하는 경우 약 1.1 내지 약 2.1, 다른 구현예에서, 약 1.1 내지 약 1.8, 다른 구현예에서, 약 1.1 내지 약 1.5, 다른 구현예에서, 약 1.3 내지 약 2.3, 다른 구현예에서, 약 1.5 내지 약 2.3, 다른 구현예에서, 약 1.8 내지 약 2.3, 및 다른 구현예에서, 약 2.0 내지 약 2.3의 다분산성(Ð _M)을 가질 것이다.
명백해지는 바와 같이, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 이들을 조직 스캐폴드와 같은 중합체 구조의 생산에 유용하도록 만드는 다른 폴리(프로필렌 푸마레이트) 중합체과 동일한 방식으로 디에틸 푸마레이트(DEF)를 사용하여 광화학적으로 가교결합될 수 있다. 이들 구현예들 중 하나 이상에서, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 3-D 프린트가능한 수지로 형성될 수 있다. 이들 구현예에서, 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체는 디에틸 푸마레이트(DEF) 내로 용해되며 통상의 광개시제 및 광 산란제(light scattering agent)가 수지 전체에 균일하게 혼합된다. 3D 프린트가능한 수지를 제형화하는데 요구되는 DEF의 양은 PPF를 희석시키는데 DEF가 거의 필요하지 않고 락톤 블록의 존재는 보다 긴 PPF 블록을 허용하여, 가교결합에 필요한 DEF의 양을 감소시키므로, 본 발명의 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체의 경우 현저히 감소되는 것으로 밝혀졌다. 수지는 이후에 3-D 프린트되며 cDLP 프린터 또는 다른 적합한 3-D 프린터와 광-가교결합하여 스캐폴드 또는 다른 중합체 구조물을 형성한다.
다른 구현예에서, 본 발명은 상술한 폴리(락톤-b-프로필렌 푸마레이트) 블록 공중합체를 제조하는 방법에 관한 것이다. 다양한 구현예에서, 본 발명의 말단 작용화된 폴리(락톤-b- 프로필렌 푸마레이트) 블록 공중합체는 3개의 단계 공정을 사용하여 제조된다: (i) 출발 알코올 및 마그네슘 촉매를 사용한 락톤의 개환 중합을 통한 말단 작용화된 폴리(락톤) 분절(블록)(이는 말단 작용화될 수 있거나 말단 작용화되지 않을 수 있다)의 형성; (ii) 말레산 무수물 및 프로필렌 옥사이드의 개환 중합을 통한 말단 작용화된 폴리(락톤) 분절(블록)의 말단에서 폴리(프로필렌 말레에이트) 분절(블록)의 형성; 및 (iii) 폴리(락톤-b- 프로필렌 푸마레이트) 블록 공중합체를 형성하기 위한 이러한 목적을 위해 당해 분야에 공지된 어떠한 방법을 사용하는 폴리(프로필렌 말레에이트) 분절(블록)의 이의 트랜스-이성체(폴리(프로필렌 푸마레이트)) 형태로의 이성체화.
제1 단계에서, 락톤 알코올, 락톤 단량체, 및 마그네슘 촉매, 바람직하게 Mg(BHT)₂(THF)₂는 앰플(ampule) 또는 다른 적합한 반응 용기 용해 위치하여 톨루엔과 같은 적합한 용매 속에 용해된다. 용매의 선택은 특별히 제한되지 않으며 당해 분야의 통상의 기술자는 과도한 실험없이 적합한 용매를 선택할 것이다.
위에 설정된 바와 같이, 어떠한 락톤도 이것이 Mg(BHT)₂(THF)₂와 같은 적합한 촉매를 사용하여 알코올 개시제로부터 개환중합할 수 있으면 락톤 단량체로서 사용될 수 있다. 적합한 락톤 단량체는 δ-발레로락톤(δVL), ε-카프로락톤(εCL), α-클로로-ε-카프로락톤, 4-클로로-ε-카프로락톤, 4-메틸-7-이소프로필-ε-카프로락톤(멘티드), 2,5-옥세판디온(OPD), 7-메틸-4-(1-메틸에테닐)-2-옥세파논(디하이드로카바이드), 7-(프로프-2-이닐)옥세판-2-온, γ-메틸-ε- 카프로락톤 (γmεCL)을 포함하나, 이에 한정되지 않는 알킬-치환된 락톤, ε-헵타락톤(εHL), ε-데카락톤 (εDL), ω-펜타데카락톤(PDL)을 포함하나, 이에 한정되지 않는 마크로락톤, θ-프로파르길-ε-노나락톤(θpεNL)을 포함하나, 이에 한정되지 않는 작용성 락톤, α-프로파르길-ε-카프로락톤(αpεCL) 및 이의 이성체 혼합물, 또는 이의 어떠한 조합을 포함할 수 있으나, 이에 한정되지 않는다.
개시 알코올은 특별히 제한되지 않지만, 상이한 개시 알코올은 상이한 속도 상수를 가질 것이며 상이한 속도에서 반응을 구동할 것임을 주목하여야 한다. 하나 이상의 구현예에서, 적합한 개시 알코올은 벤질 알코올, 에탄올, 이소프로판올, 글리세롤, 프로파르길 알코올, 알릴 알코올, 4-디벤지오사이클로옥티놀, 4-하이드록시부탄-2-온, 3-하이드록시프로판-2-온, 5-하이드록시펜탄-2-온, 6-하이드록시헥산-2-온, 7-하이드록시헵탄-2-온, 8-하이드록시옥탄-2-온, 5-노르보르넨-2-올, α-브로모이소부티릴 4-메탄올 벤질메타노에이트, 폴리(에틸렌 글리콜) 또는 이의 조합을 포함하나, 이에 한정되지 않는다.
상기 설정된 바와 같이, 작용성 말단 그룹은 개시 알코올을 통해 중합체에 첨가될 수 있다. 이들 물질은 개환 중합 반응을 개시하는 하이드록실 그룹 및 중합 및 이성체화 반응 둘 다에서 생존하는 중합후 반응에 유용한 작용 말단 그룹을 갖는다. 이들 작용 말단 그룹은, 이들이 중합 및 이성체화 반응 후 이들의 반응성 중 적어도 일부를 유지하는 한 특별히 제한되지 않으며, 벤질 그룹, 알킨 그룹, 프로파르길 그룹, 알릴 그룹, 알켄 그룹, 4-디벤조사이클로옥틴 그룹, 사이클로옥틴 그룹, 케톤 그룹, 알데하이드 그룹, 및 3차 할로겐 그룹 또는 이의 조합을 포함하나, 이에 한정되지 않는다.
다양한 구현예에서, 마그네슘 촉매는 어떠한 마그네슘 또는 실질적으로 무-독성이고 소비되지 않고 락톤의 ROP 및 말레산 무수물 및 프로필렌 옥사이드 단량체의 ROP를 촉매할 수 있는 다른 유기금속성 촉매일 수 있으나, 바람직하게는 Mg(BHT)₂(THF)₂이다.
사용된 반응 용매는 특별히 제한되지 않으며 단계 1에서 락톤 단량체뿐만 아니라, 단계 2의 말레산 무수물 및 프로필렌 옥사이드 단량체도 용해할 수 있고 말레산 무수물 및 프로필렌 옥사이드 단량체를 용해하는데 사용된 용매와 혼화성인 어떠한 적합한 용매 또는 용매 조합일 수 있다. 다양한 구현예에서, 적합한 용매는 톨루엔, 헥산, 헵탄, 헥산, 옥탄, 또는 이의 조합을 포함하나, 이에 한정되지 않는다. 당해 분야의 통상의 기술자는 과도한 실험없이 적합한 용매를 선택할 수 있을 것이다.
다양한 구현예에서, 출발 용액 속의 락톤 단량체의 농도는 약 0.5M 내지 약 10 M일 것이다. 락톤 단량체 농도는 일부 구현예에서 약 1M 내지 약 7M, 다른 구현예에서, 약 2M 내지 약 5M, 다른 구현예에서, 약 3M 내지 약 5M, 다른 구현예에서, 약 0.5M 내지 약 4M, 다른 구현예에서, 약 0.5M 내지 약 3M, 및 다른 구현예에서, 약 0.5M 내지 약 2M이다. 이후에, 반응 용기를 밀봉하고 락톤 용액을 약 40℃ 내지 약 100℃의 온도로 가열하여 개시 알코올에 의해 개시되고 마그네슘 촉매에 의해 촉매되는, 락톤의 개환 중합 반응을 개시하고/하거나 유지시켜 폴리(락톤) 중합체 중간체를 수득한다. 일부 구현예에서, 락톤 용액은 약 40℃ 내지 약 50℃, 다른 구현예에서 약 40℃ 내지 약 60℃, 다른 구현예에서 약 40℃ 내지 약 70℃, 다른 구현예에서 약 40℃ 내지 약 80℃, 및 다른 구현예에서 약 40℃ 내지 약 90℃의 온도로 가열된다. 명백해지는 바와 같이, 이들 폴리(락톤) 중합체 중간체는 경우에 따라, 하나의 말단에 개시 알코올로부터의 작용 말단 그룹 및 다른 말단에 하이드록실(OH) 그룹을 가질 것이다. 일부 구현예에서, 락톤 용액은 락톤 모두(98% 이상)이 반응할 때까지 가열된다.
다양한 구현예에서, 락톤 용액은 약 1 시간 내지 약 96 시간 동안 가열된다. 일부 구현예에서, 락톤 용액은 약 1 시간 내지 약 84 시간, 다른 구현예에서, 약 1 시간 내지 약 72 시간, 다른 구현예에서, 약 1 시간 내지 약 60 시간, 다른 구현예에서, 약 1 시간 내지 약 48 시간, 다른 구현예에서, 약 1 시간 내지 약 36 시간, 다른 구현예에서, 약 1 시간 내지 약 24 시간, 및 다른 구현예에서, 약 1 시간 내지 약 12 시간 동안 가열된다.
제2 단계에서, 말레산 무수물 단량체 및 프로필렌 옥사이드 단량체는 톨루엔과 같은 적합한 용매 속에 약 0.5M 내지 약 10M의 총 단량체 농도로 용해되어 폴리(락톤) 중합체 중간체를 함유하는 반응 용기에 첨가된다. 일부 구현예에서, 총 단량체 농도는 약 1M 내지 약 7M, 다른 구현예에서, 약 2M 내지 약 5M, 다른 구현예에서, 약 3M 내지 약 5M, 다른 구현예에서, 약 0.5M 내지 약 4M, 다른 구현예에서, 약 0.5M 내지 약 3M, 및 다른 구현예에서, 약 0.5M 내지 약 2M이다.
명백해지는 바와 같이, 폴리(락톤) 중합체 중합체가 말레산 무수물 및 프로필렌 옥사이드 단량체의 ROP를 위한 개시 알코올로 작용하고 마그네슘 촉매가 락톤의 ROP로부터 말레산 무수물 및 프로필렌 옥사이드 단량체의 ROP로 촉매하는 것을 단순히 스위칭하기 때문에 당해 단계에서 추가의 촉매 또는 개시 알코올이 필요하지 않다. 일부 구현예에서, 작용화된 프로필렌 옥사이드 단량체를 사용하여 블록 공-중합체의 PPF 블록으로 단량체 작용성 그룹을 도입할 수 있다.
수득되는 용액을 이후에 약 40℃ 내지 약 100℃의 온도로 가열하여 폴리(락톤) 중합체 중간체 상의 말단 OH 그룹에 대한 말레산 무수물 단량체 및 프로필렌 옥사이드 단량체의 개환 중합 잔응을 개시하고/하거나 유지시켜 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체를 형성한다. 일부 구현예에서, 용액은 약 40℃ 내지 약 50℃, 다른 구현예에서 약 40℃ 내지 약 60℃, 다른 구현예에서 약 40℃ 내지 약 70℃, 다른 구현예에서 약 40℃ 내지 약 80℃, 및 다른 구현예에서 약 40℃ 내지 약 90℃의 온도로 가열된다. 일부 구현예에서, 용액은 실질적으로 모든(80% 이상) 단량체가 반응할 때까지 가열된다. 일부 구현예에서, 용액은 약 1 시간 내지 약 96 시간, 다른 구현예에서, 약 12 시간 내지 약 96 시간, 다른 구현예에서, 약 24 시간 내지 약 96 시간, 다른 구현예에서, 약 48 시간 내지 약 96 시간, 다른 구현예에서, 약 62 시간 내지 약 96 시간, 다른 구현예에서, 약 1 시간 내지 약 62 시간, 및 다른 구현예에서, 약 1 시간 내지 약 48 시간 동안 가열된다.
하나 이상의 구현예에서, 말단 작용화된 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 1에 나타낸 바와 같이 형성될 수 있다;
반응식 1
락톤 및 폴리(프로필렌 말레에이트)를 함유하는 블록 공중합체에 대한 제안된 합성 방법

여기서, R은 상술한 바와 같은 말단 그룹 또는 말단 작용성 그룹이고; n은 약 1 내지 약 20의 정수이며; m은 약 1 내지 약 500의 정수이고; k는 약 1 내지 약 100의 정수이다. 다양한 구현예에서, R은 알킨 그룹, 프로파르길 그룹, 알켄 그룹, 하이드록실 그룹, 케톤 그룹, 티올 그룹, 할라이드 그룹, 니트로벤질 그룹, 또는 할라이드 그룹 또는 니트로벤질 그룹과 같은 이러한 작용성 그룹으로 용이하게 전환될 수 있는 그룹일 수 있다.
일부 구현예에서, n은 약 1 내지 약 15, 다른 구현예에서, 약 1 내지 약 10, 다른 구현예에서, 약 1 내지 약 8, 다른 구현예에서, 약 1 내지 약 6, 다른 구현예에서, 약 1 내지 약 4, 다른 구현예에서, 약 5 내지 약 20, 및 다른 구현예에서, 약 10 내지 약 20의 정수일 수 있다. 일부 구현예에서, m은 약 1 내지 약 400, 다른 구현예에서, 약 1 내지 약 300, 다른 구현예에서, 약 1 내지 약 200, 다른 구현예에서, 약 1 내지 약 100, 다른 구현예에서, 약 1 내지 약 50, 다른 구현예에서, 약 1 내지 약 25, 다른 구현예에서, 약 100 내지 약 400, 및 다른 구현예에서, 약 200 내지 약 400의 정수일 수 있다. 일부 구현예에서, k는 약 1 내지 약 80, 다른 구현예에서, 약 1 내지 약 60, 다른 구현예에서, 약 1 내지 약 40, 다른 구현예에서, 약 1 내지 약 20, 다른 구현예에서, 약 1 내지 약 10, 다른 구현예에서, 약 20 내지 약 80, 다른 구현예에서, 약 40 내지 약 80, 다른 구현예에서, 약 50 내지 약 80, 및 다른 구현예에서, 약 60 내지 약 100의 정수일 수 있다.
일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 2에 나타낸 바와 같이 합성될 수 있다.
반응식 2

여기서, m 및 n은 각각 약 1 내지 약 500의 정수이고; R은 상술한 바와 같은 말단 그룹 또는 말단 작용성 그룹이다.
일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 3에 나타낸 바와 같이 합성될 수 있다:
반응식 3

여기서 m 및 n은 각각 약 1 내지 약 500의 정수이고; R은 후술한 바와 같이 말단 그룹 또는 말단 작용성 그룹이다.
일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 4에 나타낸 바와 같이 합성될 수 있다:
반응식 4

여기서, m 및 n은 각각 약 1 내지 약 500의 정수이고; R은 후술된 바와 같이 말단 그룹 또는 말단 작용 그룹이다.
일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 5에 나타낸 바와 같이 합성될 수 있다:
반응식 5

여기서, m 및 n은 각각 약 1 내지 약 500의 정수이고; R은 후술된 바와 같이 말단 그룹 또는 말단 작용성 그룹이다.
일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 하기 반응식 6에 나타낸 바와 같이 합성될 수 있다.
반응식 6

여기서, m 및 n은 각각 약 1 내지 약 500의 정수이고; R은 후술된 바와 같이 말단 그룹 또는 말단 작용성 그룹이다.
일부 구현예에서, 폴리(락톤-b-락톤-b-프로필렌 말레에이트) 트리블록 중합체 중간체는 하기 반응식 7에 나타낸 바와 같이 합성될 수 있다:
반응식 7

여기서, m, n 및 k는 각각 약 1 내지 약 500의 정수이고; R은 후술된 바와 같이 말단 그룹 또는 말단 작용성 그룹이다.
일부 구현예에서, 폴리(락톤-b-락톤-b-프로필렌 말레에이트) 트리블록 중합체 중간체는 하기 반응식 8에 나타낸 바와 같이 합성될 수 있다:
반응식 8

여기서, m, n 및 k는 각각 약 1 내지 약 1000의 정수이고; R은 후술된 바와 같이 말단 그룹 또는 말단 작용성 그룹이다.
폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 및/또는 폴리(락톤-b-락톤-b-프로필렌 말레에이트) 트리블록 중합체 중간체는 어떠한 공지된 방법을 사용하여서도 분리하여 정제할 수 있다. 일부 구현예에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 및/또는 폴리(락톤-b-락톤-b-프로필렌 말레에이트) 트리블록 중합체 중간체는 과도한 디에틸 에테르 속에 침전시켜 회수할 수 있다.
제3 단계에서, 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 및/또는 폴리(락톤-b-락톤-b-프로필렌 말레에이트) 트리블록 중합체 중간체의 폴리(프로필렌 말레에이트) 분절(블록)은 이의 트랜스-이성체(폴리(프로필렌 푸마레이트))로 이성체화되어 본 발명의 구현예에 따른 폴리(락톤-b- 프로필렌 푸마레이트) 블록 공중합체를 형성한다(참고: 도 1). 용어 이성체화는 본원에서 시스-이성체(PPM)를 트랜스-이성체(PPF) 형태로 전환하는 반응을 언급하기 위해 사용된다. 이성체화 단계가 중합체로의 일부 다른 변화를 초래할 수 있지만, 대략적인 M _n, Ð _M, 및 T _g 범위와 같은, 본 발명의 구현예의 말단 작용화된 PPF 중합체의 가장 일반적인 국면은 이성체화 단계 전에 측정된다. 그러나, 심지어 비교적 소량의 PPM 중합체 쇄가 중합체 속에 남아있다고 해도, 이는 3D 프린팅 및 다른 유사한 적용에 이를 부적절하도록 하는 가교 결합에 대한 중합체의 능력에 부정적으로 영향을 미칠 것이다. 따라서, 중합체가 이들 적용에 사용되어야 하는 경우 필수적으로 모든 폴리(프로필렌 말레에이트)를 폴리(프로필렌 푸마레이트)로 전환시키는 것이 중요하다.
폴리(프로필렌 말레에이트) 분절(블록)은 이의 개시내용이 본원에 이의 전문으로 참고로 포함된, 제WO 2016/081587호로서 공개된, 국제 출원 제PCT/US2015/061314호에 기술된 방법을 포함하나, 이에 한정되지 않는 어떠한 통상의 방법을 사용하여서도 이성체화할 수 있다. 일부 구현예에서, 이들 블록 공중합체의 폴리(프로필렌 말레에이트) 분절(블록)은 하기 실시예 11에 나타낸 바와 같이 이성체화될 수 있다.
다양한 구현예에서, 말단 작용화된 폴리(락톤-b-프로필렌 말레에이트) 블록 공중합체 중간체는 환저 플라스크와 같은 적합한 용기 속에 두며, 클로로포름, 테트라하이드로푸란(THF), 디옥산, 디에틸 에테르, 또는 이의 조합과 같은 적합한 용매 속에서, 불활성 대기 하에 용해시킨다. 선택되는 용매에 상관없이 과도한 곤란성 또는 비용없이, 이를 제거할 수 있다는 것이 고려되며, 일부 구현예에서, 용매는 클로로포름이다. 일단 PPM 중간체가 용해되면, 촉매, 바람직하게는 디에틸아민을 첨가하고 용기를 응축기에 연결하여 약 5℃ 내지 약 80℃의 반응 온도로 가열한다. 일부 구현예에서, 반응 온도는 약 5℃ 내지 약 70℃, 다른 구현예에서, 약 5℃ 내지 약 65℃, 다른 구현예에서, 약 5℃ 내지 약 55℃, 다른 구현예에서, 약 20℃ 내지 약 80℃, 다른 구현예에서, 약 40℃ 내지 약 80℃, 및 다른 구현예에서, 약 60℃ 내지 약 80℃이다. 일부 구현예에서, 반응 온도는 약 55℃ 내지 약 65℃이다.
이들 구현예에서, 용액은 약 5 내지 약 100 시간, 약 5 시간 내지 약 80 시간, 다른 구현예에서, 약 5 시간 내지 약 60 시간, 다른 구현예에서, 약 5 시간 내지 약 50 시간, 다른 구현예에서, 약 5 시간 내지 약 40 시간, 다른 구현예에서, 약 20 시간 내지 약 100 시간, 다른 구현예에서, 약 40 시간 내지 약 100 시간, 및 다른 구현예에서, 약 60 시간 내지 약 100 시간 동안 가열하여 이성체화된 중합체를 생산한다(참고: 도 1). 일부 구현예에서, 용액은 약 24 내지 약 48 시간 동안 가열한다. 이성체화 반응이 완료되면, 본 발명의 말단 작용화된 폴리(락톤-b- 프로필렌 푸마레이트) 블록 공중합체를 당해 목적을 위해 당해 분야에 공지된 어떠한 적합한 방법으로도 분리하여 정제할 수 있다.
본 발명의 방법이 폴리(락톤-b-프로필렌 푸마레이트) 디블록 공중합체를 참고로 주로 논의되었지만, 이들 방법은 폴리(락톤-b-프로필렌 푸마레이트) 디블록 공중합체에 대해 상기 설정된 바와 같이, 블록 전에 형성시키기 위해 사용된 시약이 고갈되는 경우 락톤 단량체(추가의 락톤 블록을 형성하기 위한) 또는 프로필렌 옥사이드/말레산 무수물 단량체(추가의 PPF 블록을 형성하기 위한)의 순차적인 첨가에 의해 3개 이상을 블록을 지닌 블록 공중합체를 형성하는데 사용될 수 있다. 상기 논의된 디블록 공중합체를 사용함으로써, 앞서의 블록의 말단에서의 하이드록실 그룹이 다음의 락톤 또는 말레산 무수물/프로필렌 옥사이드 ROP에 대한 개시제로서 작용하고, 마그네슘 촉매가 새로운 블록에 대한 ROP를 촉매하기 위해 스위치되므로 추가의 촉매 또는 개시 알코올이 요구되지 않는다. 일부 다른 구현예에서, ABA 블록 공중합체는 이-작용성 개시 알코올을 사용하여 형성시킬 수 있다. 이들 구현예에서, 제1 블록(B)은 2개의 활성 작용성 그룹을 가질 것이고 2개(A)의 블록은 상술한 바와 같이 첨가되어 ABA 블록 공중합체를 형성할 수 있다.
다양한 구현예에서, 본 발명의 폴리(락톤-b- 프로필렌 푸마레이트) 블록 공중합체는 3D 프린팅가능한 수지, 의료 장치, 조직 가공, 상처 치유, 화장품, 및 약물 및 단백질 전달과 같은 다수의 적용에서 사용될 수 있다. Brief description of the drawing
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention in conjunction with the accompanying drawings, where:
1 shows DP 50 poly (ε-Caprolactone-b-Propylene maleate) (bottom) and poly (ε-Caprolactone-b-Propylene fumarate) (top) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
Figure 2 DP 100 poly (ε-Caprolactone-b-Propylene maleate) (500 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
3 shows DP 100 poly (ε-Caprolactone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) represents the carbonyl diad resonance peak¹³C NMR spectrum.
Figure 4 is polyε-Caprolactone-b-Diffusion ordered NMR spectroscopy ("DOSY" or "DOSY NMR") spectrum for propylene maleate (500 MHz, 298 K, CDCl₃)to be.
Figure 5 [εCL]₀: [MAn]₀ : [PO]₀ : [BnOH]₀ : [Cat.]₀ = 50: 50: 50: 1: 1, total initial monomer concentration = DP 50 poly of maleic anhydride and propylene oxide, performed at 80 ° C. in toluene using 2 Mε-Caprolactone) for the copolymerization (kinetic plot).
FIG. 6 shows an increase in MAn conversion for the same copolymerization, measured by SEC for poly (styrene) standards.M _n AndÐ _MIt is a graph showing the increase in.
Figure 7 is a poly (δ-Valerolactone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
Figure 8 is polyδ-Valerolactone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
Figure 9 is polyε-Heptalactone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
10 is a poly (ε-Heptalactone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
11 is a poly (γ-methyl-ε-Caprolactone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
12 is a poly (γ-methyl-ε-Caprolactone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
13 is a poly (α-Propargyl-ε-Caprolactton-b-θ-Propargyl-ε-Nonnalactone-b-ε-caprolactton-b-Propylene fumarate) (125 MHz, CDCl₃, 303 K) of this carbonyl diad region¹³C NMR spectrum.
Figure 14 is a poly (α-Propargyl-ε-Caprolactton-b-θ-Propargyl-ε-Nonnalactone-b-ε-caprolactton-b-Propylene fumarate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
15 is a poly (ε-Decaractone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
16 is a poly (ε-Decaractone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
Fig. 17 shows poly (ω-pentadecaractone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
Figure 18 is poly (ω-pentadecaractone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
Figure 19 is a poly (δ-Valerolactone-nose-ε-Caprolactone-b-Propylene maleate) (125 MHz, CDCl₃, 303 K) of the carbonyl diad region¹³C NMR spectrum.
Figure 20 is poly (δ-Valerolactone-Nose-ε-Caprolactone-b-Propylene maleate) (500 MHz, 298 K, CDCl₃) Is the DOSY NMR spectrum.
Figure 21 is a poly (δ-Valerolactone-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene maleate).
Figure 22 is a poly (ε-Caprolactone-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene maleate).
23 is a poly (ε-Heptalactone-bDSC temperature records for (propylene maleate) (secondary heating curve, -50 to 150 ° C).
24 is a poly (γ-methyl-ε-Caprolactone-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene maleate).
25 is a poly (α-Propargyl-ε-Caprolactton-b-θ-Propargyl-ε-Nonnalactone-b-ε-caprolactton-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene fumarate).
26 is a poly (ε-Decaractone-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene maleate).
Figure 27 shows poly (ω-pentadecaractone-bDSC thermogram (secondary heating curve, -50 to 150 ° C) for -propylene maleate).
28 is a poly (δ-Valerolactone-Nose-ε-Caprolactone-b-DSC thermogram for (propylene maleate) (secondary heating curve, -50 ° C to 150 ° C).
29 is poly (propylene maleate)-b-ε-Decalactoneb-Propylene maleate) (300 MHz, CDCl₃, For 303 K)^OneH NMR spectrum.
30 is poly (propylene maleate)-b-ε-Decalactoneb-Propylene maleate) (125 MHz, CDCl₃, For 303 K)¹³C NMR spectrum.
Figure 31 is a poly (α-Propargyl-ε-Caprolactton-b-θ-Propargyl-ε-Nonnalactone-b-ε-caprolactton-b-Propylene fumarate) (300 MHz, CDCl₃, For 303 K)^OneH NMR spectrum.
32 is a poly (α-Propargyl-ε-Caprolactton-b-θ-Propargyl-ε-Nonnalactone-b-ε-caprolactton-b-SEC chromatogram for propylene fumarate). Molecular weights were measured against poly (styrene) standards.
Figure 33α-Propargil-ε-Caprolactone and θ-propargyl-ε-Nonalactone (300 MHz, CDCl₃, 303 K) of the isomer mixture^OneH NMR spectrum.
34 is a poly (δ-Valerolactone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
35 is a poly (δ-Valerolactone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Figure 36 is a poly (ε-Heptalactone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
37 is poly (ε-Heptalactone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
38 is a poly (γ-methyl-ε-Caprolactone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
Figure 39 is a poly (γ-methyl-ε-Caprolactone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Figure 40 is poly (ε-Decaractone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
Figure 41 is polyε-Decaractone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Figure 42 is poly (ω-pentadecaractone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
Figure 43 is poly (ω-pentadecaractone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Figure 44 is a poly (δ-Valerolactone-co-ε-Caprolactone-b-Propylene maleate) (300 MHz, CDCl₃, 303 K)^OneH NMR spectrum.
Figure 45 is polyδ-Valerolactone-Nose-ε-Caprolactone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Figure 46 is poly (ε-Caprolactone-b-SEC chromatogram for propylene maleate). Molecular weights were measured against poly (styrene) standards.
Detailed description of exemplary embodiments
One or more embodiments of the present invention are well-defined, non-toxic, resorbable end functionalized poly (lactone-) with limited and predictable material properties suitable for 3D printing and other regenerative pharmaceutical applications.b-Propylene fumarate) block copolymers (and related methods for their preparation and use). These block copolymers are completely resorbable and PPF based materials are unique in that they can be crosslinked photochemicals in many applications, including 3D printing. The type and composition of special lactide blocks confers the ability to tune physical, chemical and decomposition properties for specific applications. In particular, it has been found that by adding the lactone block to the PPF polymer, the viscosity of the resulting block copolymer can be precisely controlled. Moreover, the amount of DEF required to formulate a 3D printable resin reduces the amount of DEF required for crosslinking, allowing little PPF to dilute PPF and allowing longer PPF blocks with the presence of a lactone block. It was found to be significantly reduced. In certain embodiments, the present invention is a well-defined biodegradable poly (lactone-b-Propylene fumarate) polymers and scalable methods of making and functionalizing them.
In various embodiments, the poly (lactone-) of the inventionb-Propylene fumarate) block copolymers will have poly (lactone) segments (blocks) and poly (propylene fumarate) segments (blocks), with terminal functional groups and / or functionalized lactones optionally introduced through the starting alcohol It may optionally include one or more other functional groups introduced through the monomer.
In various embodiments, the poly (lactone-) of the inventionb-The poly (lactone) segment (block) of the propylene fumarate) block copolymer is formed through ring-opening polymerization of one or more lactone monomers from the starting alcohol, which may or may contain terminal functional groups, as described below. You may not. The poly (lactone) segment (block) will comprise a polymer chain formed from it and consisting of residues of lactone to be bound at one end to the residue of the starting alcohol and to the other end to the poly (propylene fumarate) segment (block). will be. As used herein, the term “residue (s)” generally refers to a portion of a monomer or other chemical unit introduced into a polymer or other macromolecule. Any lactone capable of ring-opening polymerization from alcohols using a suitable catalyst can be used. In one or more embodiments, the poly (lactone) segment (block) is δ-valerolactone (δVL), ε-caprolactone (εCL), α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε-caprolactone (mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxepanone (dihydrocarbide), 7- (prop-2-ynyl) oxepan-2-one,γ-methyl-ε-Caprolactone (γmεCL) alkyl-substituted lactones, including but not limited to,ε-Heptalactone (εHL), ω-pentadecaractone (PDL).ε-Decaractone (εDL) Macrolactone, θ-propargyl-ε-Nonalactone (θpεNL), functional but not limited to,α-Propargil-ε-Caprolactone (αpεCL), and isomer mixtures thereof.
In various embodiments, the poly (lactone) segment will include from about 0.1 mole percent to about 99 mole percent of the terminal functionalized block co-polymer. In some embodiments, the poly (lactone) segment is from about 0.1 mole percent to about 90 mole percent, in other embodiments from about 0.1 mole percent to about 75 mole percent, in other embodiments from about 0.1 mole percent to about 50 mole percent , In other embodiments, from about 0.1 mole percent to about 40 mole percent, in other embodiments from about 0.1 mole percent to about 25 mole percent, and in other embodiments, from about 0.1 mole percent to about 10 mole percent of the terminal action Block copolymers.
As set forth above, the poly (lactone-) of the present inventionb-Propylene fumarate) block copolymers also include poly (propylene fumarate) (PPF) segments (blocks). As will be familiar to those skilled in the art, PPF segments (blocks) are formed by isomerization of poly (propylene maleate) segments formed by ring-opening polymers at the ends of poly (lactone) segments (blocks) of maleic anhydride and propylene oxide. Formed and will contain isomerized residues of these maleic anhydride and propylene oxide monomers. In various embodiments, the poly (lactone-) of the inventionb-PPF segments of propylene fumarate) block copolymers will comprise from about 0.1 mole percent to about 99 mole percent of the terminal functionalized block co-polymer. In some embodiments, the PPF segment is from about 0.1 mole percent to about 90 mole percent, in other embodiments from about 0.1 mole percent to about 75 mole percent, in other embodiments from about 0.1 mole percent to about 50 mole percent, in other embodiments In examples, from about 0.1 mole percent to about 40 mole percent, in other embodiments, from about 0.1 mole percent to about 25 mole percent, in other embodiments, from about 0.1 mole percent to about 10 mole percent, in other embodiments, about 10 Mole percent to about 99 mole percent, in other embodiments, about 25 mole percent to about 99 mole percent of the terminal functionalized block co-polymer, in other embodiments, about 50 mole percent to about 99 mole percent, other embodiments In an example, from about 75 mole percent to about 99 mole percent.
Further, the block copolymer of the present invention will have at least one lactone segment and at least one PPF segment, but in some other embodiments, the block copolymer of the present invention may have one or more lactone blocks and / or one or more PPF blocks. You can. Also, in one or more of these embodiments, one or more types of lactone blocks can be used as termolymers in the same block or in separate lactone blocks. In some other embodiments, a single lactone block can contain a mixture of residues of one or more different lactones. In some of these embodiments, the block copolymers of the present invention may have two or more lactones or two or more PPF blocks having different chain lengths.
As set out above, the poly (lactone-) of the present inventionb-Propylene fumarate) block copolymers, in some embodiments, may include one or more functional groups to promote post-polymerization addition of the desired material, such as a bioactive material or other functional species, to the polymer. As used herein, the terms "bioactive molecule (s)" and "bioactive substance (s)" are used interchangeably to refer to substances that affect cellular function and are used as peptides, carbohydrates, proteins, oligos. Nucleotides and small molecule drugs. The term “functional species”, as used in the content of a substance that can be attached to the functionalized PPF polymer of the present invention, can be added to the functionalized PPF polymer of the present invention to provide added advantages and provide fluorescence and Refers to substances other than bioactive substances, which may include other markers, small molecule dyes, and / or drugs.
In some embodiments, poly (lactone-) of the inventionb-Propylene fumarate) block copolymers may contain terminal functional groups introduced through the starting alcohol. These terminal functional groups are not particularly limited except that they retain at least some of their reactivity after the polymerization and isomerization reactions discussed below, and benzyl groups, alkyne groups, propargyl groups, allyl groups, alkenes Group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group, or combinations thereof.
In some embodiments, poly (lactone-) of the inventionbThe PPF block of the -propylene fumarate) block copolymer can also include one or more groups of monomers introduced via functionalized monomers. In these embodiments, the PPF segment (block) will contain isomerized residues of maleic anhydride monomers and functionalized propylene oxide monomer residues used in its formation. As will be apparent, when the maleic anhydride monomer and the functionalized propylene oxide monomer react to form a polymer, the maleic anhydride monomer and the functionalized propylene oxide functionality of the functionalized propylene oxide monomer forming an active side chain Together with the groups it will form the backbone of the PPM / PPF polymer. In various embodiments, the functional group on the residue of the functionalized propylene oxide monomer is an alkyne group, propargyl group, alkene group, hydroxyl group, ketone group, thiol group, halide group, nitrobenzyl group, or halide group, Or groups that can be readily converted to such functional groups, such as nitrobenzyl groups. In the same way, in other embodiments, functional groups can be introduced into the block copolymers of the present invention via lactone monomers, which may contain or be functionalized to contain additional functional groups.
As used herein, the term “residue (s)” is generally used to refer to a portion of a monomer or other chemical unit incorporated into a polymer or macromolecule. Upon expansion, the terms "residues of maleic anhydride monomer" and "residues of functionalized propylene oxide monomer" refer to the poly (lactone-b-Propylene fumarate) maleic anhydride monomer and functionalized propylene oxide monomer, which are introduced into the PPM and PPF blocks of the block copolymer, respectively. The term "isomerized residue of the maleic anhydride monomer" specifically refers to the poly (lactone-b-Propylene fumarate) refers to the residue of a maleic anhydride monomer in the PPF block of the block copolymer, where the double bond is accompanied by the formation of a functionalized PPF polymer.Sheath In the rescueTrans Isomerized into a structure.
In various embodiments, the functional group on the residue of the functionalized propylene oxide monomer is an alkyl group, propargyl group, alkene group, hydroxyl group, ketone group, thiol group, halide group, nitrobenzyl group, or halide group, or It may include a group that can be easily converted to a functional group such as a nitrobenzyl group, but is not limited thereto. It has been found that using a monomer functionalization method increases the amount of functional groups available compared to only end-group functionalization, even when using a process in which the functional groups rarely survive. It has also been found that the monomers of the PPF polymers of the present invention do not significantly affect the required mechanical, thermal, decomposition, and / or toxic properties of the polymer.
In some embodiments, poly (lactone-) of the inventionbThe functional group added to the -propylene fumarate) block copolymer will be a group capable of a well-known "click" reaction to promote post-polymerization addition of the required material, such as bioactive compounds, to the polymer. . As used herein, the terms “click reaction”, “click chemistry”, “click chemistry method”, “click chemistry reaction” are generally referred to in the art as “click” reactions that meet the following prerequisites: Used interchangeably to refer to a group of orthogonal conjugation reactions: (i) high yield, almost quantitative conversion; (ii) biologically benign conditions (aqueous solution, ambient temperature, and near physiological pH); (iii) Restricted or non-existent by-products. These reactions are typically simple to perform, highly efficient, stereospecific, broad in scope, produce only byproducts that can be removed without chromatography, and can be carried out in a solvent that is easily removable or positive. Similarly, the term “clickable” refers to a molecule or functional group capable of binding through a click reaction.
The "click" chemistry concept currently represents a number of orthogonal reactions, which are rich, selective, efficient, high yield, copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) reactions (Huisgen Cycloaddition reactions (also known as Huisgen cycloaddition reactions), thiol-ene radical addition reactions, oxime linkage reactions, Michael-addition reactions, thiol-Michael-addition reactions, Mannich-type addition reaction, "end-type" addition reaction, thiol-ene radical addition, stress-enhanced azide-alkyne cycloaddition (SPAAC) reaction, non-unstable Stadinger connection (non-traceless Staudinger ligation), traceless Staudinger ligation, Diels-Alder reaction, hetero Diels-Alder reaction, reverse electron demand di Els-Alder reaction (inverse electro n demand Diels-Alder reaction, tandem [3 + 2] cycloaddition-retro-Diels-Alder (tamdem crD-A) reaction, thiol-alkyne reaction, thiol- Pyridyl disulfide reactions, thiol-halogen linkages, natural chemical linkages, and thiazolidine linkage reactions. In one or more embodiments, suitable “clickable” moieties may include, but are not limited to, alkyne groups, alkene groups, azide groups, ketones or repressed cyclooctin groups.
In one or more of these embodiments, the bioactive or other substance to be attached to the polymer is functionalized with a moiety known to bind the functional group used through a click reaction. The clickable moiety selected and the means of attachment thereof will, of course, depend on the bioactive or other material to be attached and the specific click reaction to be used. Those skilled in the art will be able to attach appropriate clickable moieties to the bioactive or other material to be attached without undue experimentation.
In one or more embodiments, the block co-polymers of the invention will have the formula:

In the above formula,
n is an integer from about 1 to about 500; m is an integer from about 1 to about 500; x is an integer from about 1 to about 20; R is a terminal group comprising residues of the starting alcohol and preferably includes a terminal functional group; R_OneSilver hydrogen atom, propargyl group, or C_One-C₁₀ Alkyl group; R₂Is a hydrogen atom, methyl group, butyl group, propargyl group or C_One-C₁₀ Alkanes.
In one or more of these embodiments, R is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenziocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group And poly (ethylene glycol) groups, and combinations thereof. In some of these embodiments, n is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, other In embodiments, from about 500 to about 500, in other embodiments, from about 150 to about 500, in other embodiments, from about 250 to about 500, and in other embodiments, from about 350 to about 500. In some of these embodiments, m is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, other In embodiments, from about 500 to about 500, in other embodiments, from about 150 to about 500, in other embodiments, from about 250 to about 500, and in other embodiments, from about 350 to about 500.
In some of these embodiments, x is from about 1 to about 20, in other embodiments, from about 1 to about 15, in other embodiments, from about 1 to about 10, in other embodiments, from about 1 to about 5, other In embodiments, an integer from about 1 to about 3. In some of these embodiments, R_OneSilver hydrogen atom, propargyl group or C_One-C₁₀ It may be an alkyl group. In some of these embodiments, R₂Is a hydrogen atom, methyl group, butyl group, propargyl group or C_One-C₁₀ It may be an alkyl group.
In some embodiments, block co-polymers of the present invention may have the following formula:

,

,

,

,

 or

In the above formula,
n is an integer from about 1 to about 500; m is an integer from about 1 to about 500; k is an integer from about 1 to about 500; R is a terminal group containing the residue of the starting alcohol, and preferably includes a terminal functional group, as described above.
In one or more of these embodiments, R is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenziocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group And poly (ethylene glycol) groups, or combinations thereof. In some of these embodiments, n is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, other In embodiments, from about 500 to about 500, in other embodiments, from about 150 to about 500, in other embodiments, from about 250 to about 500, and in other embodiments, from about 350 to about 500. In some of these embodiments, m is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, other In embodiments, from about 500 to about 500, in other embodiments, from about 150 to about 500, in other embodiments, from about 250 to about 500, and in other embodiments, from about 350 to about 500. In some of these embodiments, k is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, other In embodiments, from about 500 to about 500, in other embodiments, from about 150 to about 500, in other embodiments, from about 250 to about 500, and in other embodiments, from about 350 to about 500.
In some embodiments, the block copolymers of the present invention^OneNumber average molecular weight (about 0.5 kDa to about 500 kDa) as measured by end-group analysis using H NMR spectroscopyM _n ). In some embodiments, poly (lactone-) of the inventionb-Propylene fumarate) block copolymer^OneAbout 0.5 kDa to about 400 kDa, in other embodiments, from about 0.5 kDa to about 300 kDa, in other embodiments, from about 0.5 kDa to about 200 kDa, other implementations, as measured by end-group analysis using H NMR spectroscopy In examples, from about 0.5 kDa to about 100 kDa, in other embodiments, from about 50 kDa to about 500 kDa, in other embodiments, from about 150 kDa to about 500 kDa, and in other embodiments, from about 250 kDa to about 500 kDa The number average molecular weight ofM _n ).
In some embodiments, the block copolymers of the present invention have a number average molecular weight (about 0.5 kDa to about 500 kDa) as measured by size exclusion chromatography (SEC) in THF against poly (styrene) standards.M _n ). In some embodiments, poly (lactone-) of the inventionb-Propylene fumarate) block copolymers from about 0.5 kDa to about 400 kDa, as measured by size exclusion chromatography (SEC) in THF for poly (styrene) standards, in other embodiments, from about 0.5 kDa to about 300 kDa, in other embodiments, from about 0.5 kDa to about 200 kDa, in other embodiments, from about 0.5 kDa to about 100 kDa, in other embodiments, from about 50 kDa to about 500 kDa, in other embodiments, from about 150 kDa to From about 500 kDa, and in other embodiments, from about 250 kDa to about 500 kDa, a number average molecular weight (M _n ).
In some embodiments, the block copolymers of the present invention have a weight average molecular weight (about 2 kDa to about 500 kDa as measured in SEC in THF for poly (styrene) standards)M _w ). In some embodiments, poly (lactone-) of the inventionb-Propylene fumarate) block copolymers from about 2 kDa to about 250 kDa, as measured by size exclusion chromatography (SEC) in THF for poly (styrene) standards, in other embodiments, from about 2 kDa to about 100 kDa, in other embodiments, from about 2 kDa to about 50 kDa, in other embodiments, from about 2 kDa to about 25 kDa, in other embodiments, from about 2 kDa to about 10 kDa, weight average molecular weight (M _w ).
In various embodiments, the poly (lactone-) of the inventionbPropylene fumarate) block copolymers have a polydispersity of about 1.1 to about 2.3 when measured in SEC in THF for poly (styrene) standards (Ð _M). In some embodiments, poly (lactone-) of the inventionb-Propylene fumarate) block copolymers from about 1.1 to about 2.1, in other embodiments, from about 1.1 to about 1.8, in other embodiments, from about 1.1 to about 1.1, as measured in SEC in THF for poly (styrene) standards. Polydispersity of about 1.5, in other embodiments, from about 1.3 to about 2.3, in other embodiments, from about 1.5 to about 2.3, in other embodiments, from about 1.8 to about 2.3, and in other embodiments, from about 2.0 to about 2.3 (Ð _M).
As will be apparent, the poly (lactone-) of the present inventionb-Propylene fumarate) block copolymers are photochemically crosslinked using diethyl fumarate (DEF) in the same way as other poly (propylene fumarate) polymers that make them useful for the production of polymer structures such as tissue scaffolds. You can. In one or more of these embodiments, the poly (lactone-b-Propylene fumarate) block copolymers can be formed from 3-D printable resins. In these embodiments, poly (lactone-b-Propylene fumarate) block copolymer is dissolved in diethyl fumarate (DEF) and a conventional photoinitiator and light scattering agent are uniformly mixed throughout the resin. The amount of DEF required to formulate a 3D printable resin requires little DEF to dilute PPF, and the presence of a lactone block allows for a longer PPF block, reducing the amount of DEF required for crosslinking. Poly (lactone-b-Propylene fumarate) has been found to be significantly reduced for block copolymers. The resin is then 3-D printed and photo-crosslinked with a cDLP printer or other suitable 3-D printer to form a scaffold or other polymer structure.
In another embodiment, the present invention is a poly (lactone-b-Propylene fumarate). In various embodiments, the terminal functionalized poly (lactone-) of the inventionb-Propylene fumarate) block copolymers are prepared using a three step process: (i) terminal functionalized poly (lactone) segments (blocks) (opening end) through ring-opening polymerization of lactones using starting alcohol and magnesium catalyst Formation, which may or may not be functionalized); (ii) formation of a poly (propylene maleate) segment (block) at the end of the terminal functionalized poly (lactone) segment (block) through ring-opening polymerization of maleic anhydride and propylene oxide; And (iii) poly (lactone-b-Its trans-isomer (poly (propylene fumarate)) form of poly (propylene maleate) segments (blocks) using any method known in the art for this purpose to form propylene fumarate) block copolymers Isomerization of furnaces.
In the first step, lactone alcohol, lactone monomer, and magnesium catalyst, preferably Mg (BHT)₂(THF)₂Is placed in the dissolution of an ampule or other suitable reaction vessel and dissolved in a suitable solvent such as toluene. The choice of solvent is not particularly limited and those skilled in the art will select a suitable solvent without undue experimentation.
As set out above, any lactone has Mg (BHT)₂(THF)₂It can be used as a lactone monomer if it can be ring-opened polymerized from an alcohol initiator using a suitable catalyst such as. Suitable lactone monomers are δ-valerolactone (δVL), ε-caprolactone (εCL), α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε-caprolactone (mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxepanone (dihydrocarbide), 7- (prop-2-ynyl) oxepan-2-one, γ-methyl-ε-Caprolactone (γmεCL) alkyl-substituted lactones, including but not limited to,ε-Heptalactone (εHL),ε-Decaractone (εDL), ω-pentadecaractone (PDL), but not limited to macrolactone, θ-propargyl-ε-Nonalactone (θpεNL), functional but not limited to,α-Propargil-ε-Caprolactone (αpεCL) and isomer mixtures thereof, or any combination thereof.
It should be noted that the starting alcohol is not particularly limited, but different starting alcohols will have different rate constants and will drive the reaction at different rates. In one or more embodiments, suitable starting alcohols are benzyl alcohol, ethanol, isopropanol, glycerol, propargyl alcohol, allyl alcohol, 4-dibenziocyclooctinol, 4-hydroxybutan-2-one, 3-hydroxypropane -2-one, 5-hydroxypentan-2-one, 6-hydroxyhexan-2-one, 7-hydroxyheptan-2-one, 8-hydroxyoctan-2-one, 5-norbornene -2-ol, α-bromoisobutyryl 4-methanol benzylmethanoate, poly (ethylene glycol), or combinations thereof.
As set out above, functional end groups can be added to the polymer via the starting alcohol. These materials have hydroxyl groups that initiate ring-opening polymerization reactions and functional end groups useful for post-polymerization reactions that survive both polymerization and isomerization reactions. These functional end groups are not particularly limited as long as they retain at least some of their reactivity after polymerization and isomerization reactions, and benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzocyclo Octin groups, cyclooctin groups, ketone groups, aldehyde groups, and tertiary halogen groups or combinations thereof.
In various embodiments, the magnesium catalyst can be any magnesium or other organometallic catalyst capable of catalyzing the ROP of lactone and maleic anhydride and propylene oxide monomers that are substantially non-toxic and not consumed, but are preferably Mg. (BHT)₂(THF)₂to be.
The reaction solvent used is not particularly limited and any suitable that is capable of dissolving the lactone monomer in step 1 as well as the maleic anhydride and propylene oxide monomer of step 2 and is miscible with the solvent used to dissolve the maleic anhydride and propylene oxide monomer. It can be a solvent or a combination of solvents. In various embodiments, suitable solvents include, but are not limited to, toluene, hexane, heptane, hexane, octane, or combinations thereof. Those skilled in the art will be able to select a suitable solvent without undue experimentation.
In various embodiments, the concentration of lactone monomer in the starting solution will be from about 0.5M to about 10M. The lactone monomer concentration is from about 1M to about 7M in some embodiments, from about 2M to about 5M in other embodiments, from about 3M to about 5M in other embodiments, from about 0.5M to about 4M in other embodiments, other embodiments In examples, from about 0.5M to about 3M, and in other embodiments, from about 0.5M to about 2M. Thereafter, the reaction vessel is sealed and the lactone solution is heated to a temperature of about 40 ° C. to about 100 ° C. to initiate and / or maintain the ring-opening polymerization reaction of the lactone, initiated by the starting alcohol and catalyzed by the magnesium catalyst, and / or Lactone) to obtain a polymer intermediate. In some embodiments, the lactone solution is from about 40 ° C to about 50 ° C, in other embodiments from about 40 ° C to about 60 ° C, in other embodiments from about 40 ° C to about 70 ° C, in other embodiments from about 40 ° C to about 80 ° C. ° C, and in other embodiments, to a temperature of about 40 ° C to about 90 ° C. As will be apparent, these poly (lactone) polymer intermediates will, if desired, have functional end groups from the starting alcohol at one end and hydroxyl (OH) groups at the other end. In some embodiments, the lactone solution is heated until all of the lactones (98% or more) have reacted.
In various embodiments, the lactone solution is heated for about 1 hour to about 96 hours. In some embodiments, the lactone solution is from about 1 hour to about 84 hours, in other embodiments from about 1 hour to about 72 hours, in other embodiments from about 1 hour to about 60 hours, in other embodiments from about 1 hour To about 48 hours, in other embodiments, from about 1 hour to about 36 hours, in other embodiments, from about 1 hour to about 24 hours, and in other embodiments, from about 1 hour to about 12 hours.
In the second step, maleic anhydride monomer and propylene oxide monomer are dissolved in a suitable solvent such as toluene at a total monomer concentration of about 0.5M to about 10M and added to the reaction vessel containing poly (lactone) polymer intermediate. In some embodiments, the total monomer concentration is from about 1M to about 7M, in other embodiments from about 2M to about 5M, in other embodiments from about 3M to about 5M, in other embodiments from about 0.5M to about 4M, other In embodiments, from about 0.5M to about 3M, and in other embodiments, from about 0.5M to about 2M.
As will be evident, simply switching the poly (lactone) polymer polymer acting as the starting alcohol for the ROP of maleic anhydride and propylene oxide monomer and the magnesium catalyst catalyzing the ROP of lactone to maleic anhydride and propylene oxide monomer. No additional catalyst or starting alcohol is needed at this stage. In some embodiments, functionalized propylene oxide monomers can be used to introduce monomer functional groups into the PPF block of the block co-polymer.
The resulting solution is then heated to a temperature of about 40 ° C. to about 100 ° C. to initiate and / or maintain the ring-opening polymerization reaction of maleic anhydride monomers and propylene oxide monomers to the terminal OH groups on the poly (lactone) polymer intermediate, and / or (Lactone-b-Propylene maleate) block copolymer intermediates. In some embodiments, the solution is from about 40 ° C to about 50 ° C, in other embodiments from about 40 ° C to about 60 ° C, in other embodiments from about 40 ° C to about 70 ° C, in other embodiments from about 40 ° C to about 80 ° C. , And in other embodiments, to a temperature of about 40 ° C to about 90 ° C. In some embodiments, the solution is heated until substantially all (80% or more) monomer has reacted. In some embodiments, the solution is from about 1 hour to about 96 hours, in other embodiments from about 12 hours to about 96 hours, in other embodiments from about 24 hours to about 96 hours, in other embodiments from about 48 hours to Heated for about 96 hours, in other embodiments, from about 62 hours to about 96 hours, in other embodiments, from about 1 hour to about 62 hours, and in other embodiments, from about 1 hour to about 48 hours.
In one or more embodiments, the terminal functionalized poly (lactone-b-Propylene maleate) block copolymer intermediates can be formed as shown in Scheme 1 below;
Scheme 1
LactoneAnd proposed synthesis method for block copolymers containing poly (propylene maleate)

Where R is an end group or end functional group as described above; n is an integer from about 1 to about 20; m is an integer from about 1 to about 500; k is an integer from about 1 to about 100. In various embodiments, R is easy with such functional groups such as alkyne groups, propargyl groups, alkene groups, hydroxyl groups, ketone groups, thiol groups, halide groups, nitrobenzyl groups, or halide groups or nitrobenzyl groups. It can be a group that can be switched.
In some embodiments, n is from about 1 to about 15, in other embodiments, from about 1 to about 10, in other embodiments, from about 1 to about 8, in other embodiments, from about 1 to about 6, in other embodiments , From about 1 to about 4, in other embodiments, from about 5 to about 20, and in other embodiments, from about 10 to about 20. In some embodiments, m is from about 1 to about 400, in other embodiments, from about 1 to about 300, in other embodiments, from about 1 to about 200, in other embodiments, from about 1 to about 100, in other embodiments , From about 1 to about 50, in other embodiments, from about 1 to about 25, in other embodiments, from about 100 to about 400, and in other embodiments, from about 200 to about 400. In some embodiments, k is from about 1 to about 80, in other embodiments, from about 1 to about 60, in other embodiments, from about 1 to about 40, in other embodiments, from about 1 to about 20, in other embodiments , From about 1 to about 10, in other embodiments, from about 20 to about 80, in other embodiments, from about 40 to about 80, in other embodiments, from about 50 to about 80, and in other embodiments, from about 60 to about It may be an integer of 100.
In some embodiments, poly (lactone-b-Propylene maleate) block copolymer intermediates can be synthesized as shown in Scheme 2 below.
Scheme 2

Where m and n are each integers from about 1 to about 500; R is a terminal group or a terminal functional group as described above.
In some embodiments, poly (lactone-b-Propylene maleate) block copolymer intermediates can be synthesized as shown in Scheme 3 below:
Scheme 3

Where m and n are each integers from about 1 to about 500; R is a terminal group or a terminal functional group as described below.
In some embodiments, poly (lactone-b-Propylene maleate) block copolymer intermediates can be synthesized as shown in Scheme 4 below:
Scheme 4

Where m and n are each integers from about 1 to about 500; R is a terminal group or terminal functional group as described below.
In some embodiments, poly (lactone-b-Propylene maleate) block copolymer intermediates can be synthesized as shown in Scheme 5 below:
Scheme 5

Where m and n are each integers from about 1 to about 500; R is a terminal group or a terminal functional group as described below.
In some embodiments, poly (lactone-b-Propylene maleate) block copolymer intermediates can be synthesized as shown in Scheme 6 below.
Scheme 6

Where m and n are each integers from about 1 to about 500; R is a terminal group or a terminal functional group as described below.
In some embodiments, poly (lactone-b-Lactone-b-Propylene maleate) triblock polymer intermediates can be synthesized as shown in Scheme 7 below:
Scheme 7

Where m, n and k are each integers from about 1 to about 500; R is a terminal group or a terminal functional group as described below.
In some embodiments, poly (lactone-b-Lactone-b-Propylene maleate) triblock polymer intermediates can be synthesized as shown in Scheme 8 below:
Scheme 8

Where m, n and k are each integers from about 1 to about 1000; R is a terminal group or a terminal functional group as described below.
Poly (lactone-b-Propylene maleate) block copolymer and / or poly (lactone-b-Lactone-b-Propylene Maleate) Triblock polymer intermediates can be isolated and purified using any known method. In some embodiments, poly (lactone-b-Propylene maleate) block copolymer and / or poly (lactone-b-Lactone-b-Propylene maleate) Triblock polymer intermediates can be recovered by precipitating in excess diethyl ether.
In the third step, poly (lactone-b-Propylene maleate) block copolymer and / or poly (lactone-b-Lactone-b-The poly (propylene maleate) segment (block) of the propylene maleate) triblock polymer intermediate isomerized to its trans-isomer (poly (propylene fumarate)) to form a poly (lactone-) according to an embodiment of the invention.b-Propylene fumarate) to form a block copolymer (reference: Fig. 1). The term isomerization is used hereinSheath-Isomer (PPM)Trans-Used to refer to a reaction that converts to isomer (PPF) form. The isomerization step may result in some other change to the polymer, but the approximateM _n,Ð _M, AndT _g The most common aspect of the end functionalized PPF polymer of embodiments of the invention, such as the range, is measured prior to the isomerization step. However, even if a relatively small amount of PPM polymer chains remain in the polymer, this will negatively affect the polymer's ability to crosslink, making it unsuitable for 3D printing and other similar applications. Therefore, it is important to essentially convert all poly (propylene maleate) to poly (propylene fumarate) when the polymer must be used for these applications.
Poly (propylene maleate) segments (blocks) include the methods described in International Application PCT / US2015 / 061314, published as WO 2016/081587, the disclosure of which is incorporated herein by reference in its entirety. However, isomerization can be carried out using any conventional method, not limited to this. In some embodiments, poly (propylene maleate) segments (blocks) of these block copolymers can be isomerized as shown in Example 11 below.
In various embodiments, the terminal functionalized poly (lactone-bThe propylene maleate) block copolymer intermediate is placed in a suitable container such as a round bottom flask and dissolved in an inert atmosphere in a suitable solvent such as chloroform, tetrahydrofuran (THF), dioxane, diethyl ether, or combinations thereof. . It is contemplated that, regardless of the solvent selected, it can be removed without excessive difficulty or cost, and in some embodiments, the solvent is chloroform. Once the PPM intermediate is dissolved, a catalyst, preferably diethylamine, is added and the vessel is connected to a condenser and heated to a reaction temperature of about 5 ° C to about 80 ° C. In some embodiments, the reaction temperature is from about 5 ° C to about 70 ° C, in other embodiments from about 5 ° C to about 65 ° C, in other embodiments from about 5 ° C to about 55 ° C, in other embodiments, from about 20 ° C To about 80 ° C, in other embodiments, from about 40 ° C to about 80 ° C, and in other embodiments, from about 60 ° C to about 80 ° C. In some embodiments, the reaction temperature is between about 55 ° C and about 65 ° C.
In these embodiments, the solution is about 5 to about 100 hours, about 5 hours to about 80 hours, in other embodiments, about 5 hours to about 60 hours, in other embodiments, about 5 hours to about 50 hours, other embodiments In examples, from about 5 hours to about 40 hours, in other embodiments, from about 20 hours to about 100 hours, in other embodiments, from about 40 hours to about 100 hours, and in other embodiments, from about 60 hours to about 100 hours During heating, an isomerized polymer is produced (see Figure 1). In some embodiments, the solution is heated for about 24 to about 48 hours. Upon completion of the isomerization reaction, the terminal functionalized poly (lactone-b-Propylene fumarate) block copolymers can be isolated and purified by any suitable method known in the art for this purpose.
The method of the present invention is poly (lactone-b-Propylene fumarate) diblock copolymers were mainly discussed with reference, but these methods are poly (lactone-b-Propylene fumarate) As set out above for diblock copolymers, lactone monomers (to form additional lactone blocks) or propylene oxide / maleic anhydride monomers (addition) when the reagents used to form before the block are depleted Can be used to form block copolymers with three or more blocks by sequential addition of (to form a PPF block of). By using the diblock copolymers discussed above, the hydroxyl group at the end of the preceding block acts as an initiator for the next lactone or maleic anhydride / propylene oxide ROP, and the magnesium catalyst catalyzes the ROP for the new block. In order to switch, no additional catalyst or starting alcohol is required. In some other embodiments, ABA block copolymers can be formed using bi-functional starting alcohols. In these embodiments, the first block (B) will have two active functional groups and the two (A) blocks can be added as described above to form an ABA block copolymer.
In various embodiments, the poly (lactone-) of the inventionb-Propylene fumarate) block copolymers can be used in many applications such as 3D printable resins, medical devices, tissue processing, wound healing, cosmetics, and drug and protein delivery.

Example

To further define and organize the embodiments of the present invention for implementation, ROP of ε CL and subsequent ROCOP of equimolar mixtures of MAn and PO were investigated. Homopolymerization of ε CL using Mg (BHT) ₂ (THF) ₂ as catalyst and benzyl alcohol (BnOH) as primary alcohol initiator was performed at 80 ° C. in a sealed, N ₂ atmosphere at a concentration of 2M in toluene. . Homopolymerization was continued for 1 hour before the 2M solutions of MAn and PO in toluene were added to the reaction. Both the preparation of the MAn and PO solutions and their subsequent injection into the PCL solution were performed in anhydrous N ₂ environment to maintain the atmosphere of the initial reaction. After the polymerization was continued for 5 days after injection, the polymer was recovered by precipitation in cold hexane. Monomer conversion of ε CL and MAn was measured using ¹ H NMR spectroscopy of the crude reaction solution taken immediately after polymerization termination. The low vapor pressure and boiling point of PO creates an unreliable integration of resonance peaks at the reaction temperature, so PO conversion is not recorded. ¹ H NMR spectroscopy analysis of the recovered material showed proton resonance corresponding to PCL, PPM, and BnOH initiators. No resonance was observed corresponding to the methylene proton of the single polymerized PO ( δ = 3.3-3.5 ppm), demonstrating that the preference for alternating copolymerization of MAn and PO provided Mg (BHT) ₂ (THF) ₂ (Reference: FIGS. 2-4).

The structure and regioregularity of the recovered polymer was further investigated using quantitative ¹³ C NMR spectroscopy and diffusion aligned NMR spectroscopy (DOSY). ¹³ C NMR spectrum is different ε CL εCL carbonyl adjacent to the repeating unit - dominant carbonyl Dia de resonance in corresponding to (ε CL * ε CL, where * indicates the observed carbonyl), δ = 173.4 ppm, And two predominant diad resonance peaks at δ = 164.57 ppm and δ = 164.19 ppm, corresponding to MAn * -PO. Two very small resonance also occurs at δ = 173.2 ppm, and δ = 164.9 ppm, which ε * CL * -MAn MAn and respectively correspond to ε CL. The integration of the carbonyl diad resonance peak represents a block similar to the sequence, where one block is the PCL homopolymer and the other block is poly (propylene maleate) (PPM) (see FIG. 3). DOSY NMR spectroscopy showed only one polymer species, the same sequence of poly ( ε -caprolactone-block-propylene maleate) (P (CL- b- PM)) as opposed to individual PCL and PPM chains. Prove the block (see Figures 5 and 6).

To utilize the alkene functionality present in the PPF block for stereolithographic printing, poly ( ε -caprolactone- b -propylene fumarate) of P (CL- b- PM) without cleavage or side reactions (P Isomerization to (CL- b -PF)) must occur. Thus, a 0.5 M solution of P (CL- b- PM) in CHCl ₃ containing diethylamine (0.15 molar equivalents per alkene) was heated at reflux overnight, as previously reported (ref. Luo, Y .; Dolder, CK; Walker, JM; . Mishra, R .; Dean, D .; Becker, ML, Synthesis and Biological Evaluation of Well-Defined Poly (propylene fumarate) Oligomers and Their Use in 3D Printed Scaffolds Biomacromolecules 2016, 17 (2 ), 690-697, the disclosures of which are incorporated herein by reference in their entirety). Diethylamine was removed by washing with 0.5 M sodium phosphate buffer solution via rotary evaporation prior to solvent removal. Complete reduction of the cis -alkene resonance ( δ = 6.2 ppm) and the new resonance ( δ = 6.7 ppm) corresponding to the trans -alkene proton was shown using ¹ H NMR spectroscopy (see Figure 1).

The kinetics of MAn and PO to ROCOP ε CL blocks were studied under the same conditions using a targeted degree of polymerization (DP) of 50 repeat units for both PCL and PPM blocks. Aliquots were collected every 24 hours over a period of 6 days after propylene oxide and maleic anhydride were injected into the polymerization solution. MAn conversion was measured using ¹ H NMR spectroscopy of the crude mixture. The molecular weight and molecular weight distribution ( Ð _M ) were measured using SEC of the recovered material. Class 1 In analogy to ROCOP of MAn and PO from the alcohol initiator, the polymerization is also pseudo-specified in the first dynamics (pseudo -first order kinetics). The conversion of monomers is significantly impeded as a result of the catalytic affinity of the lactone macroinitiator, where ROCOP competes with proliferation. This is similar to the polymerization kinetics observed in the copolymerization of lactones and macrolactones in the previous report using Mg (BHT) ₂ (THF) ₂ as catalyst (see Wilson, JA; Hopkins, SA; Wright, PM; Dove, AP, 'Immortal' ring-opening polymerization of ω-pentadecalactone by Mg (BHT) ₂ (THF) ₂ .Polym.Chem . 2014, 5 (8), 2691-2694, the disclosure of which is hereby incorporated by reference in its entirety. Immediately after injection, the Ð _M value is an indicator of the transesterification during ε CL homopolymerisation, but the molecular weight proliferation of Ð _M and linear during ROCOP is counter to the further transesterification side reactions for MAn and PO to the ROCOP. Provides evidence of controlled polymerization and preference (see Scheme 9 below).

Scheme 9

Polymerization cycle involved in sequential copolymerization of ring-opening blocks

Using the same catalyst, primary alcohol initiator, and the temperature described above, polymerization of ε CL, MAn, and PO was also tested using single step synthesis, followed by ROCOP of MAn and PO followed by ε CL It was injected. Equimolar ratios of ε CL, MAn, and PO were used in both reactions. ¹ H NMR spectroscopy analysis of the recovered material did not show ε CL incorporation into the polymer produced in any of these reactions. We predict that this is not the result of the carboxylic acid chain-terminus of ring-opening MAn or the secondary alcohol chain-terminus of ring-opened PO that can initiate ring opening of ε CL. The copolymer produced by sequential lactone ROP and MAn and PO ROCOP does not contain a grading region between blocks. It also suggests a high degree of reggioregularity in the copolymerization of MAn and PO catalyzed by Mg (BHT) ₂ (THF) ₂ .

Smaller lactones ( δ -valerolactone ( δ VL)), to further test the feasibility of Mg (BHT) ₂ (THF) ₂ as a catalyst for ROP “switch” ROCOP of MAn and PO and polyester, Alkyl-substituted lactones ( γ -methyl- ε -caprolactone ( γ m ε CL), ε -heptalactone ( ε HL) and ε -decaractone ( ε DL)), macrolactone (PDL), and functionality Synthesis was investigated using lactones (an isomer mixture of θ-propargyl- ε -nonaralactone (θp ε NL) and α -propargyl- ε -caprolactone ( α p ε CL)) 10).

Scheme 10 .

Lactone monomer used for copolymerization with poly (propylene fumarate)

Except for δ VL, γ m ε CL and PDL, all lactones were sealed in a sealed N ₂ atmosphere using Mg (BHT) ₂ (THF) ₂ as catalyst and BnOH as primary alcohol, 80 at 2M concentration in toluene. Homopolymerization was carried out at 24C for 24 hours. δ VL, γ m ε CL, and PDL were homopolymerized for 1 hour, 1 hour, and 8 hours, respectively, using the same conditions. After homopolymerization, it was dried and 2M solutions of MAn and PO in toluene were injected into each reaction. ¹ H NMR spectroscopy was performed 5 days after injection of PO and MAn in the crude reaction mixture to measure monomer conversion before precipitation of the polymer obtained in hexane. The results of these experiments are summarized in Table 1 below.

Mg (BHT) as catalyst with changed lactone monomer feed and targeted DP ₂ (THF) ₂ Characteristics of PPF-based block copolymers produced using Lactone monomer (L) Target [L]: [PM] Time (h) Lactone conversion rate (%) ^a MAn conversion rate (%) ^a Actual [L]: [PM] ^b M _n  (kDa) ^b   NMR M _n  (kDa) ^c  SEC M _w  (kDa) ^c  SEC Ð _M ^c  _SEC T _m
(℃) ^d DSC T _c
(℃) ^d DSC T _g
(℃) ^d  DSC δ VL [50]: [50] One 94 84 [42]: [33] 9.4 6.5 8.3 1.85 47 4 - ε CL [50]: [50] One 85 90 [46]: [41] 11.6 7.0 15.0 2.14 58 18 - ε HL [50]: [50] 24 95 90 [48]: [42] 12.7 4.5 9.8 1.80 15 -12 - γ m ε CL [50]: [50] One 94 81 [46]: [47] 13.2 4.5 9.2 2.02 - - -18 Θ p ε NL [50]: [50] 24 89 84 [35]: [38] 11.3 7.4 14.6 1.97 - - -11 ε DL [50]: [50] 8 90 81 [40]: [29] 11.3 2.6 4.0 1.56 - - 11 ωPDL [50]: [50] 24 82 78 [30]: [25] 11.1 5.5 7.8 1.41 93 75 - δ VL / ε CL [50]: [50] 24 92 72 [50]: [29] 9.9 1.6 3.2 1.97 16 -10 -

^a Measurement by ¹ H NMR spectroscopy of the crude reaction mixture and comparison of monomeric proton resonance to the corresponding polymer proton resonance ( δ = 6.26 ppm). ^b Measured by end-group analysis by ¹ H NMR spectroscopy of the reaction mixture. ^c Measured in SEC in THF for poly (styrene) standards. ^d Measured by differential scanning calorimeter. ¹³ C and DOSY NMR spectroscopy demonstrate the presence of polylactone blocks and PPM blocks in all recovered products (see Figures 3, 4 and 7-20). ¹ H NMR spectroscopy showed that the PPM block did not reach the target DP, which appears to be the result of impaired dynamics onto the lactone-based macroinitiator, which produces incomplete monomer conversion. However, polymerization leading to conversion of less than 70% of maleic anhydride was not observed.

Interestingly, incorporation of carbonyl diad resonance peaks in the quantitative ¹³ C NMR spectrum of polymers containing θp ε NL, in addition to separate PM blocks, ωp ε NL, α p ε CL, and a small amount of ε produced during monomer synthesis The same block as the order of CL is shown. To confirm this effect, polymers targeting 25 propargyl substituted lactone units, 25 ε CL units, and 50 PM units were polymerized with an isomer mixture of θp ε NL and α p ε CL and ε CL and subsequently It was synthesized by injecting MAn and PO using the same conditions as the previous polymerization. ¹ H NMR spectroscopy demonstrated the presence of each monomeric species, and quantitative ¹³ C NMR spectroscopy once again suggested a block sequence of θp ε NL, α p ε CL, and ε CL, in addition to alternating blocks of MAn and PO. . The exact mechanism behind this sequence is outside the scope of the present disclosure and is not essential to understanding and practicing the present invention, but all prior polymerizations of ε CL and other ε -substituted ε -lactones ( ε S ε L) are in random order. It is worth noting that the stereoselectivity and isomer selectivity seen with these monomers in these polymerizations have been reported to have. This may be the result of a propargyl group that is easily coordinated with a catalyst that results in preferential polymerization as compared to ε CL and a first example of a one-step ε CL block copolymer with other lactones.

ROCOP synthesis of δ VL and ε CL followed by ROCOP of MAn and PO was also tested. Δ VL and ε CL were copolymerized in toluene at 80 ° C. for 24 hours at 2 M concentration using Mg (BHT) ₂ (THF) ₂ as the catalyst and BnOH as the initiator once again. ¹ H NMR spectroscopy showed equivalent incorporation of δ VL and ε CL into the polymer chain in addition to the incorporation of MAn and PO. Analysis of carbonyl diad resonance peaks by ¹³ C NMR spectroscopy revealed blocks such as the order of random incorporation of δ VL and ε CL into one block and alternating MAn and PO incorporation into the second block. . DOSY NMR spectroscopy demonstrated the presence of a single diffusing polymer species.

Thermal analysis using differential scanning calorimetry (SSC) showed a wide range of properties (cf. FIGS. 21-28). As expected, the polymer containing aliphatic lactone blocks had a melting temperature above room temperature and a crystallization temperature above 0 ° C., both of which increased with increasing intra-skeletal chain length. The exception to this is P ( δ VL- co - ε CL- b -PM), where the melting point ( T _m ) is below room temperature and the crystallization temperature ( T _C ) is below 0 ° C. This control is the result of a random distribution of esters along the backbone that disrupts the regular packing structure observed in poly ( δ -valerolactone) (PVL) or PCL chains. This is an unexpected result since most random lactone copolymers were observed to produce T _m s and T _c s between those of the corresponding lactone homopolymers, based on the molar ratio. P ( ε HL- b -PM) had a thermal property between those containing aliphatic lactone blocks and those containing substituted lactone blocks, with a melting temperature just below room temperature and a crystallization temperature below 0 ° C.

As predicted, P ( γ m ε CL- b -PM), P (ωp ε NL -b-α p ε CL -b-ε CL -b -PM), and P ( ε DL- b -PM) As a result of the pendant side chain breaking any crystallization of the silver backbone, it showed no crystalline behavior and was all viscous liquid at room temperature (cf. Figs. 24, 25, 26). Interestingly, γ m ε CL and ε HL are isomers ε S ε L, and the substitution of methyl-substitution has a significant effect on the crystallization of the copolymer to the extent that all crystallization is destroyed in γ m ε CL but not in ε HL. Crazy The size of the substitution was also observed to affect the T _g of the amorphous copolymer, with longer chain lengths indicating increased T _g . This seems to be the result of the increased flexibility in the longer chain of ε DL which allows for better chain packing rather than the short stiffness methyl substitution of γ m ε CL which creates pockets of poor packing in the network.

ROBOCOP with Mg (BHT) ₂ (THF) ₂ allowed the production of well-defined, diblock copolymers, and the synthesis of ABA type triblock copolymers was briefly investigated. Homopolymerization of εDL with Mg (BHT) ₂ (THF) ₂ as catalyst and 1,3-benzenedimethanol (BDM) as initiator, at a total monomer concentration of 2M in toluene at 80 ° C. in a sealed, N ₂ atmosphere. Was performed. Homopolymerization was continued for 24 hours before injecting equimolar amounts of MAn and PO into the reaction. This monomer addition resulted in the growth of the triblock copolymer as a result of the bifunctionality of the single starting species. ¹ H NMR spectroscopy analysis of the recovered material showed individual proton resonances corresponding to PDL ( δ = 4.86, 2.27, 0.88 ppm), PPM, ( δ = 6.27, 5.27, 4.26 ppm) and BDM (5.10 ppm) ( Note: Figure 29). Block order was confirmed by analysis of carbonyl diad resonance peaks from quantitative ¹³ C NMR spectroscopy (Ref. 30).

Finally, P (ωp ε NL -b - α p ε CL -b-ε CL -b- PM) polymers were prepared from resins to introduce some of the potential applications of these polymers (see FIGS. 13, 14, 25, 31 and 32). To prepare the resin, the 11.3 kDA polymer was dissolved in the same weight percent diethyl fumarate with the previously reported mixture of photoinitiator and light dispersant (4.1 wt.%). The stamp was printed using an EnvisionTEC Micro continuous digital light processing (cDLP) printer prior to the attachment of the Chromeo® 546-azide dye through copper-mediated azide-alkyne cycloaddition (CuAAC). It should be noted that cDLP printing of PPF using this resin composition was reported only for M _n below 3.2 kDA. To attach the dye, the stamp was stamped for 1 hour into a solution containing Chromeo® 546-azide dye, copper sulfate, and sodium ascorbate in an isopropyl alcohol and water mixture. The film was washed three times with deionized water before imaging with a fluorescence microscope confirming the attachment of the Chromeo® 546-azide dye to the stamp.

Synthesis of chemically complex, orderly defined polyesters is essential to diversify the properties needed for more desired applications, but few technologies are available that provide this selectivity without reducing industrial diversity. Therefore, we introduce Mg (BHT) ₂ (THF) ₂ as an inexpensive catalyst for ROBOCOP of the library of MAn and PO and lactones. To our knowledge, this is the first example of a "switch" system using a magnesium-based catalyst. The ubiquity of this technique has been demonstrated through polymerization with various lactones of different sizes, substitutions, and functionality. Although additional testing is needed to measure the tunability of these polymers, the ability to extend polymerization to tri-block copolymers is printed via stereolithography methods and post-polymerization and post-print using functional groups. Modifications demonstrate the utility of these materials in a wide range of applications.

Example

The following examples are provided to more fully illustrate the present invention, but should not be construed as limiting its scope. Also, although some of the examples may include conclusions as to how the present invention may work, the inventors are not intended to be bound by these conclusions, but they are presented as possible explanations only. Moreover, unless indicated using the past tense, the present form of the examples does not imply that the experiments or procedures have been or have not been performed or that the results have actually been obtained or not obtained. Efforts have been made to ensure precision with respect to the numbers used (eg, quantity, temperature), but some experimental errors and deviations may exist. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

Abbreviation

ROP, ring-opening polymerization; ROCOP, ring-opening copolymerization; CHO, cyclohexene oxide; ε CL, ε -caprolactone; βBL, β-butyrolactone; PCL, poly ( ε -caprolactone); PLLA, poly ( l -lactic acid); PPF, poly (propylene fumarate); ROBOCOP, ring-opening block-order copolymerization; Mg (BHT) _2- (THF) ₂ , 2,6- di - tert -butyl-4-methylphenoxide; MAn, maleic anhydride; PO, propylene oxide; BnOH, benzyl alcohol; DOSY, diffusion-order NMR spectroscopy; PPM, poly (propylene maleate); δ VL, δ -valerolactone; γ m ε CL, γ -methyl- ε -caprolactone; ε HL, ε -heptalactone; ε DL, ε -decaractone; θ p ε NL, θ -propargyl- ε -nonaralactone; α p ε CL, α -propargyl- ε -caprolactone; ε S ε Ls, ε -substituted ε -lactone; DSC, differential scanning calorimeter; BDM, 1,4-benzenedimethanol; CuAAC, copper-mediated azide-alkyne cycloaddition, cDLP, continuous digital light processing.

matter

All reagents were purchased from Sigma-Aldrich and only 2,6-di-tert-4-methylphenol was purchased from Acros. Mg (BHT) ₂ (THF) ₂ was synthesized according to the previously reported procedure. Note: Calabrese, J .; Cushing, MA; Ittel, SD; Sterically hindered magnesium aryloxides. Inorg. Chem. 1988 , 27 , 867-870, the disclosures of which are incorporated herein by reference in their entirety. ε -heptalactone, γ m ε CL, and θ-propargyl- ε -nonaralactone were synthesized using a Bayer-Villager oxidation reaction according to a modified version of the previously reported process. . Note: van der Mee, L .; Helmich, F .; de Bruijn, R .; Vekemans, JAJM, Palmans, ARA; Meijer, EW; Investigation of Lipase-Catalyzed Ring-Opening Polymerizations of Lactones with Various Ring Sizes: Kinetic Evaluation. Macromolecules 2006, 39, 5021-5027; Jazkewitsch, O .; Mondrzyk, A .; Staffel, R .; Ritter, H .; Cyclodextrin-Modified Polyesters from Lactones and from Bacteria: An Approach to New Drug Carrier Systems. Macromolecules 2011, 44 (6), 1365-1371; And Wegener, M .; Huber, F .; Bolli, C .; Jenne, C .; Kirsch, SF; Silver-Free Activation of Ligated Gold ( I) Chlorides: The Use of [Me 3 NB 12 Cl 11] - as a Weakly Coordinating Anion in Homogeneous Gold Catalysis. Chem. Eur. J. 2015 , 21 , 1328-1336, the disclosure of which is incorporated herein by reference in its entirety. All solvents were purchased from Fisher to Innovative Technology Inc. Dry using a Pure Solv MD-3 solvent purification system. Benzyl alcohol, propylene oxide, δ -valerolactone, ε -caprolactone, and ε -dekalactone were dried over calcium hydride overnight before vacuum distillation. ω-pentadecaractone was dissolved in 75 wt.% toluene and dried on a 3 Å molecular sieve. After sublimation of maleic anhydride, it was dried in vacuo on P ₂ O _{5 for} 5 days. All other reagents were used as received.

Instrumental Method

Proton ( ¹ H) NMR spectra were recorded using a Varian Mercury 300 spectrometer. Carbon ( ¹³ C) NMR spectra were recorded using a Varian NMRS 500 spectrometer. All chemical shifts were reported in parts ^per million (ppm) relative to the reference peak of the chloroform solvent for ¹ H and ¹³ C NMR spectra, respectively at δ = 7.26 and 77.16 ppm. Molecular weight was determined by size exclusion chromatography (SEC) using Tosoh EcoSEC HLC-8320GPC on a series of TSKgel GMH _HR- M columns with refractive index (RI) detection. The molecular weight was calculated using a polystyrene standard using tetrahydrofuran (THF) as an eluent flowing at 1.0 mL min ^-1 and a calibration curve measured from a sample concentration of 10 mg mL ^-1 . DSC heating and cooling curves were obtained using TA Instruments DSC 2910. The heating and cooling curves were performed three times in a 40 μL aluminum crucible at a heating rate of ± 10 ° C. per minute under a nitrogen atmosphere. The stamp was printed using an Envisiontec ^™ Micro Plus Advantage® continuous digital light processing (cDLP) printer.

Example 1

Synthesis of ε-heptalactone and γ-methyl-ε-caprolactone

Cool the one-neck round bottom flask containing 250 mL of methylene chloride in an ice bath before adding 223 mmol of 2-methylcyclohexanone or 4-methylcyclohexanone and 275 mmol of m -chloroperoxybenzoic acid Ordered. After refluxing for 3 days, the reaction mixture was cooled in an ice bath, filtered over Celite, 10% Na ₂ S ₂ O ₃ solution, saturated Na ₂ CO ₃ solution and brine. Then, the organic layer was dried over MgSO ₄ and filtered before removing the solvent through rotary evaporation. Both products were dried over calcium hydride overnight and distilled under vacuum before use.

ε-heptalactone :

The presence of ε -heptalactone was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 4.44 (m, C H ₂ (CH ₃ ) O), 2.64 (m, C (= O) C H ₂ ), 1.73 (m, C H ₂ CH (CH ₃ )), 1.42 (m, C H ₂ CH ₂ CH (CH ₃ )).

γ-methyl-ε-caprolactone :

The presence of γ-methyl - ε-caprolactone was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 4.23 (m, C H ₂ O), 2.75 (m, C (= O) C H ₂ ), 1.73 (m, C H ₂ CH (CH ₃ )), 1.40 (m, CH ₂ C H (CH ₃ )), 0.96 (m, CH ₂ CH (C H ₃ )).

Example 2

Synthesis of θ-propargyl-ε-nonaralactone

30.0 mL of cyclohexanone (28.4 g, 289 mmol), 28.5 mL pyrrolidine (24.7 g, 347 mmol), and 55.0 mg of p-toluenesulfonic acid monohydrate (0.289 mmol) were added to 60 mL of toluene- It was dissolved in a round bottom flask equipped with a Star-Stark apparatus and a reflux condenser. The solution was stirred at 150 ° C. for 16 hours. The resulting solution was cooled to room temperature and dried with MgSO ₄ and washed with water and brine before solvent removal under reduced pressure. The product was purified by fractional distillation under vacuum (31.4 g, bp 107-114 ° C) to give a pale yellow oil. This was dissolved in anhydrous MeCN in a two-neck round bottom flask equipped with a reflux condenser before adding 26.8 mL of propargyl bromide (80% in toluene, 37.0 g, 249 mmol) dropwise, then dropwise. The reaction was stirred under reflux overnight and then cooled to room temperature before removing the solvent under reduced pressure. 220 mL of deionized water was added to the residue and the solution was stirred under reflux for 1 hour. The product was extracted with Et ₂ O, washed with brine and dried over MgSO ₄ . Fractional distillation under vacuum gave θ-propargyl- ε -nonaralactone and α -propargyl- ε -caprolactone as colorless oils (12.9 g, 94.7 mmol, bp 93-95 ° C./16 mbar). 160 mL of methylene chloride were mixed with θ-propargyl- ε -nonaralactone and α -propargyl- ε -caprolactone mixture (12.9 g, 94.7 mmol) and m -chloroperoxybenzoic acid (24.5 g, 142.1 mmol) It was cooled in an ice bath before adding. The reaction mixture was refluxed for 48 hours, cooled to room temperature and filtered. The product was washed with concentrated aqueous sodium sulfite solution and the solvent was dried over MgSO ₄ before removal using a rotary evaporator. The final product was dried over calcium hydride overnight and distilled under vacuum before use (reference; FIG. 33).

Example 3

Synthesis of magnesium 2,6- di -tert-butyl-4-methylphenoxide (Mg (BHT) ₂ (THF) ₂

Using standard Schlenk line technique, Schlenk was charged with 2,6- di - tert -butyl-4-methylphenol (BHT) (6.66 g, 30 mmol) and cannular delivery transfer) to anhydrous toluene (30 ml). Di - n -butylmagnesium (1M in hexane, 15 ml, 15 mmol) was added dropwise to the reaction with stirring. After the reaction was stirred for an additional 2 hours, the solvent was removed. Hexane (12.5 ml) was added to the reaction vessel followed by tetrahydrofuran (THF) (2.5 ml). After stirring for 2 hours under N ₂ , the solvent can be removed, and the final product is obtained as a solid (Ref: Scheme 11).

Scheme 11

Synthesis of magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg (BHT) ₂ (THF) ₂ )

Example 4

General procedure for sequential polymerization

Using standard Schlenk line technology, the ampoules were filled with a magnesium catalyst such as Mg (BHT) ₂ (THF) ₂ , a starting alcohol such as benzyl alcohol, and a lactone such as ε-caprolactone. The reagent was dissolved into toluene at a total monomer concentration of 2 M. The ampoule was sealed and heated at about 80 ° C. for about 24 hours or until all lactones reacted. Then a 2 M solution of propylene oxide and maleic anhydride dissolved in toluene is added to the polymerization via cannula and heating is continued at about 80 ° C. for an additional 120 hours. Thereafter, the obtained poly (lactone-b-propylene maleate) polymer is recovered by precipitating it in an excess of diethyl ether.

Example 5

General synthesis of poly (lactone-b-propylene maleate) copolymers

Using a standard glovebox technique, the ampoules were filled with a 2 M solution of Mg (BHT) ₂ (THF) ₂ in toluene, benzyl alcohol, and lactone monomer. The sealed ampoule was heated at 80 ° C. After a defined time, a 2 M solution of propylene oxide and maleic anhydride in toluene was added to the reaction ampoule in an N ₂ environment. The resealed ampoule was again heated to 80 ° C. for 5 days. The obtained polymer was recovered by precipitating in hexane. Specific reaction conditions for various synthesized poly (lactone-b-propylene maleate) copolymers are set forth in Table 2 below.

Lactone monomer (L) Time (h) Molar of initiator Volume of initiator (mL) Mole of catalyst Catalyst mass (g) Lacton Mall Volume of lactone (mL) Mall of MAn Mass of MAn (g) PO Mall Volume of PO (mL) Molar concentration δ VL One 0.97 0.1 0.97 0.59 0.048 4.496 0.048 4.74 0.048 3.394 2 ε CL One 5.375 ε HL 24 6.216 γ m ε CL One 6.216 Θ p ε NL 24 6.765 ε DL 8 8.460 ωPDL 24 24.25 * δ VL / ε CL 24 2.248 / 2.768 * ωPDL was prepared as a 2 M solution in toluene prior to use. The volume shown is the volume of the solution used for polymerization.

P (δVL-b-PM) :

P (δVL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.33 (m, Ar), 6.24 (m, OC (= O) H = C H (= O) O), 5.24 (m, CH ₂ C H (CH ₃ ) O), 5.10 (s, C = OOC H _2- Ar), 4.23 (m, PO C H ₂ OC = O), 4.06 (m, δVL C H ₂ OC = O), 2.31 (s, δVL C H ₂ C = OO), 1.30 (m, PO CH ₂ CH (C H ₃ ) O), 1.66 ( All remaining hydrogen) ppm (reference; FIG. 34); ¹³ C NMR (125 MHz, 303K, CDCl ₃ ): δ = 173.32 (δVL * -δVL, O C OCH ₂ ), 173.12 (δVL * -PO, O C OCH ₂ ), 165.15 (MAn * -δVL, O C OCH ₂ ), 164.77 and 164.49 (MAn * -PO, O C OCH ₂ ), 130.54 and 130.00 (MAn * -PO, O (O) C * C H = CH), 129.40 and 129.13 (MAn * -PO, O ( O) C * CH = C H), 128.33 and 128.31 (εCL-MAn *, O (O) C C H = CH), 69.26 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.56 ( MAn * -PO, O C H (CH ₃ ) CH ₂ ), 64.01 (δVL *-δVL, O C H ₂ ), 33.81 (δVL * -δVL, OCO C H ₂ ), 28.22 (δVL, OCH ₂ C H ₂ ), 21.55 (δVL, OCOCH ₂ C H ₂ ) and 16.34 (PO, CH ₂ CH ( C H ₃ ) O) ppm (reference: FIG. 7); And SEC (THF): M _n = 6.5 kDa, M _w = 8.3 kDa, Ð _M = 1.85. Yield: 89% (reference: Figure 35).

P (εHL-b-PM) :

The P (εHL-b-PM) polymer was produced as described above and characterized by: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.32 (m, Ar), 6.23 (m, OC (= O) H = C H (= O) O), 5.22 (m, CH ₂ C H (CH ₃ ) O), 5.07 (s, C = OOC H _2- Ar), 4.85 (m, εHL C H ₂ OC = O), 4.23 (m, PO C H ₂ OC = O), 2.23 (s, C H ₂ C = OO), 1.16 (m, εHL C H ₃ ), 1.63-1.22 (all remaining hydrogen) ppm (reference: Figure 36); ¹³ C NMR (125 MHz, 303K, CDCl ₃ ): δ = 173.10 (εHL * -εHL, OCOCH ₂ ), 165.02 (MAn * -εHL, O C OCH ₂ ), 164.63 and 164.39 (MAn * -PO, O C OCH ₂ ), 130.40 and 129.91 (MAn * -PO, O (O) C * C H = CH), 129.77 and 129.24 (MAn * -PO, O (O) C * CH = C H), 125.43 (εHL-MAn *, O () OC C H = CH), 77.53, 70.37 (εHL * -εHL, O C H ₂ ), 69.12 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.33 (MAn *- PO, O C H (CH ₃ ) CH ₂ ), 35.51 (εHL * -εHL, C H ₂ CH ₂ COO), 34.44 (εHL, CH ₂ C H ₂ CH (CH ₃ )), 16.17 (PO, CH ₂ CH ( C H ₃ ) O), 19.89 (εHL, C H ₃ CH (CH ₂ ) ₂ ), 30.29 and 24.89 (all remaining carbon) ppm (see Figure 9); And SEC (THF): M _n = 4.5 kDa, M _w = 9.8 kDa, Ð _M = 1.80. Yield: 92% (reference: Figure 37).

P (γmεCL-b-PM) :

P (γmεCL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.32 (m, Ar), 6.26 (m, OC (= O) H = C H (= O) O), 5.26 (m, CH ₂ C H (CH ₃ ) O), 5.11 (s, C = OOC H _2- Ar), 4.26 (m, PO C H ₂ OC = O), 4.10 (m, γmεCL C H ₂ OC (= O)), 2.29 (s, C H ₂ C = OO), 1.16 (m, γmεCL CH (C H ₃ )), 1.63-1.22 ( All remaining hydrogen) ppm (reference: Figure 38); ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 173.53 (γmεCHL *-γmεCHL, OCOCH ₂ ), 164.44 (MAn *-γmεCHL, O C OCH ₂ ), 164.19 and 163.82 (MAn * -PO, O C OCH ₂ ), 130.29 and 129.94 (MAn * -PO, O (O) C * C H = CH), 129.04 and 128.77 (MAn * -PO, O (O) C * CH = C H), 125.24 (γmεCHL -MAn *, O () OC C H = CH), 77.34, 69.12 (γmεCHL *-γmεCHL, O C H ₂ ), 68.10 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.36 (MAn *- PO, O C H (CH ₃ ) CH ₂ ), 35.02 (γmεCHL * -γmεCHL, C H ₂ CH ₂ COO), 34.56 (γmεCHL, CH ₂ C H ₂ CH (CH ₃ )), 16.13 (PO, CH ₂ CH ( C H ₃ ) O), 18.87 (γmεCHL, C H ₃ CH), 31.66 and 29.36 (all remaining carbon) ppm (see Figure 11); And SEC (THF): M _n = 7.4 kDa, M _w = 9.2 kDa, Ð _M = 2.02. Yield: 87% (reference: Figure 39).

P (θpεNL-b-PM) :

P ( θ pεNL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.34 (m, Ar), 6.85 (m, OC (= O) H = C H (= O) O), 5.29 (m, CH ₂ C H (CH ₃ ) O), 5.10 (s, C = OOC H _2- Ar), 4.92 (m, C H (CH ₂ CCH)) 4.34 (m, PO C H ₂ OC = O), 4.05 (m, αpεCL, C H ₂ OC (= O)), 2.45 (m, C H ₂ CCH), 2.34 (s, C H ₂ C = OO), 2.01 (s, CC H ), 1.65-1.39 (all remaining hydrogen) ppm; ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 174.12 (αpεCL *-αpεCL, OCOCH ₂ ), 173.42 (εCL * -εCL, OCOCH2), 172.87 ( θ pεNL * -θ pεNL), 164.36 and 163.98 (MAn * -PO, O C OCH ₂ ), 133.99 and 133.75 (MAn * -PO, O (O) C * C H = CH), 133.50 and 133.26 (MAn * -PO, O (O) C * CH = C H ), 81.21 (αpεCL and θ pεNL, CH ( C H ₂ CCH ₃ )), 78.57 ( θ pεNL, C H (CH ₂ CCH ₃ )), 71.25 (αpεCL, OC (= O) C ), 70.53 (εCL, OC (= O) C ), 70.07 (αpεCL and εCL, C OC (= O)), 69.22 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 67.89 (αpεCL and θ pεNL, CH (CH ₂ C C H ₃ )), 66.57 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 16.33 (PO, CH ₂ CH ( C H ₃ ) O), 36.42-21.08 (all remaining carbon) ppm ; And SEC (THF): M _n = 7.4 kDa, M _w = 14.6 kDa, Ð _M = 1.97. Yield: 86%.

P (εDL-b-PM):

The P (εDL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.33 (m, Ar), 6.25 (m, OC (= O) H = C H (= O) O), 5.25 (m, CH ₂ C H (CH ₃ ) O), 5.09 (s, C = OOC H _2- Ar), 4.84 (m, εDL C H ₂ OC = O), 4.24 (m, PO C H ₂ OC = O), 2.26 (s, C H ₂ C = OO), 0.87 (m, εDL C H ₃ (C H ₂ ) ₃ ), 1.65-1.20 (All remaining hydrogen) ppm (reference: FIG. 40); ¹³ C NMR (125 MHz, 303K, CDCl ₃ ): δ = 173.41 (εDL * -εDL, OCOCH ₂ ), 164.81 and 164.53 (MAn * -PO, O C OCH ₂ ), 130.59 and 130.11 (MAn * -PO, O (O) C * C H = CH), 129.96 and 129.47 (MAn * -PO, O (O) C * CH = C H), 125.65 (εDL-MAn *, O () OC C H = CH), 74.04 (εDL * -εDL, O C H ₂ ), 69.30 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.58 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 34.64 ( εDL * -εDL, OCO C H ₂ ), 33.93 (εDL, CH ₂ C H ₂ CH (Bu)), 16.37 (PO, CH ₂ CH ( C H ₃ ) O), 14.12 (εDL, C H ₃ (CH ₂ ) ₃ ), 30.48, 27.60, 25.13 and 22.71 (all remaining carbon) ppm (reference: FIG. 15); And SEC (THF): M _n = 2.6 kDa, M _w = 4.0 kDa, Ð _M = 1.56. Yield: 85% (reference: Figure 41).

P (PDL-b-PM):

The P (PDL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.32 (m, Ar), 6.24 (m, OC (= O) H = C H (= O) O), 5.23 (m, CH ₂ C H (CH ₃ ) O), 5.08 (s, C = OOC H _2- Ar), 4.23 (m, PO C H ₂ OC = O), 4.02 (m, PDL C H- ₂ OC = O), 2.25 (s, PDL C H ₂ C = OO), 1.60-1.23 (all remaining hydrogen) ppm (reference: FIG. 42); ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 173.93 (PDL *-PDL, O C OCH ₂ ), 173.63 (PDL * -PO, O C OCH ₂ ), 165.12 (MAn *-PDL, O C OCH ₂ ), 164.69 and 164.41 (MAn * -PO, O C OCH ₂ ), 129.97 and 129.82 (MAn * -PO, O (O) C * C H = CH), 129.35 and 129.27 (MAn * -PO, O ( O) C * CH = C H), 128.55 and 128.18 (PDL-MAn *, O (O) C C H = CH), 69.18 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.45 ( MAn * -PO, O C H (CH ₃ ) CH ₂ ), 64.13 (PDL *-PDL, O C H ₂ ), 34.12 (PDL *-PDL, OCO C H ₂ ), 30.34 (PDL, OCH ₂ C H ₂ ), and 16.22 (PO, CH ₂ CH ( C H ₃ ) O) ppm (reference: FIG. 17); And SEC (THF): M _n = 5.5 kDa, M _w = 7.8 kDa, Ð _M = 1.41. Yield: 84% (reference: Figure 43).

P (δVL-co-εCL-b-PM) :

P (δVL-co-εCL-b-PM) polymer was produced as set out above and characterized as follows: ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.32 (m, Ar), 6.24 (m, OC (= O) H = C H (= O) O), 5.21 (m, CH ₂ C H (CH ₃ ) O), 5.08 (s, C = OOC H _2- Ar), 4.26 (m , PO C H ₂ OC = O), 4.03 (m, C H ₂ OC = O), 2.28 (s, C H ₂ C = OO), 1.65-1.28 (all remaining hydrogen) ppm (see Figure 44); ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 173.49 (εCL * -εCL, O C OCH ₂ ), 173.46 (εCL * -δVL, O C OCH ₂ ), 173.25 (δVL * -εCL, O C OCH ₂ ), 173.23 (δVL * -δVL, O C OCH ₂ ), 173.01 (δVL * -PO or εCL * -PO, O C OCH ₂ ), 165.06 (MAn * -δVL or MAn * -εCL, O C OCH ₂ ), 164.68 and 164.40 (MAn * -PO, O C OCH ₂ ), 130.54 and 130.00 (MAn * -PO, O (O) C * C H = CH), 129.40 and 129.13 (MAn * -PO, O (O ) C * CH = C H), 128.33 and 128.31 (εCL-MAn * or δVL-MAn *, O (O) C C H = CH), 69.26 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.56 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 64.01 (δVL or εCL, O C H ₂ ), 33.81 (δVL or εCL, OCO C H ₂ ), 28.22 (δVL or εCL, OCH ₂ C H ₂ ), 21.55 (δVL or εCL, OCOCH ₂ C H ₂ ) and 16.34 (PO, CH ₂ CH ( C H ₃ ) O) ppm (reference: FIG. 19); And SEC (DMF): M _n = 1.6 kDa, M _w = 3.2 kDa, Ð _M = 1.97. Yield: 82% (reference: Figure 45).

Example 6

Synthesis of poly (δ-valerolactone-b-propylene maleate)

Poly (δ-valerolactone-b-propylene maleate) was used using the general method set forth in Example 4 using δ-valerolactone as shown in Scheme 12 below and using the reaction parameters shown in Table 3 below. Was synthesized.

Scheme 12

Sequential polymerization of copolymerization of δ-valerolactone followed by maleic anhydride and propylene oxide.

Initiator Molar equivalent δVL Molar equivalent PO Parent Equivalent MA T  (℃) 1 hour (h) 2 hours (h) M _{n, NMR}  (kDa) M _{n, GPC} (kDa) Ð _M BnOH 50 50 50 80 24 120 8.5 6.5 1.90

The presence of poly (δ-valerolactone-b-propylene maleate) product was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.33 (m, Ar), 6.24 (m, OC ( = O) H = C H (= O) O), 5.24 (m, CH ₂ C H (CH ₃ ) O), 5.10 (s, C = OOC H _2- Ar), 4.23 (m, PO C H ₂ OC = O), 4.06 (m, δVL C H ₂ OC = O), 2.31 (s, δVL C H ₂ C = OO), 1.30 (m, PO CH ₂ CH (C H ₃ ) O), 1.66 (all Remaining hydrogen) ppm (see Figure 34); ¹³ C NMR (125 MHz, 303K, CDCl ₃ ): δ = 173.32 (δVL * -δVL, O C OCH ₂ ), 173.12 (δVL * -PO, O C OCH ₂ ), 165.15 (MAn * -δVL, O C OCH ₂ ), 164.77 (MAn * -PO, O C OCH ₂ ), 164.49 (MAn * -εCL, O C OCH ₂ ), 130.54 and 130.00 (MAn * -PO, O (O) C * C H = CH), 129.40 and 129.13 (MAn * -PO, O (O) C * CH = C H), 128.33 and 128.31 (εCL-MAn *, O (O) C C H = CH), 69.26 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.56 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 64.01 (δVL * -δVL, O C H ₂ ), 33.81 (δVL * -δVL, OCO C H ₂ ), 28.22 (δVL, OCH ₂ C H ₂ ), 21.55 (δVL, OCOCH ₂ C H ₂ ) and 16.34 (PO, CH ₂ CH ( C H ₃ ) O) ppm (reference: FIG. 7); And SEC (DMF): M _n = 6.5 kDa, M _w = 12.5 kDa, Ð _M = 1.90. The DOSY NMR spectrum (500 MHz, 303 K, CDCl ₃ ) of poly ( δ -valerolactone- b -propylene maleate) is attached as FIG. 8.

Example 7

Synthesis of poly (ε-caprolactone-b-propylene maleate)

Poly (ε-caprolactone-b-propylene maleate) was synthesized using ε-caprolactone as shown in Scheme 13 below and using the reaction parameters shown in Table 4 below.

Scheme 13

Sequential polymerization of copolymerization of ε-caprolactone followed by maleic anhydride and propylene oxide.

Initiator Molar equivalent εCL Molar equivalent PO Molar equivalent MA T  (℃) 1 hour (h) 2 hours (h) M _{n, NMR}  (kDa) M _{n, GPC} (kDa) Ð _M BnOH 25 25 25 80 24 120 8.8 12.5 1.24

The presence of poly (ε-caprolactone-b-propylene maleate) product was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.29 (m, Ar), 6.22 (m, OC (= O) H = C H (= O) O), 5.19 (m, CH ₂ C H (CH ₃ ) O), 5.06 (s, C = OOC H _2- Ar), 4.20 (m, C H ₂ OC = O), 2.25 (s, εCL C H ₂ C = OO), 1.26 (m, CH ₂ CH (C H ₃ ) O), 1.60 and 1.33 (all remaining hydrogen) ppm (reference: FIG. 2); ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 173.35 (εCL * -εCL, OCOCH ₂ ), 173.11 (εCL * -PO, O C OCH ₂ ), 164.97 (MAn * -εCL, O C OCH ₂ ) , 164.57 (MAn * -PO, O C OCH ₂ ), 164.29 (MAn * -εCL, O C OCH ₂ ), 130.33 and 129.72 (MAn * -PO, O (O) C * C H = CH), 129.86 and 129.20 (MAn * -PO, O (O) C * CH = C H), 128.42 and 128.03 (εCL-MAn *, O (O) C C H = CH), 69.03 (MAn * -PO, O C H ( CH ₃ ) CH ₂ ), 66.29 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 65.98 (MAn * -εCL, O C H ₂ ), 63.99 (εCL * -εCL, O C H ₂ ) , 33.99 (εCL * -εCL, OCO C H ₂ ), 28.23 (εCL, OCH ₂ C H ₂ ), 25.41 (εCL, OCOCH ₂ C H ₂ ), 24.46 (εCL, OCOCH ₂ CH ₂ C H ₂ ) and 16.10 (PO, CH ₂ CH ( C H ₃ ) O) ppm (Reference: Figure 3); And SEC (DMF): M _n = 12.5 kDa, M _w = 15.5 kDa, Ð _M = 1.24 (see Figure 46).

Example 8

Synthesis of poly (ε-caprolactone-b-propylene maleate)

Using standard Schlenk line technology, the ampoules were Mg (BHT) ₂ (THF) ₂ (586.8 mg, 0.97 mmol), benzyl alcohol (0.1 mL, 0.97 mmol) and ε-caprolactone (5.35 mL, 48.3 mmol). Charged. The reagent was dissolved in toluene to a total monomer concentration of 2M. The ampoule was sealed and heated at 80 ° C. for 24 hours. A 2 M solution of propylene oxide (3.38 mL, 48.3 mmol) and maleic anhydride (4.74 g, 48.3 mmol) in toluene was added to the polymer via cannula and heated at 80 ° C. for an additional 120 hours. The resulting polymer was recovered by precipitation in excess diethyl ether.

Example 9

Synthesis of poly (ε-heptalactone-b-propylene maleate)

Poly (ε-heptalactone-b-propylene maleate) was synthesized using the method set forth in Example 4 using ε-heptalactone as shown in Scheme 14 and using the reaction parameters shown in Table 5 below. Did.

Scheme 14

Sequential polymerization of copolymerization of ε-heptalactone followed by maleic anhydride and propylene oxide

Initiator Molar equivalent εHL Molar equivalent PO Molar equivalent MA T  (℃) 1 hour (h) 2 hours (h) M _{n, NMR}  (kDa) M _{n, GPC} (kDa) Ð _M BnOH 50 50 50 80 24 120 9.6 13.5 1.27

The presence of poly (ε-heptalactone-b-propylene maleate) product was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.32 (m, Ar), 6.23 (m, OC ( = O) H = C H (= O) O), 5.22 (m, CH ₂ C H (CH ₃ ) O), 5.07 (s, C = OOC H _2- Ar), 4.85 (m, εHL C H ₂ OC = O), 4.23 (m, PO C H ₂ OC = O), 2.23 (s, C H ₂ C = OO), 1.16 (m, εHL C H ₃ ), 1.63-1.22 (all remaining hydrogen) ppm ( Note: Figure 36); ¹³ C NMR (125 MHz, 303K, CDCl ₃ ): δ = 173.13 (εHL * -εHL, OCOCH ₂ ), 164.83 (MAn * -εHL, O C OCH ₂ ), 164.66 and 164.39 (MAn * -PO, O C OCH ₂ ), 130.43 and 129.94 (MAn * -PO, O (O) C * C H = CH), 129.80 and 129.20 (MAn * -PO, O (O) C * CH = C H), 125.46 (εDL-MAn *, O () OC C H = CH), 77.36, 70.56 (εHL * -εHL, O C H ₂ ), 69.13 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.39 (MAn *- PO, O C H (CH ₃ ) CH ₂ ), 35.54 (εHL * -εHL, C H ₂ CH ₂ COO), 34.47 (εHL, CH ₂ C H ₂ CH (CH ₃ )), 16.20 (PO, CH ₂ CH ( C H ₃ ) O), 19.92 (εHL, C H ₃ CH (CH ₂ ) ₂ ), 30.32 and 24.87 (all remaining carbon) ppm (see Figure 9); And SEC (DMF): M _n = 13.5 kDa, M _w = 17.1 kDa, Ð _M = 1.27. The DOSY NMR spectrum of poly ( ε -heptalactone- b -propylene maleate) (500 MHz, 303 K, CDCl ₃ ) is appended as Figure 37.

Example 10

Synthesis of poly (ε-decaractone-b-propylene maleate)

Poly (ε-decaractone-b-propylene maleate) was synthesized using the method set forth in Example 4 using ε-decaractone as shown in Scheme 15 below and using the reaction parameters shown in Table 6 below. .

Scheme 15

Sequential polymerization of copolymerization of ε-decaractone followed by maleic anhydride and propylene oxide.

Initiator Molar equivalent εDL Molar equivalent PO Molar equivalent MA T  (℃) 1 hour (h) 2 hours (h) M _{n, NMR}  (kDa) M _{n, GPC} (kDa) Ð _M BnOH 50 50 50 80 24 120 10.7 10.8 2.10

Poly (ε-decaractone-b-propylene maleate) The product was confirmed by ¹ H NMR (300 MHz, 303 K, CDCl ₃ ): δ = 7.33 (m, Ar), 6.25 (m, OC (= O) H = C H (= O) O), 5.25 ( m, CH ₂ C H (CH ₃ ) O), 5.09 (s, C = OOC H _2- Ar), 4.84 (m, εDL C H ₂ OC = O), 4.24 (m, PO C H ₂ OC = O ), 2.26 (s, C H ₂ C = OO), 0.87 (m, εDL C H ₃ (C H ₂ ) ₃ ), 1.65-1.20 (all remaining hydrogen) ppm (reference: FIG. 40); ¹³ C NMR (125MHz, 303K, CDCl ₃ ): δ = 173.41 (εDL * -εDL, OCOCH ₂ ), 164.81 (MAn * -εDL, O C OCH ₂ ), 164.53 (MAn * -PO, O C OCH ₂ ) , 130.59 and 130.11 (MAn * -PO, O (O) C * C H = CH), 129.96 and 129.47 (MAn * -PO, O (O) C * CH = C H), 125.65 (εDL-MAn *, O () OC C H = CH), 74.04 (εDL * -εDL, O C H ₂ ), 69.30 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 66.58 (MAn * -PO, O C H (CH ₃ ) CH ₂ ), 34.64 (εDL * -εDL, OCO C H ₂ ), 33.93 (εDL, CH ₂ C H ₂ CH (Bu)), 16.37 (PO, CH ₂ CH ( C H ₃ ) O ), 14.12 (εDL, C H ₃ (CH ₂ ) ₃ ), 30.48, 27.60, 25.13 and 22.71 (all remaining carbon) ppm (see Figure 15); And SEC (DMF): M _n = 10.8 kDa, M _w = 22.3 kDa, Ð _M = 2.10 (see Figure 41). The DOSY NMR spectrum of poly ( ε -decaractone- b -propylene maleate) (500 MHz, 303 K, CDCl ₃ ) is attached to FIG. 16.

Example 11

General process for isomerization of poly (lactone-b-propylene maleate)

Poly (ε-caprolactone) -b- (propylene maleate) (1.0 g, 12 mol. Eq. Olefin) was dissolved in chloroform (50 mL) and diethylamine (0.01 mL, 0.15 mol. Eq. Olefin) was added. Added. The solution was refluxed for 24 hours under a nitrogen atmosphere. After cooling to room temperature, the organic solution was washed with 0.5 M phosphate buffer solution (150 mL, pH = 6) before removing the solvent through rotary evaporation.

In view of the above, the present invention significantly improves the technology by providing a structurally and functionally improved poly (lactone-b-propylene fumarate) block copolymer in a number of ways. While specific embodiments of the invention are described in detail herein, it should be appreciated that the invention is not so limited or that modifications to the invention will be readily appreciated by those skilled in the art. The scope of the invention will be recognized from the following claims.

Claims (30)

Block co-polymers comprising poly (lactone) segments and poly (propylene fumarate) segments. The method according to claim 1, wherein the poly (lactone) segment is δ-valerolactone, ε-caprolactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl- ε-caprolactone (mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxephanone (dihydrocarbide), 7- (prop -2-ynyl) oxepan-2-one, alkyl-substituted lactones, γ -methyl- ε -caprolactone, ε -heptalactone, ε -decalactone macrolactone, ω-pentadecaractone (PDL), action Add a residue of lactone selected from the group consisting of sex lactone, θ-propargyl- ε -nonaractone (ωp ε NL), α -propargyl- ε -caprolactone ( α p ε CL), and combinations thereof Block copolymer comprising a. The method according to claim 1, Benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group and poly (ethylene glycol) Block co-polymers further comprising functional end groups selected from the group consisting of groups, and combinations thereof. The block co-polymer of claim 1, wherein the poly (propylene fumarate) segment comprises from about 0.1 mole percent to about 99 mole percent of the terminal functionalized block co-polymer. The block co-polymer of claim 1, wherein the poly (lactone) segment comprises from about 0.1 mole percent to about 99 mole percent of the terminal functionalized block co-polymer. The block co-polymer of claim 1, having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa as measured by NMR. The block copolymer of claim 1 having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa as measured by GPC. The block co-polymer of claim 1, having a polydispersity index ( Ð _m ) of about 1.1 to about 2.3. The method according to claim 1, block co-polymer having the following structural formula:

In the above formula,
n is an integer from about 1 to about 1000; m is an integer from about 1 to about 1000; x is an integer from about 1 to about 20; R is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, tertiary halogen group, poly (ethylene glycol) group, and A terminal functional group selected from the group consisting of combinations thereof; R ₁ is a hydrogen atom, a propargyl group, or a C ₁ -C ₁₀ alkyl group; R ₂ is a hydrogen atom, a methyl group, a butyl group, a propargyl group or a C ₁ -C ₁₀ alkyl group. The method according to claim 1, block co-polymer having the following structural formula:

,

,

,

,

, or

In the above formula,
n is an integer from about 1 to about 500; m is an integer from about 1 to about 500; k is an integer from about 1 to about 500; R is a terminal functional group. A block co-polymer comprising reaction products of poly (lactone), maleic anhydride, and propylene oxide. The block co-polymer of claim 11, wherein the poly (lactone) is a terminal functionalized poly (lactone). The method according to claim 12, wherein the terminal functionalized poly (lactone) is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group, ketone group, aldehyde group, A block co-polymer comprising tertiary functional groups selected from the group consisting of tertiary halogen groups and poly (ethylene glycol) groups, and combinations thereof. The method according to claim 11, wherein the poly (lactone) is δ-valerolactone, ε-caprolactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε -Caprolactone (mented), 2,5-oxepanedione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxephanone (dihydrocarbide), 7- (prop- 2-Inyl) oxepan-2-one, alkyl-substituted lactones, γ -methyl- ε -caprolactone, ε -heptalactone, ε -decalactone macrolactone, ω-pentadecaractone (PDL), functional A block co-polymer selected from the group consisting of lactone, θ-propargyl- ε -nonaralactone (θp ε NL), α -propargyl- ε -caprolactone ( α p ε CL), and combinations thereof. The block co-polymer of claim 11, comprising from about 0.1 mole percent to about 99 mole percent of a residue functionalized poly (lactone) residue. The block co-polymer of claim 11, having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa as measured by NMR. The block co-polymer of claim 11, having a number average molecular weight ( M _n ) of about 0.5 kDa to about 500 kDa, as measured by GPC. The block co-polymer of claim 11, having a polydispersity index ( Ð _m ) of about 1.1 to about 2.3. A. preparing the starting alcohol;
B. combining the starting alcohol, magnesium catalyst, and lactone in a suitable reaction vessel;
C. dissolving the contents of the reaction vessel with a suitable solvent;
D. Sealing the solution of step C, followed by heating to induce or maintain ring-opening polymerization of lactones, initiated by the starting alcohol, thereby forming a poly (lactone) polymer;
E. Dissolving maleic anhydride and propylene oxide in a suitable solvent and adding them to the reaction vessel;
F. heating the solution of step E to form a block co-polymer comprising poly (lactone) segments and poly (propylene maleate) segments; And
G. A method of making a block co-polymer according to claim 1 or 11 comprising isomerizing the poly (propylene maleate) segment to form a poly (lactone-b-propylene fumarate) polymer. The method according to claim 19, wherein the starting alcohol is benzyl alcohol, propargyl alcohol, allyl alcohol, 4-dibenzylcyclooctinol, 4-hydroxybutan-2-one, 3-hydroxypropan-2-one, 5 -Hydroxypentan-2-one, 6-hydroxyhexan-2-one, 7-hydroxyheptan-2-one, 8-hydroxyoctan-2-one, 5-norbornene-2-ol, PEG A method selected from the group consisting of diols, α-bromoisobutyryl 4-methanol benzylmethanoate, and combinations thereof. 20. The poly (lactone) segment of step F and poly (propylene maleate) according to claim 19, wherein the starting alcohol of step A is terminal functionalized, and the poly (lactone) polymer formed in step D is terminal functionalized. ) The block co-polymer comprising segments is end functionalized, and the poly (lactone-b-propylene fumarate) polymer produced in step G is a terminal functionalized poly (lactone-b-propylene fumarate) polymer . The method according to claim 21, wherein the terminal functionalized poly (lactone-b-propylene fumarate) polymer is a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzocyclooctin group, cyclooctin group , A method comprising a terminal functional group selected from the group consisting of ketone groups, aldehyde groups, tertiary halogen groups and poly (ethylene glycol) groups and combinations thereof. The method according to claim 19, wherein the lactone is δ-valerolactone, ε-caprolactone, α-chloro-ε-caprolactone, 4-chloro-ε-caprolactone, 4-methyl-7-isopropyl-ε-caprolactone (Mented), 2,5-oxepandione (OPD), 7-methyl-4- (1-methylethenyl) -2-oxepanone (dihydrocarbide), 7- (prop-2-ynyl) ) Oxepan-2-one, alkyl-substituted lactone, γ -methyl- ε -caprolactone, ε -heptalactone, ε -decaractone macrolactone, ω-pentadecaractone (PDL), functional lactone, θ - propargyl - ε - no hell tone (ε θp NL), α-propargyl-ε-caprolactone (CL ε α p), and is selected from the group consisting of a combination thereof. The method of claim 19, wherein the magnesium catalyst is Mg (BHT) ₂ (THF) ₂ . The method of claim 19, wherein the concentration of the lactone in the solution of step C is from about 0.5M to about 10M. The method of claim 19, wherein the total concentration of maleic anhydride and propylene oxide in the solution of step E is from about 0.5M to about 10M. The method of claim 19, wherein the lactone solution of step C is heated to a temperature of about 40 ° C. to about 100 ° C. (step D). The method of claim 19, wherein the solution of step C is heated (step D) for about 1 hour to about 96 hours. The method of claim 19, wherein the solution of step E is heated to a temperature of about 40 ° C. to about 100 ° C. (step F). The method of claim 19, wherein the solution of step E is heated (step F) for about 1 hour to about 96 hours.

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