BLOCK COPOLYMERS OF LACTONES AND POLY(PROPYLENE FUMARATE)
20200231760 ยท 2020-07-23
Inventors
- Matthew Becker (Stow, OH)
- James WILSON (Wolverhampton, West Midlands, GB)
- Shannon PETERSEN (Youngwood, PA, US)
Cpc classification
B33Y70/00
PERFORMING OPERATIONS; TRANSPORTING
C08G63/52
CHEMISTRY; METALLURGY
C08G63/6858
CHEMISTRY; METALLURGY
A61L27/18
HUMAN NECESSITIES
A61L27/18
HUMAN NECESSITIES
C08G63/83
CHEMISTRY; METALLURGY
C08L63/10
CHEMISTRY; METALLURGY
B33Y80/00
PERFORMING OPERATIONS; TRANSPORTING
C08G81/027
CHEMISTRY; METALLURGY
C08G63/823
CHEMISTRY; METALLURGY
C08G63/918
CHEMISTRY; METALLURGY
A61L27/54
HUMAN NECESSITIES
International classification
C08G81/02
CHEMISTRY; METALLURGY
C08G63/52
CHEMISTRY; METALLURGY
Abstract
In various embodiments, the present invention provides well-defined biodegradable poly(lactone-b-propylene fumarate) diblock and triblock polymers formed using a novel one-pot, scalable ring-opening block-order copolymerization (ROBOCOP) technique that utilizes magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg(BHT).sub.2(THF).sub.2) to switch from the ROP of cyclic esters to the ROCOP of maleic anhydride (MAn) and propylene oxide (PO) to produce PPF based block copolymers for application in additive manufacturing and patient specific regenerative medicine. These block copolymers are fully resorbable and can be photochemically crosslinked in a number of applications, including 3D printing. By adding the lactone block to the PPF polymer, the viscosity of the resulting block copolymer at working temperatures can be precisely controlled and the quantity of the reactive diluent in printable resins can be reduced or eliminated.
Claims
1. A block co-polymer comprising a poly(lactone) segment and a poly(propylene fumarate) segment.
2. The block co-polymer of claim 1 wherein said poly(lactone) segment comprises the residue of a lactone selected from the group consisting of -valerolactone, -caprolactone, -chloro--caprolactone, 4-chloro--caprolactone, 4-methyl-7-isopropyl--caprolactone (menthide), 2,5-oxepanedione (OPD), 7-methyl-4-(1-methylethenyl)-2-oxepanone (dihydrocarvide), 7-(prop-2-ynyl) oxepan-2-one, alkyl-substituted lactones, -methyl--caprolactone, -heptalactone, -decalactone macrolactones, -pentadecalactone (PDL), functional lactones, -propargyl--nonalactone (pNL), -propargyl--caprolactone (pCL), and combinations thereof.
3. The block co-polymer of claim 1 further comprising a functional end group selected from the group consisting of benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups and poly(ethylene glycol) groups, and combinations thereof.
4. The block co-polymer of claim 3 wherein said poly(propylene fumarate) segment comprises from about 0.1 mole percent to about 99 mole percent of said end functionalized block co-polymer.
5. The block co-polymer of claim 3 wherein said poly(lactone) segment comprises from about 0.1 mole percent to about 99 mole percent of said end functionalized block co-polymer.
6. The block co-polymer of claim 1 having a number average molecular weight (M.sub.a) of from about 0.5 kDa to about 500 kDa.
7. (canceled)
8. The block co-polymer of claim 1 having a polydispersity index (.sub.m) of from about 1.1 to about 2.3.
9. The block co-polymer of claim 1 having the formula: ##STR00020## wherein 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 an end functional group selected from the group consisting of benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups, poly(ethylene glycol) groups, and combinations thereof; R.sub.1 is a hydrogen atom, a propargyl group, or a C.sub.1-C.sub.10 alkyl group; and R.sub.2 is a hydrogen atom, a methyl group, a butyl group, a propargyl group or a C.sub.1-C.sub.10 alkyl group.
10. The block co-polymer of claim 1 having the formula: ##STR00021## where n is an integer from about 1 to about 500; and m is an integer from about 1 to about 500; k is an integer from about 1 to about 500 and R is an end functional group.
11. A block co-polymer comprising the reaction product of a poly(lactone), maleic anhydride, and propylene oxide.
12. The block co-polymer of claim 11 wherein said poly(lactone) is an end functionalized poly(lactone).
13. The block co-polymer of claim 12 wherein said end functionalized poly(lactone) comprises an end functional group selected from the group consisting of benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups and poly(ethylene glycol) groups, and combinations thereof.
14. The block co-polymer of claim 11 wherein said poly(lactone) is selected from the group consisting of -valerolactone, -caprolactone, -chloro--caprolactone, 4-chloro--caprolactone, 4-methyl-7-isopropyl--caprolactone (menthide), 2,5-oxepanedione (OPD), 7-methyl-4-(1-methylethenyl)-2-oxepanone (dihydrocarvide), 7-(prop-2-ynyl)oxepan-2-one, alkyl-substituted lactones, -methyl--caprolactone, -heptalactone, -decalactone macrolactones, -pentadecalactone (PDL), functional lactones, -propargyl--nonalactone (pNL), -propargyl--caprolactone (pCL), and combinations thereof.
15. (canceled)
16. The block co-polymer of claim 11 having a number average molecular weight (M.sub.n) of from about 0.5 kDa to about 500 kDa.
17. (canceled)
18. The block co-polymer of claim 11 having a polydispersity index (.sub.m) of from about 1.1 to about 2.3.
19. A method for making the block co-polymer as claimed in claim 1 comprising: A. preparing an initiating alcohol; B. combining said initiating alcohol, a magnesium catalyst, and a lactone in a suitable reaction vessel; C. dissolving the contents of said reaction vessel with a suitable solvent; D. sealing and then heating the solution of Step C to cause or maintain the ring opening polymerization of said lactone, initiated by said initiating alcohol, thereby forming a poly(lactone) polymer; E. dissolving maleic anhydride and propylene oxide in a suitable solvent and adding them to said 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. isomerizing said poly(propylene maleate) segments to form the poly(lactone-b-propylene fumarate) polymer.
20. The method of claim 19 wherein said initiating alcohol is selected from the group consisting of benzyl alcohol, propargyl alcohol, allyl alcohol, 4-dibenzyocyclooctynol, 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-norbornen-2-ol, PEG diol, -bromoisobtyryl 4-methanol benzylmethanoate, and combinations thereof.
21. The method of claim 19 wherein the initiating alcohol of Step A is end functionalized, the poly(lactone) polymer formed in step D is an end functionalized lactone polymer, the block co-polymer comprising poly(lactone) segments and poly(propylene maleate) segments of step F is end functionalized, and the poly(lactone-b-propylene fumarate) polymer produced in Step G is an end functionalized poly(lactone-b-propylene fumarate) polymer.
22. The method of claim 21 wherein said end functionalized poly(lactone-b-propylene fumarate) polymer comprises an end functional group selected from the group consisting of benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups and poly(ethylene glycol) groups and combinations thereof.
23. The method of claim 19 wherein said lactone is selected from the group consisting of -valerolactone, -caprolactone, -chloro--caprolactone, 4-chloro--caprolactone, 4-methyl-7-isopropyl--caprolactone (menthide), 2,5-oxepanedione (OPD), 7-methyl-4-(1-methylethenyl)-2-oxepanone (dihydrocarvide), 7-(prop-2-ynyl)oxepan-2-one, alkyl-substituted lactones, -methyl--caprolactone, -heptalactone, -decalactone macrolactones, -pentadecalactone (PDL), functional lactones, -propargyl--nonalactone (pNL), -propargyl--caprolactone (pCL), and combinations thereof.
24. The method of claim 19 wherein said magnesium catalyst is Mg(BHT).sub.2(THF).sub.2.
25. The method of claim 19 wherein the concentration of said lactone in the solution of Step C is from about 0.5M to about 10M.
26. The method of claim 19 wherein the total concentration of said maleic anhydride and said propylene oxide in the solution of Step E is from about 0.5M to about 10M.
27. The method of claim 19 wherein the solution of Step C is heated (Step D) to a temperature of from about 40 C. to about 100 C. and the solution of Step E is heated (Step F) to a temperature of from about 40 C. to about 100 C.
28. The method of claim 19 wherein the solution of Step C is heated (Step D) for from about 1 hour to about 96 hours and the solution of Step E is heated (Step F) for from about 1 hours to about 96 hours.
29. (canceled)
30. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] 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 along with the accompanying figures in which:
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DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS
[0073] One or more embodiments of the present invention provide a well-defined, non-toxic, resorbable end functionalized poly(lactone-b-propylene fumarate) block copolymers (and related methods for their making and use) having constrained and predictable material properties suitable for 3D printing and other regenerative medicine applications. These block copolymers are fully resorbable and PPF based materials are unique in that they can be crosslinked photochemical in a number of applications, including 3D printing. The type and composition of the specific lactide block affords the ability to tune the physical, chemical and degradation 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 and can be precisely controlled. Moreover, it has been found that the amount of DEF required to formulate 3D printable resin is greatly reduced, both because less DEF is required to dilute the PPF and because the presence of the lactone block allow for longer PPF blocks, reducing the amount of DEF necessary for crosslinking. In certain embodiments, the present invention relates to a well-defined biodegradable poly(lactone-b-propylene fumarate) polymers and scalable methods for making and functionalizing same.
[0074] In various embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention will have a poly(lactone) segment (block) and a poly(propylene fumarate) segment (block), and may optionally include an end functional group introduced through the initiating alcohol and/or one or more other functional groups introduced through a functionalized lactone monomer.
[0075] In various embodiments, the poly(lactone) segment (block) of poly(lactone-b-propylene fumarate) block copolymers of the present invention are formed through ring opening polymerization of one or more lactone monomers from an initiating alcohol, which may, or may not, include an end functional group, as described below. The poly(lactone) segment (block) will comprise a polymer chain formed of the residues of the lactones from which it was formed and will be bonded on one end to the residue of the initiating alcohol and on the other end to the poly(propylene fumarate) segment (block). As used herein, the term residue(s) is used to refer generally to the part of a monomer or other chemical unit that has been incorporated into a polymer or other large molecule. Any lactone capable of ring opening polymerization from an alcohol using a suitable catalyst may be used. In one or more embodiments, the poly(lactone) segment (block) may include the residue of lactones such as -valerolactone (VL), -caprolactone (ECL), -chloro--caprolactone, 4-chloro--caprolactone, 4-methyl-7-isopropyl--caprolactone (menthide), 2,5-oxepanedione (OPD), 7-methyl-4-(1-methylethenyl)-2-oxepanone (dihydrocarvide), 7-(prop-2-ynyl)oxepan-2-one, alkyl-substituted lactones including, but not limited to, -methyl--caprolactone (ymECL), -heptalactone (EHL), -decalactone (EDL) macrolactones, including, but not limited to, -pentadecalactone (PDL), functional lactones including, but not limited to, -propargyl--nonalactone (OpENL), -propargyl--caprolactone (apECL), and isomeric mixtures thereof.
[0076] In various embodiments, the poly(lactone) segment will comprise from about 0.1 mole percent to about 99 mole percent of said end functionalized block co-polymer. In some embodiments, the poly(lactone) segment will comprise 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 said end functionalized block co-polymer.
[0077] As set forth above, the poly(lactone-b-propylene fumarate) block copolymers of the present invention also comprise a the poly(propylene fumarate) (PPF) segment (block). As will be appreciated by those of skill in the art, the PPF segment (block) is formed by the isomerization of a poly(propylene maleate) segment formed by ring opening polymerization of maleic anhydride and propylene oxide onto the end of the poly(lactone) segment (block) and will comprise the isomerized residue of those maleic anhydride and propylene oxide monomers. In various embodiments, the PPF segment of the poly(lactone-b-propylene fumarate) block copolymers of the present invention will comprise from about 0.1 mole percent to about 99 mole percent of said end functionalized block co-polymer. In some embodiments, the PPF segment will comprise 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, in other embodiments, from about 0.1 mole percent to about 10 mole percent, in other embodiments, from about 10 mole percent to about 99 mole percent, in other embodiments, from about 25 mole percent to about 99 mole percent of said end functionalized block co-polymer, in other embodiments, from about 50 mole percent to about 99 mole percent, in other embodiments, from about 75 mole percent to about 99 mole percent.
[0078] Further, while the block copolymers of the present invention will have at least one lactone segment and at least one PPF segment, in some other embodiments, the block copolymers of the present invention may have more than one lactone block and/or more than one PPF block. In addition, in one or more of these embodiments, more than one type of lactone block may be used, either in the same block as a termolymer or in separate lactone blocks. In some other embodiments, the a single lactone block may contain a mixture of the residues of more than one different lactone. In some of these embodiments, the block copolymers of the present invention may have two or more lactone or two or more PPF blocks that have different chain lengths.
[0079] As set forth above, the poly(lactone-b-propylene fumarate) block copolymers of the present invention may in some embodiments include one or more functional groups to facilitate post polymerization addition of desirable materials, such as bioactive materials or other functional species, to the polymer. As used herein, the terms bioactive molecule(s) and bioactive material(s) are used interchangeably to refer to substances that influence cellular function and may include, without limitation, peptides, carbohydrates, proteins, oligonucleotides and small molecule drugs. As used in the context of substances that may be attached to the functionalized PPF polymers of the present invention, the term functional species refers to substances other than bioactive materials that may be added to the functionalized PPF polymers of the present invention to provide an added benefit and may include such things as fluorescent and other markers, small molecule dyes, and/or drugs.
[0080] In some embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention may include an end functional group introduced through the initiating alcohol. These end functional groups are not particularly limited provided that they maintain at least some of their reactivity after the polymerization and isomerization reactions discussed below, and may include without limitation, benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, tertiary halogen groups or a combination thereof.
[0081] In some other embodiments, the PPF block of the poly(lactone-b-propylene fumarate) block copolymers of the present invention may also include one or more monomer functional groups introduced through a functionalized monomer. In these embodiments, the PPF segment (block) will comprise the isomerized residue of the maleic anhydride monomer and the residue of a functionalized propylene oxide monomer used in its formation. As will be apparent, when the maleic anhydride monomer and the functionalized propylene oxide monomer react to form the polymer, the maleic anhydride monomer and functionalized propylene oxide will form the backbone of the PPM/PPF polymer, with the functional group of the functionalized propylene oxide monomer forming an active side chain. In various embodiments, the functional group on the residue of the functionalized propylene oxide monomer may include, without limitation, an alkyne group, a propargyl group, an alkene group, a hydroxyl group, a ketone group, a thiol group, a halide group, a nitrobenzyl group, or a group that can easily be converted into such a functional group such as a halide group, or a nitrobenzyl group. In the same way, in other embodiments, functional groups may be introduced into the block co polymers of the present invention through the lactone monomers, which may contain, or be functionalized to contain, additional functional groups.
[0082] As used herein, the term residue(s) is used to refer generally to the part of a monomer or other chemical unit that has been incorporated into a polymer or large molecule. By extension, the terms residue of the maleic anhydride monomer and the residue of functionalized propylene oxide monomer are used to refer to the parts of the maleic anhydride monomer and functionalized propylene oxide monomer, respectively, that has been incorporated into the PPM and PPF block of the poly(lactone-b-propylene fumarate) block copolymers of the present invention. The term isomerized residue of a maleic anhydride monomer specifically refers to the residue of the maleic anhydride monomer in the PPF block of the poly(lactone-b-propylene fumarate) block copolymers of the present invention wherein the double bond has been isomerized from the cis configuration to the trans configuration with the formation of the functionalized PPF polymer.
[0083] In various embodiments, the functional group on the residue of the functionalized propylene oxide monomer may include, without limitation, an alkyne group, a propargyl group, an alkene group, a hydroxyl group, a ketone group, a thiol group, a halide group, a nitrobenzyl group, or a group that can easily be converted into such a functional group such as a halide group or a nitrobenzyl group. It has been found that using the monomer functionalization method increases the quantity of available functional groups compared to only end-group functionalization, even with less functional groups surviving processing. It has also been found that the monomer of the PPF polymers of the present invention to not significantly affect the desired mechanical, thermal, degradation, and/or toxicity properties of the polymers.
[0084] In some embodiments, the functional groups added to the poly(lactone-b-propylene fumarate) block copolymers of the present invention will be groups capable of well known click reactions to facilitate post polymerization addition of desirable materials, such as bioactive compounds, to the polymer. As used herein, the terms click reaction, click chemistry, click chemistry methods, click chemistry reactions, are used interchangeably to refer to a group of orthogonal conjugation reactions, generally referred to in the art as click reactions, that fulfill the following prerequisites: (i) high yield, nearly quantitative conversion; (ii) biologically benign conditions (aqueous solution, ambient temperature, and near physiologic pH); (iii) limited or no residual byproduct. These reactions are typically simple to perform, high yielding, stereospecific, wide in scope, create only byproducts that can be removed without chromatography, and can be conducted in easily removable or benign solvents. Similarly, the term clickable refers to a molecule or functional group capable of bonding via a click reaction.
[0085] The click chemistry concept currently represents a number of orthogonal reactions, which are robust, selective, efficient, and high yielding, including, without limitation, copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) reactions (a.k.a. Huisgen cycloaddition reactions), thiol-ene radical addition reactions, oxime ligation reactions, Michael-addition reactions, thiol-Michael-addition reactions, Mannich-type addition reactions, ene-type addition reactions, thiol-ene radical addition, strain promoted azide-alkyne cycloaddition (SPAAC) reactions, non-traceless Staudinger ligation, traceless Staudinger ligation, Diels-Alder reactions, hetero Diels-Alder reactions, inverse electron demand Diels-Alder reactions, tandem [3+2] cycloaddition-retro-Diels-Alder (tandem crD-A) reactions, thiol-alkyne reactions, thiol-pyridyl disulfide reactions, thiol-halogen ligation, native chemical ligation, and thiazolidine ligation reactions. In one or more embodiments, suitable clickable moieties may include, without limitation, alkyne groups, alkene groups, azide groups, ketones or strained cyclooctyne groups
[0086] In one or more of these embodiments, the bioactive or other material to be attached to the polymer is functionalized with a moiety known to bond the functional group used via a click reaction. The clickable moiety chosen and means for its attachment will, of course, depend upon the bioactive or other material to be attached and the specific click reaction to be used. One of ordinary skill in the art will be able to attach the appropriate clickable moiety to the bioactive or other material to be attached without undue experimentation.
[0087] In one or more embodiments, the block co-polymer of present invention will have the formula:
##STR00003##
wherein 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 an end group comprising the residue of the initiating alcohol and preferably comprises an end functional group; R.sub.1 is a hydrogen atom, a propargyl group, or a C.sub.1-C.sub.10 alkyl group; and R.sub.2 is a hydrogen atom, a methyl group, a butyl group, a propargyl group or a C.sub.1-C.sub.10 alkane.
[0088] In one or more of these embodiments, R may be a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzyocyclooctyne group, cyclooctyne group, ketone group, aldehyde group, tertiary halogen group and poly(ethylene glycol) group, and combinations thereof. In some of these embodiments, n is an integer 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 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 an integer 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 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.
[0089] In some of these embodiments, x is an integer 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, in other embodiments, from about 1 to about 3. In some of these embodiments, R.sub.1 may be a hydrogen atom, a propargyl group or a C.sub.1-C.sub.10 alkyl group. In some of these embodiments, R.sub.2 may be a hydrogen atom, a methyl group, a butyl group, a propargyl group or a C.sub.1-C.sub.10 alkyl group.
[0090] In some embodiments, the block co-polymers of the present invention may have the formula:
##STR00004##
where 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; and R is an end group comprising the residue of the initiating alcohol, and preferably comprises an end functional group, as described above.
[0091] In one or more of these embodiments, R may be a benzyl group, alkyne group, propargyl group, allyl group, alkene group, 4-dibenzyocyclooctyne group, cyclooctyne group, ketone group, aldehyde group, tertiary halogen group and poly(ethylene glycol) group, or a combination thereof. In some of these embodiments, n is an integer 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 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 an integer 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 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 an integer 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 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.
[0092] In some embodiments, the block copolymers of the present invention may have a number average molecular weight (M.sub.n) of from about 0.5 kDa to about 500 kDa, as determined by end-group analysis using .sup.1H NMR spectroscopic analysis. In some embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention will have a number average molecular weight (M.sub.n) of from about 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, 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 about 500 kDa, and in other embodiments, from about 250 kDa to about 500 kDa, as determined by end-group analysis using .sup.1H NMR spectroscopic analysis.
[0093] In some embodiments, the block copolymers of the present invention may have a number average molecular weight (M.sub.a) of from about 0.5 kDa to about 500 kDa, as determined by size exclusion chromatography (SEC) in THF against poly(styrene) standards. In some embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention will have a number average molecular weight (M.sub.n) of from about 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, 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 about 500 kDa, and in other embodiments, from about 250 kDa to about 500 kDa, as determined by size exclusion chromatography (SEC) in THF against poly(styrene) standards.
[0094] In some embodiments, the block copolymers of the present invention may have a weight average molecular weight (M.sub.w) of from about 2 kDa to about 500 kDa, as determined by SEC in THF against poly(styrene) standards. In some embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention will have a weight average molecular weight (M.sub.w) of from about 2 kDa to about 250 kDa, 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, as determined by size exclusion chromatography (SEC) in THF against poly(styrene) standards.
[0095] In various embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention may have a polydispersity (.sub.M) of from about 1.1 to about 2.3, as determined by SEC in THF against poly(styrene) standards. In some embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention will have a polydispersity (.sub.M) of 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 1.5, 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, as determined by SEC in THF against poly(styrene) standards.
[0096] As will be apparent, the poly(lactone-b-propylene fumarate) block copolymers of the present invention may be photochemically crosslinked using diethyl fumarate (DEF) in the same manner as other poly(propylene fumarate) polymers, making them useful for the production of polymer structures such as tissue scaffolds. In one or more of these embodiments, the poly(lactone-b-propylene fumarate) block copolymers of the present invention may be are formed into a 3-D printable resin. In these embodiments, the poly(lactone-b-propylene fumarate) block copolymer is dissolved into diethyl fumarate (DEF) and conventional photoinitiators and light scattering agents are mixed evenly throughout the resin. It has been found that the amount of DEF required to formulate 3D printable resin is greatly reduced for the poly(lactone-b-propylene fumarate) block copolymers of the present invention, both because less DEF is required to dilute the PPF and because the presence of the lactone block allow for longer PPF blocks, reducing the amount of DEF necessary for crosslinking. The resin is then 3-D printed and photo-crosslinked with a DLP printer or other suitable 3-D printer to form a scaffold or other polymer structure.
[0097] In another aspect, the present invention is directed to a method of making the poly(lactone-b-propylene fumarate) block copolymers described above. In various embodiments, the end functionalized poly(lactone-b-propylene fumarate) block copolymers of the present invention are made using a three step process: (i) formation of the end functionalized poly(lactone) segment (block) (which may or may not be end functionalized) via ring opening polymerization of a lactone using a starting alcohol and a magnesium catalyst; (ii) formation of a poly(propylene maleate) segment (block) on the end of the end functionalized poly(lactone) segment (block) via ring opening polymerization of maleic anhydride and propylene oxide; and (iii) isomerization of the poly(propylene maleate) segment (block) into its trans-isomer (poly(propylene fumarate)) form using any method known in the art for that purpose to form a poly(lactone-b-propylene fumarate) block copolymer.
[0098] In the first step, an initiating alcohol, a lactone monomer, and a magnesium catalyst, preferably Mg(BHT).sub.2(THF).sub.2, are placed in 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 one of ordinary skill in the art will be able to select a suitable solvent without undue experimentation.
[0099] As set forth above, any lactone may be used as the lactone monomer provided it is capable of ring opening polymerization from an alcohol initiator using a suitable catalyst such as Mg(BHT).sub.2(THF).sub.2. Suitable lactone monomers may include, without limitation, -valerolactone (VL), -caprolactone (CL), -chloro--caprolactone, 4-chloro--caprolactone, 4-methyl-7-isopropyl--caprolactone (menthide), 2,5-oxepanedione (OPD), 7-methyl-4-(1-methylethenyl)-2-oxepanone (dihydrocarvide), 7-(prop-2-ynyl)oxepan-2-one, alkyl-substituted lactones including, but not limited to, -methyl--caprolactone (ymECL), -heptalactone (EHL), -decalactone (EDL), macrolactones, including, but not limited to, -pentadecalactone (PDL), functional lactones including, but not limited to, -propargyl--nonalactone (OpENL), -propargyl--caprolactone (apECL) and isomeric mixtures thereof, or any combination thereof.
[0100] The initiating alcohol is not particularly limited, but it should be noted that different initiating alcohols will have different rate constants and will drive the reaction at different rates. In one or more embodiment, suitable initiating alcohols may include, without limitation, benzyl alcohol, ethanol, isopropanol, glycerol, propargyl alcohol, allyl alcohol, 4-dibenzyocyclooctynol, 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-norbornen-2-ol, -bromoisobtyryl 4-methanol benzylmethanoate, poly(ethylene glycol)s or a combination thereof.
[0101] As set forth above, a functional end group may be added to the polymer through the initiating alcohol. These materials have a hydroxyl group that initiates the ring open polymerization reaction and a functional end group useful for post polymerization reactions that survives both the polymerization and isomerization reactions. These functional end groups are not particularly limited provided that they maintain at least some of their reactivity after the polymerization and isomerization reactions, and may include without limitation, benzyl groups, alkyne groups, propargyl groups, allyl groups, alkene groups, 4-dibenzyocyclooctyne groups, cyclooctyne groups, ketone groups, aldehyde groups, and tertiary halogen groups or a combination thereof.
[0102] In various embodiments, the magnesium catalyst may be any magnesium or other organometallic catalyst that is substantially non-toxic and capable of catalyzing the ROP of lactones and the ROP of maleic anhydride and propylene oxide monomers without out being consumed, but is preferably Mg(BHT).sub.2(THF).sub.2.
[0103] The reaction solvent used is not particularly limited, and may be any suitable solvent or solvent combination that can dissolve not only the lactone monomers in step 1, but also the maleic anhydride and propylene oxide monomers of step 2 and is miscible with the solvent used to dissolve the maleic anhydride and propylene oxide monomers. In various embodiments, suitable solvents may include, without limitations, toluene, hexanes, heptane, hexane, octane, or a combination thereof. One of ordinary skill in the art will be able to select a suitable solvent without undue experimentation.
[0104] In various embodiments, the concentration of the lactone monomer in the starting solution will be from about 0.5M to about 10 M. In some embodiments, the lactone 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, in other embodiments, from about 0.5M to about 3M, and in other embodiments, from about 0.5M to about 2M. Next, the reaction vessel is then sealed and the lactone solution heated to a temperature of from about 40 C. to about 100 C. to begin and/or maintain a ring opening polymerization reaction of the lactone, initiated by the initiating alcohol and catalyzed by the magnesium catalyst, to form a poly(lactone) polymer intermediate. In some embodiments, the lactone solution is heated to a temperature of 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 from about 40 C. to about 90 C. As will be apparent, these poly(lactone) polymer intermediates will have the functional end group from the initiating alcohol, if any, on one end and a hydroxyl (OH) group on the other end. In some embodiments, the lactone solution is heated until substantially all (98% or more) of the lactone has reacted.
[0105] In various embodiments, the lactone solution may be heated for from about 1 hour to about 96 hours. In some embodiments, the lactone solution is heated for 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.
[0106] In the second step, a maleic anhydride monomer and a propylene oxide monomer are dissolved in a suitable solvent, such as toluene, to a total monomer concentration of from about 0.5M to about 10M and added to the reaction vessel containing the 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, in other embodiments, from about 0.5M to about 3M, and in other embodiments, from about 0.5M to about 2M.
[0107] As will be apparent, no additional catalyst or initiating alcohol is required in this step since the poly(lactone) polymer intermediate functions as the initiating alcohol for the ROP of the maleic anhydride and propylene oxide monomers and the magnesium catalyst simply switches from catalyzing the ROP of the lactone to the ROP of the maleic anhydride and propylene oxide monomers. In some embodiments, functionalized propylene oxide monomers may be used to introduce monomer functional groups to the PPF block of the block co-polymer.
[0108] The resulting solution is then heated to a temperature of from about 40 C. to about 100 C. to begin and/or maintain a ring opening polymerization reaction of the maleic anhydride monomer and propylene oxide monomer to the terminal OH group on the poly(lactone) polymer intermediate to form a poly(lactone-b-propylene maleate) block copolymer intermediate. In some embodiments, the solution is heated to a temperature of 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 from about 40 C. to about 90 C. In some embodiments, the solution is heated until substantially all (80% or more) of the monomer has reacted. In some embodiments, the solution is heated for from about 1 hour to about 96 hours, in other embodiments, from about 12 hour to about 96 hours, in other embodiments, from about 24 hour to about 96 hours, in other embodiments, from about 48 hour to about 96 hours, in other embodiments, from about 62 hour 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.
[0109] In one or more embodiments, an end functionalized poly(lactone-b-propylene maleate) block copolymer intermediate may be formed as shown in Scheme 1, below:
##STR00005##
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; and k is an integer from about 1 to about 100. In various embodiments, R may be a an alkyne group, a propargyl group, an alkene group, a hydroxyl group, a ketone group, a thiol group, a halide group, a nitrobenzyl group, or a group that can easily be converted into such a functional group such as a halide group or a nitrobenzyl group.
[0110] In some embodiments, n may be an integer 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 may be an integer 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 may be an integer 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 100.
[0111] In some embodiments, poly(lactone-b-propylene maleate) block copolymer intermediate may be synthesized as shown in Scheme 2, below.
##STR00006##
where m and n are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0112] In some embodiments, poly(lactone-b-propylene maleate) block copolymer intermediate may be synthesized as shown in Scheme 3, below:
##STR00007##
where m and n are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0113] In some embodiments, poly(lactone-b-propylene maleate) block copolymer intermediate may be synthesized as shown in Scheme 4, below:
##STR00008##
where m and n are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0114] In some embodiments, poly(lactone-b-propylene maleate) block copolymer intermediate may be synthesized as shown in Scheme 5, below:
##STR00009##
where m and n are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0115] In some embodiments, poly(lactone-b-propylene maleate) block copolymer intermediate may be synthesized as shown in Scheme 6, below.
##STR00010##
where m and n are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0116] In some embodiments, a poly(lactone-b-lactone-b-propylene maleate) triblock polymer intermediate may be synthesized as shown in Scheme 7, below:
##STR00011##
where m n and k are each an integer from about 1 to about 500; and R is an end group or end functional group as described above.
[0117] In some embodiments, poly(lactone-b-lactone-b-propylene maleate) triblock polymer intermediate may be synthesized as shown in Scheme 8, below:
##STR00012##
where m n and k are each an integer from about 1 to about 1000; and R is an end group or end functional group as described above.
[0118] The poly(lactone-b-propylene maleate) block copolymer and/or poly(lactone-b-lactone-b-propylene maleate) triblock polymer intermediates may be isolated and purified using any known method. In some embodiments, the poly(lactone-b-propylene maleate) block copolymer and/or poly(lactone-b-lactone-b-propylene maleate) triblock polymer intermediates may be recovered by precipitation in excess diethyl ether.
[0119] In the third step, the poly(propylene maleate) segment (block) of the poly(lactone-b-propylene maleate) block copolymer and/or poly(lactone-b-lactone-b-propylene maleate) triblock polymer intermediates is isomerized into its trans-isomer (poly(propylene fumarate)) to form a poly(lactone-b-propylene fumarate) block copolymer according to embodiments of the present invention. (See
[0120] The poly(propylene maleate) segment (block) may be isomerized using any conventional method including, but not limited to the methods described in International Application No. PCT/US2015/061314, published as WO 2016/081587, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, poly(propylene maleate) segment (block) of these block copolymers may be isomerized as shown in Example 11, below.
[0121] In various embodiments, the end functionalized poly(lactone-b-propylene maleate) block copolymer intermediate is placed in a suitable container, such as a round bottom flask, and dissolved in a suitable solvent such as chloroform, tetrahydrofuran (THF), dioxane, diethyl ether, or a combinations thereof, under an inert atmosphere. It is envisioned that whichever solvent is selected can be removed without undue difficulty or expense, and in some embodiments, the solvent is chloroform. Once the PPM intermediate has been dissolved, a catalyst, preferably diethylamine, is added and the container is connected to a condenser and the heated to a reaction temperature of from 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 from about 55 C. to about 65 C.
[0122] In these embodiments, the solution is heated for from about 5 to about 100 hours, from about 5 hours to about 80 hours, in other embodiments, from about 5 hours to about 60 hours, in other embodiments, from about 5 hour to about 50 hours, in other embodiments, 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 to produce the isomerized polymer. (See
[0123] While the methods of the present invention have been discussed primarily with reference to poly(lactone-b-propylene fumarate) diblock copolymers, it should be apparent that these methods may be used to form block co polymers having three or more blocks by the sequential addition of lactone monomers (to form an additional lactone block) or propylene oxide/maleic anhydride monomers (to form an additional PPF block) when reagents used to form the prior block have been depleted, as set forth above for the poly(lactone-b-propylene fumarate) diblock copolymers. As with the diblock copolymers discussed above, no additional catalyst or initiating alcohol is required since the hydroxyl group at the end of the previous block functions as the initiator for the next either lactone or the maleic anhydride/propylene oxide ROP, and the magnesium catalyst simply switches to catalyzing ROP for the new block. In some other embodiments, ABA block copolymers may be formed using a di-functional initiating alcohol. In these embodiments, the first block (B) will have two active functional groups and two (A) blocks can be added as described above to form the ABA block copolymer.
[0124] In various embodiments, poly(lactone-b-propylene fumarate) block copolymers of the present invention may be used in numerous applications such as 3D printable resins, medical devices, tissue engineering, wound healing, cosmetics, and drug and protein delivery.
Experimental
[0125] To further define and reduce embodiments of the present invention to practice, the ROP of CL and subsequent ROCOP of an equimolar mixture of MAn and PO was investigated. Homopolymerization of CL using Mg(BHT).sub.2(THF).sub.2 as a catalyst and benzyl alcohol (BnOH) as a primary alcohol initiator was conducted at a concentration of 2 M in toluene at 80 C. in a sealed, N.sub.2 atmosphere. The homopolymerization was allowed to continue for 1 h before a 2 M solution of MAn and PO in toluene was injected into the reaction. The preparation of the MAn and PO solution and its subsequent injection into the PCL reaction solution both occurred in a dry N.sub.2 environment in order to maintain the atmosphere of the initial reaction. The polymerization continued for 5 days post injection, after which the polymer was recovered by precipitation in cold hexanes. The monomer conversion of CL and MAn were determined using .sup.1H NMR spectroscopic analysis of the crude reaction solution taken immediately upon termination of the polymerization. The low vapor pressure and boiling point of PO result in unreliable integration of resonance peaks at the reaction temperature, thus the PO conversion is not reported. .sup.1H NMR spectroscopic analysis of the recovered material showed proton resonances corresponding to PCL, PPM, and the BnOH initiator. No resonances corresponding to the methylene protons of homopolymerized PO were observed (=3.3-3.5 ppm), confirming a preference for the alternating copolymerization of MAn and PO afforded with the Mg(BHT).sub.2(THF).sub.2. (See
[0126] The structure and regioregularity of the recovered polymer was investigated further using quantitative .sup.13C NMR spectroscopy and diffusion-ordered NMR spectroscopy (DOSY). The .sup.13C NMR spectra revealed a prominent carbonyl diad resonance at =173.4 ppm, corresponding to an CL carbonyl adjacent to another CL repeat unit (ECL*-ECL, in which the * denotes the observed carbonyl), and two prominent diad resonance peaks at =164.57 ppm and =164.19 ppm, which correspond to MAn*-PO. Two very small resonances are also present at =173.2 ppm and =164.9 ppm, which correspond to CL*-MAn and MAn*-CL, respectively. Integration of the carbonyl diad resonance peaks denote a block like sequencing in which one block is a PCL homopolymer and the other block is poly(propylene maleate) (PPM). See,
[0127] In order to exploit the alkene functionality present in the PPF block for stereolithographic printing, isomerization of P(CL-b-PM) into poly(-caprolactone-b-propylene fumarate) (P(CL-b-PF)) without cleavage or side reactions must occur. Hence, a 0.5 M solution of P(CL-b-PM) in CHCl.sub.3 with diethylamine (0.15 molar equivalents per alkene) was heated at reflux overnight, as reported previously. (See, Luo, Y.; Dolder, C. K.; Walker, J. M.; Mishra, R.; Dean, D.; Becker, M. L., 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 disclosure of which is incorporated herein in by reference in its entirety.) The diethylamine was removed by washing with 0.5 M sodium phosphate buffer solution prior to solvent removal via rotary evaporation. A complete reduction of the cis-alkene resonance (=6.2 ppm) and a new resonance corresponding to the trans-alkene protons (=6.7 ppm) was shown using .sup.1H NMR spectroscopy. See,
[0128] The kinetics of the ROCOP of MAn and PO onto an ECL block were studied under the same conditions with a targeted degree of polymerization (DP) of 50 repeat units for both PCL and PPM blocks. Aliquots were withdrawn every 24 h over a period of 6 d after the injection of propylene oxide and maleic anhydride into the polymerization solution. .sup.1H NMR spectroscopic analysis of the crude mixture was used to determine MAn conversion. SEC of the recovered material was used to determine molecular mass and molecular mass distribution (.sub.M). Like the ROCOP of MAn and PO from a primary alcohol initiator, the polymerization also follows pseudo-first order kinetics. The rate of monomer conversion is dramatically hindered as a consequence of catalyst affinity with the lactone macroinitiator competing with the propagation of the ROCOP. This is similar to the polymerization kinetics observed in the copolymerization of lactones and macrolactones in previous reports using Mg(BHT).sub.2(THF).sub.2 as a catalyst. (See, Wilson, J. A.; Hopkins, S. A.; Wright, P M.; Dove, A. P, Immortal ring-opening polymerization of -pentadecalactone by Mg(BHT).sub.2(THF).sub.2. Polym. Chem. 2014, 5 (8), 2691-2694, the disclosure of which is incorporated herein in by reference in its entirety. .sub.M values immediately post injection are indicative of transesterification during the CL homopolymerization, but decreasing .sub.M and linear molecular mass propagation during the ROCOP provide evidence of a controlled polymerization and preference for the ROCOP of MAn and PO as opposed to further transesterification side reactions. (See Scheme 9, below)
##STR00013##
[0129] Using the same catalyst, primary alcohol initiator, and temperature stated previously, the copolymerization of CL, MAn, and PO was also investigated using a single step synthesis and a ROCOP of MAn and PO subsequently followed by injection of CL. An equimolar ratio of CL, MAn, and PO was used in both reactions. .sup.1H NMR spectroscopic analysis of the recovered material did not reveal CL incorporation into the polymer produced in either of these reactions. We suspect this to be a consequence of neither the carboxylic acid chain-end of ring-opened MAn nor the secondary alcohol chain-end of ring-opened PO being able to initiate the ring-opening of CL. As a consequence of this selectivity, copolymers produced by the sequential lactone ROP and MAn and PO ROCOP should contain no gradation region between the blocks. This also suggests a high degree of regioregularity in the copolymerization of MAn and PO catalyzed by Mg(BHT).sub.2(THF).sub.2.
[0130] In order to further explore the viability of Mg(BHT).sub.2(THF).sub.2 as a catalyst for the ROP switch ROCOP of polyesters with MAn and PO, syntheses using a smaller lactone (-valerolactone (VL)), alkyl-substituted lactones (-methyl--caprolactone (mCL), -heptalactone (HL) and -decalactone (DL)), macrolactones (PDL), and functional lactones (an isomeric mixture of O-propargyl--nonalactone (pNL) and -propargyl--caprolactone (pCL)) were investigated. (See Scheme 10, below).
##STR00014##
[0131] With the exception of VL, mCL and PDL all lactones were homopolymerized for 24 h at 80 C. at a 2 M concentration in toluene, utilizing Mg(BHT).sub.2(THF).sub.2 as a catalyst and BnOH as a primary alcohol initiator in a sealed N.sub.2 atmosphere. VL, mCL, and PDL were homopolymerized using the same conditions for 1 h, 1 h, and 8 h respectively. After the homopolymerization, a dry, 2 M solution of MAn and PO in toluene was injected into each reaction. .sup.1H NMR spectroscopy was conducted on the crude reaction mixture 5 days after the injection of PO and MAn in order to determine monomer conversion prior to precipitation of the resultant polymer in hexanes. The results of these experiments are summarized in Table 1, below.
TABLE-US-00001 TABLE 1 Properties of PPF based block copolymers produced using Mg(BHT).sub.2(THF).sub.2 as a catalyst with varied lactone monomer feed and targeted DPs Lactone Lactone MAn M.sub.n M.sub.n M.sub.w T.sub.m T.sub.c T.sub.g monomer Target Time conv. conv. Actual (kDa).sup.b (kDa).sup.c (kDa).sup.c .sub.M.sup.c ( C.).sup.d ( C.).sup.d ( C.).sup.d (L) [L]:[PM] (h) (%).sup.a (%).sup.a [L]:[PM].sup.b NMR SEC SEC SEC DSC DSC DSC VL [50]:[50] 1 94 84 [42]:[33] 9.4 6.5 8.3 1.85 47 4 CL [50]:[50] 1 85 90 [46]:[41] 11.6 7.0 15.0 2.14 58 18 HL [50]:[50] 24 95 90 [48]:[42] 12.7 4.5 9.8 1.80 15 12 mCL [50]:[50] 1 94 81 [46]:[47] 13.2 4.5 9.2 2.02 18 pNL [50]:[50] 24 89 84 [35]:[38] 11.3 7.4 14.6 1.97 11 DL [50]:[50] 8 90 81 [40]:[29] 11.3 2.6 4.0 1.56 11 PDL [50]:[50] 24 82 78 [30]:[25] 11.1 5.5 7.8 1.41 93 75 VL/CL [50]:[50] 24 92 72 [50]:[29] 9.9 1.6 3.2 1.97 16 10 .sup.aDetermined by .sup.1H NMR spectroscopic analysis of the crude reaction mixture and comparison of the monomer proton resonance to the corresponding polymer proton resonance ( = 6.26 ppm). .sup.bDetermined by end-group analysis by .sup.1H NMR spectroscopic analysis of the crude reaction mixture. .sup.cDetermined by SEC in THF against poly(styrene) standards. .sup.dDetermined by differential scanning calorimetry.
Both .sup.13C and DOSY NMR spectroscopy confirmed the presence of a polylactone block and a PPM block in all recovered products. (See
[0132] Interestingly, integration of the carbonyl diad resonance peaks in the quantitative .sup.13C NMR spectra of the polymer containing pNL revealed a block like sequencing of the pNL, pCL, and a small amount of CL that was produced during monomer synthesis, in addition to the separate PM block. In order to confirm this effect, a polymer targeting 25 propargyl substituted lactone units, 25 CL units, and 50 PM units was synthesized by polymerizing an isomeric mixture of pNL and pCL with CL and subsequently injecting MAn and PO using the same conditions as the previous polymerization. .sup.1H NMR spectroscopy confirmed the presence of each monomer species and quantitative .sup.13C NMR spectroscopy once again suggested block sequencing of pNL, pCL, and CL in addition to the alternating block of MAn and PO. Though the exact mechanism behind this sequencing is beyond the scope of this disclosure and not necessary to understand and practice the invention, the stereoselectivity and isomeric selectivity seen with these monomers in this polymerization is worth noting, as all previous polymerizations of CL with other e-substituted -lactones (ESELs) have been reported to have random sequencing. This may be a consequence of the propargyl group readily co-ordinating with the catalyst leading to preferential polymerization compared to CL and ultimately producing the first example of a one-step CL block copolymer with another lactone.
[0133] The ROCOP synthesis of VL and CL followed by the ROCOP of MAn and PO was also explored. Once again utilizing Mg(BHT).sub.2(THF).sub.2 as a catalyst and BnOH as an initiator, VL and CL were copolymerized for 24 h at 80 C. at a 2 M concentration in toluene. .sup.1H NMR spectroscopy revealed equal incorporation of VL and CL into the polymer chain in addition to the incorporation of MAn and PO. Analysis of the carbonyl diad resonance peaks by .sup.13C NMR spectroscopy showed block like sequencing with random incorporation of VL and CL into one block and alternating MAn and PO incorporation into the second block. DOSY NMR spectroscopy confirmed the presence of a single diffusing polymer species.
[0134] Thermal analysis using differential scanning calorimetry (DSC) revealed a broad range of properties. (See
[0135] As expected, P(mCL-b-PM), P(pNL-b-pCL-b-CL-b-PM), and P(DL-b-PM) showed no crystalline behavior and were all viscous liquids at room temperature, as a consequence of the pendent side chains disrupting any crystallization of the main chain. (See
[0136] Since ROBOCOP using Mg(BHT).sub.2(THF).sub.2 allowed for the production of well-defined, diblock copolymers, the synthesis of an ABA type triblock copolymers was briefly investigated. The homopolymerization of DL using Mg(BHT).sub.2(THF).sub.2 as a catalyst and 1,4-benzenedimethanol (BDM) as an initiator was conducted at a total monomer concentration of 2 M in toluene at 80 C. in a sealed, N.sub.2 atmosphere. The homopolymerization was allowed to continue for 24 h before an equimolar quantity of MAn and PO in toluene was injected into the reaction. This monomer addition resulted in the growth of a triblock copolymer as a consequence of the bifunctionality of the sole initiating species. .sup.1H NMR spectroscopic analysis of the recovered material showed individual proton resonances corresponding to PDL (=4.86, 2.27, 0.88 ppm), PPM, (=6.27, 5.27, 4.26 ppm) and BDM (5.10 ppm). (See
[0137] Lastly, the P(pNL-b-pCL-b-CL-b-PM) polymer was made into a resin to introduce some of the potential applications of these polymers. (See
[0138] The synthesis of chemically complex, sequence defined polyesters is necessary to diversify the properties needed for more demanding applications, but few available techniques offer this selectivity without reducing industrial viability. Thus, we introduce Mg(BHT).sub.2(THF).sub.2 as a cheap, catalyst for the ROBOCOP of a library of lactones with MAn and PO. To our knowledge, this is the first example of a switch system with a magnesium based catalyst. The ubiquity of the technique has been demonstrated through polymerization with various lactones of different size, substitution, and functionality. Though additional investigation is necessary to determine the tunability of these polymers, the ability to expand the polymerization to tri-block copolymers, print via stereolithographic methods and post-polymerization and post-print modify with functional groups demonstrates the utility of the materials in a wide variety of applications.
EXAMPLES
[0139] The following examples are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. Further, while some of examples may include conclusions about the way the invention may function, the inventor do not intend to be bound by those conclusions, but put them forth only as possible explanations. Moreover, unless noted by use of past tense, presentation of an example does not imply that an experiment or procedure was, or was not, conducted, or that results were, or were not actually obtained. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature), but some experimental errors and deviations may be present. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
Abbreviations
[0140] ROP, ring-opening polymerization; ROCOP, ring-opening copolymerization; CHO, cyclohexene oxide; CL, -caprolactone; BL, -butyrolactone; PCL, poly(-caprolactone); PLLA, poly(l-lactic acid); PPF, poly(propylene fumarate); ROBOCOP, ring-opening block-order copolymerization; Mg(BHT).sub.2 (THF).sub.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); VL, -valerolactone; mCL, -methyl--caprolactone; HL, -heptalactone; DL, -decalactone; pNL, -propargyl--nonalactone; pCL, -propargyl--caprolactone; SLs, -substituted -lactones; DSC, differential scanning calorimetry; BDM, 1,4-benzenedimethanol; CuAAC, copper-mediated azide-alkyne cycloaddition, DLP, continuous digital light processing.
Materials
[0141] All reagents were purchased from Sigma-Aldrich, with the exception of 2,6-di-tert-4-methylphenol, which was purchased from Acros. Mg(BHT).sub.2(THF).sub.2 was synthesized according to a previously reported procedure. See, Calabrese, J.; Cushing, M. A.; Ittel, S. D.; Sterically hindered magnesium aryloxides. Inorg. Chem. 1988, 27, 867-870, the disclosure of which is incorporated herein by reference in its entirety. -heptalactone, mCL, and -propargyl--nonalactone were synthesized using Baeyer-Villager oxidation reactions according to modified versions of previously reported procedures. See, van der Mee, L.; Helmich, F.; de Bruijn, R.; Vekemans, J. A. J. M., Palmans, A. R. A.; Meijer, E. W.; 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, S. F.; Silver-Free Activation of Ligated Gold(I) Chlorides: The Use of [Me.sub.3NB.sub.12Cl.sub.11].sup. as a Weakly Coordinating Anion in Homogeneous Gold Catalysis. Chem. Eur. J. 2015, 21, 1328-1336, the disclosure of which are incorporated by reference in their entirety. All solvents were purchased from Fisher and dried using an Innovative Technology Inc. Pure Solv MD-3 solvent purification system. Benzyl alcohol, propylene oxide, -valerolactone, -caprolactone, and -decalactone were dried over calcium hydride overnight prior to vacuum distillation. -pentadecalactone was dissolved in 75 wt. % toluene and dried over 3 molecular sieves. Maleic anhydride was sublimated and then dried in vacuo over P.sub.2O.sub.5 for 5 d. All other reagents were used as received.
Instrumental Methods
[0142] Proton (.sup.1H) NMR spectra were recorded using a Varian Mercury 300 spectrometer. Carbon (.sup.13C) NMR spectra were recorded using a Varian NMRS 500 spectrometer. All chemical shifts were recorded in parts per million (ppm) relative to the reference peak of chloroform solvent at =7.26 and 77.16 ppm for .sup.1H and .sup.13C NMR spectra, respectively. Molecular masses were determined through size exclusion chromatography (SEC) using a Tosoh EcoSEC HLC-8320GPC on TSKgel GMH.sub.HR-M columns in series with refractive index (RI) detection. Molecular masses were calculated using a calibration curve determined from polystyrene standards with tetrahydrofuran (THF) as the eluent flowing at 1.0 mL min.sup.1 and a sample concentration of 10 mg mL.sup.1. DSC heating and cooling curves were obtained using a TA Instruments DSC 2910. Heating and cooling curves were run in triplicate in series under a nitrogen atmosphere at a heating rate of 10 C. per min in a 40 L aluminum crucible. The stamp was printed using an Envisiontec Micro Plus Advantage continuous digital light processing (DLP) printer.
Example 1
Synthesis of -heptalactone and -methyl--caprolactone
[0143] A single neck round bottom flask containing 250 mL methylene chloride was cooled in an ice bath prior to addition of 223 mmol of either 2-methylcyclohexanone or 4-methylcyclohexanone and 275 mmol of m-chloroperoxybenzoic acid. After refluxing for 3 days, the reaction mixture was cooled in an ice bath and filtered over Celite and washed with 10% Na.sub.2S.sub.2O.sub.3 solution, saturated Na.sub.2CO.sub.3 solution, and brine. The organic layer was then dried with MgSO.sub.4 and filtered prior to removal of solvent via rotary evaporation. Both products were dried over calcium hydride overnight and distilled under vacuum prior to use.
[0144] -heptalactone:
[0145] The presence of -heptalactone was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =4.44 (m, CH.sub.2(CH.sub.3)O), 2.64 (m, C(O)CH.sub.2), 1.73 (m, CH.sub.2CH(CH.sub.3)), 1.42 (m, CH.sub.2CH.sub.2CH(CH.sub.3)).
[0146] -Methyl--Caprolactone:
[0147] The presence of -methyl--caprolactone was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =4.23 (m, CH.sub.2O), 2.75 (m, C(O)CH.sub.2), 1.73 (m, CH.sub.2CH(CH.sub.3)), 1.40 (m, CH.sub.2CH(CH.sub.3)), 0.96 (m, CH.sub.2CH(CH.sub.3)).
Example 2
Synthesis of -propargyl--nonalactone
[0148] 30.0 mL cyclohexanone (28.4 g, 289 mmol), 28.5 mL pyrrolidine (24.7 g, 347 mmol), and 55.0 mg p-toluenesulfonic acid monohydrate (0.289 mmol) were dissolved in 60 mL toluene in a round bottom flask equipped with a Dean-Stark apparatus and reflux condenser. The solution was stirred at 150 C. for 16 h. The resulting solution was washed cooled to room temperature and washed with water and brine prior to drying with MgSO.sub.4 and solvent removal under reduced pressure. The product was purified by fractional distillation under vacuum (31.4 g, b.p. 107-114 C.) to give a pale yellow oil. This was dissolved in dry MeCN in a two neck round bottom flask then equipped with a reflux condenser prior to drop wide addition of 26.8 mL propargyl bromide (80% in toluene, 37.0 g, 249 mmol) was then added drop-wise to the solution. The reaction was stirred under reflux over night then cooled to room temperature prior to removal of solvent under reduced pressure. 220 mL deionized water was added to the residue and the solution stirred under reflux for 1 h. The product was extracted with Et.sub.2O then washed with brine and dried over MgSO.sub.4. Fractional distillation under vacuum yielded an isomeric mixture of -propargyl--nonalactone and -propargyl--caprolactone as a colorless oil (12.9 g, 94.7 mmol, b.p. 93-95 C./16 mbar). 160 mL of methylene chloride was cooled in an ice bath prior to addition of the -propargyl--nonalactone and -propargyl--caprolactone mixture (12.9 g, 94.7 mmol) and m-chloroperoxybenzoic acid (24.5 g, 142.1 mmol). The reaction mixture was refluxed for 48 h and filtered after cooling to room temperature. The product was washed with a concentrated aqueous sodium sulfite solution and dried over MgSO.sub.4 prior to removal of solvent using rotary evaporation. The final product was dried over calcium hydride overnight and distilled under vacuum before use. (See
Example 3
Synthesis of magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg(BHT).SUB.2.(THF).SUB.2
[0149] Using standard Schlenk line techniques, a schlenk was filled with 2,6-di-tert-butyl-4-methylphenol (BHT) (6.66 g, 30 mmol) and dissolved into dry toluene (30 ml) added by cannula transfer. Di-n-butylmagnesium (1M in hexane, 15 ml, 15 mmol) was added dropwise to the reaction with stirring. The reaction was stirred for a further 2 hours followed by removing solvent. Hexanes (12.5 ml) were added to the reaction vessel followed by addition of tetrahydrofuran (THF) (2.5 ml). After stirring for 2 hours under N.sub.2, solvent can be removed, and final product was obtained as a solid (See, Scheme 11).
##STR00015##
Example 4
General Procedure for Sequential Polymerization
[0150] Using standard Schlenk line techniques, an ampoule is filled with a magnesium catalyst, such as Mg(BHT).sub.2(THF).sub.2, an initiating alcohol such as benzyl alcohol and a lactone, such as -caprolactone. The reagents were dissolved into toluene to a total monomer concentration of 2 M. The ampoule was sealed and heated at about 80 C. for about 24 h or until all of the lactone has reacted. A 2 M solution of propylene oxide and maleic anhydride dissolved in toluene is then added to the polymerization via cannula and heating is continued at about 80 C. for a further 120 h. The resultant poly(lactone-b-propylene maleate)polymer is then recovered by precipitation in excess diethyl ether.
Example 5
General Synthesis of Poly(Lactone-b-Propylene Maleate) Copolymers
[0151] Using standard glovebox techniques, an ampoule was filled with a 2 M solution of Mg(BHT).sub.2(THF).sub.2, benzyl alcohol, and a lactone monomer in toluene. The sealed ampoule was heated at 80 C. After a defined period of time a 2 M solution of propylene oxide and maleic anhydride in toluene was added to the reaction ampoule in a N.sub.2 environment. The resealed ampoule was heated back to 80 C. for 5 days. The resultant polymer was recovered by precipitation in hexanes. The specific reactions conditions for the various poly(lactone-b-propylene maleate) copolymers synthesized are set forth in Table 2, below.
TABLE-US-00002 TABLE 2 Mass Mass Lactone Moles Vol. of Moles of Moles Vol. of Moles of Moles Vol. monomer Time of initiator of catalyst of lactone of MAn of of PO Molar (L) (h) initator (mL) catalyst (g) lactone (mL) MAn (g) PO (mL) concentration VL 1 0.97 0.1 0.97 0.59 0.48 4.496 0.048 4.74 0.048 3.394 2 CL 1 5.375 HL 24 6.216 mCL 1 6.216 NL 24 6.765 DL 8 8.460 PDL 24 24.25* VL/CL 24 2.248/ 2.768 *PDL was made into a 2M solution in toluene prior to use. The volume shown is the volume of this solution used in the polymerization.
[0152] P(VL-b-PM):
[0153] The P(VL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.33 (m, Ar), 6.24 (m, OC(O)HCH(O)O), 5.24 (m, CH.sub.2CH(CH.sub.3)O), 5.10 (s, COOCH.sub.2Ar), 4.23 (m, PO CH.sub.2OCO), 4.06 (m, VL CH.sub.2OCO), 2.31 (s, VL CH.sub.2COO), 1.30 (m, PO CH.sub.2CH(CH.sub.3)O), 1.66 (all remaining hydrogens) ppm (See
[0154] P(HL-b-PM):
[0155] The P(HL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.32 (m, Ar), 6.23 (m, OC(O)HCH(O)O), 5.22 (m, CH.sub.2CH(CH.sub.3)O), 5.07 (s, COOCH.sub.2Ar), 4.85 (m, HL CH.sub.2OCO), 4.23 (m, PO CH.sub.2OCO), 2.23 (s, CH.sub.2COO), 1.16 (m, HL CH.sub.3), 1.63-1.22 (all remaining hydrogens) ppm (See
[0156] P(mCL-b-PM):
[0157] The P(mCL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.32 (m, Ar), 6.26 (m, OC(O)HCH(O)O), 5.26 (m, CH.sub.2CH(CH.sub.3)O), 5.11 (s, COOCH.sub.2Ar), 4.26 (m, PO CH.sub.2OCO), 4.10 (m, mCL CH.sub.2OC(O)), 2.29 (s, CH.sub.2COO), 1.16 (m, mCL CH(CH.sub.3)), 1.63-1.22 (all remaining hydrogens) ppm (See
[0158] P(pNL-b-PM):
[0159] The P(pNL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.34 (m, Ar), 6.85 (m, OC(O)HCH(O)O), 5.29 (m, CH.sub.2CH(CH.sub.3)O), 5.10 (s, COOCH.sub.2Ar), 4.92 (m, CH(CH.sub.2CCH)) 4.34 (m, PO CH.sub.2OCO), 4.05 (m, pCL, CH.sub.2OC(O)), 2.45 (m, CH.sub.2CCH), 2.34 (s, CH.sub.2COO), 2.01 (s, CCH), 1.65-1.39 (all remaining hydrogens) ppm; .sup.13C NMR (125 MHz, 303K, CDCl.sub.3): =174.12 (pCL*-pCL, OCOCH.sub.2), 173.42 (CL*-CL, OCOCH2), 172.87 (pNL*-pNL), 164.36 and 163.98 (MAn*-PO, OCOCH.sub.2), 133.99 and 133.75 (MAn*-PO, O(O)C*CHCH), 133.50 and 133.26 (MAn*-PO, O(O)C*CHCH), 81.21 (pCL and pNL, CH(CH.sub.2CCH.sub.3)), 78.57 (pNL, CH(CH.sub.2CCH.sub.3)), 71.25 (pCL, OC(O)C), 70.53 (CL, OC(O)C), 70.07 (pCL and CL, COC(O)), 69.22 (MAn*-PO, OCH(CH.sub.3)CH.sub.2), 67.89 (pCL and pNL, CH(CH.sub.2CCH.sub.3)), 66.57 (MAn*-PO, OCH(CH.sub.3)CH.sub.2), 16.33 (PO, CH.sub.2CH(CH.sub.3)O), 36.42-21.08 (all remaining carbons) ppm; and SEC (THF): M.sub.n=7.4 kDa, M.=14.6 kDa, .sub.M=1.97. Yield: 86%.
[0160] P(DL-b-PM):
[0161] The P(DL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.33 (m, Ar), 6.25 (m, OC(O)HCH(O)O), 5.25 (m, CH.sub.2CH(CH.sub.3)O), 5.09 (s, COOCH.sub.2Ar), 4.84 (m, DL CH.sub.2OCO), 4.24 (m, PO CH.sub.2OCO), 2.26 (s, CH.sub.2COO), 0.87 (m, DL CH.sub.3(CH.sub.2).sub.3), 1.65-1.20 (all remaining hydrogens) ppm (See
[0162] P(PDL-b-PM):
[0163] The P(PDL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.32 (m, Ar), 6.24 (m, OC(O)HCH(O)O), 5.23 (m, CH.sub.2CH(CH.sub.3)O), 5.08 (s, COOCH.sub.2Ar), 4.23 (m, PO CH.sub.2OCO), 4.02 (m, PDL CH.sub.2OCO), 2.25 (s, PDL CH.sub.2COO), 1.60-1.23 (all remaining hydrogens) ppm (See
[0164] P(VL-co-CL-b-PM):
[0165] The P(L-co-CL-b-PM) polymer was produced as set forth above and characterized by: .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.32 (m, Ar), 6.24 (m, OC(O)HCH(O)O), 5.21 (m, CH.sub.2CH(CH.sub.3)O), 5.08 (s, COOCH.sub.2Ar), 4.26 (m, PO CH.sub.2OCO), 4.03 (m, CH.sub.2OCO), 2.28 (s, CH.sub.2COO), 1.65-1.28 (all remaining hydrogens) ppm (See
Example 6
Synthesis of Poly(-Valerolactone-b-Propylene Maleate)
[0166] Poly(-valerolactone-b-propylene maleate) was synthesized using the general method set forth in Example 4 using -valerolactone as shown in Scheme 12, below and the using reaction parameters shown in Table 3, below.
##STR00016##
TABLE-US-00003 TABLE 3 mol. mol. mol. T Time Time M.sub.n, NMR M.sub.n, GPC Initiator eq. VL eq. PO eq. MA ( C.) 1 (h) 2 (h) (kDa) (kDa) .sub.M BnOH 50 50 50 80 24 120 8.5 6.5 1.90
[0167] The presence of a Poly(-valerolactone-b-propylene maleate) product was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.33 (m, Ar), 6.24 (m, OC(O)HCH(O)O), 5.24 (m, CH.sub.2CH(CH.sub.3)O), 5.10 (s, COOCH.sub.2Ar), 4.23 (m, PO CH.sub.2OCO), 4.06 (m, VL CH.sub.2OCO), 2.31 (s, VL CH.sub.2COO), 1.30 (m, PO CH.sub.2CH(CH.sub.3)O), 1.66 (all remaining hydrogens) ppm (see,
Example 7
Synthesis of Poly(-Caprolactone-b-Propylene Maleate)
[0168] Poly(-caprolactone-b-propylene maleate) was synthesized using the general method set forth in Example 4 using -caprolactone as shown in Scheme 13, below and the using reaction parameters shown in Table 4, below.
##STR00017##
TABLE-US-00004 TABLE 4 mol. mol. mol. T Time Time M.sub.n, NMR M.sub.n, GPC Initiator eq. CL eq. PO eq. MA ( C.) 1 (h) 2 (h) (kDa) (kDa) .sub.M BnOH 25 25 25 80 24 120 8.8 12.5 1.24
[0169] The presence of a poly(-caprolactone-b-propylene maleate) product was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.29 (m, Ar), 6.22 (m, OC(O)HCH(O)O), 5.19 (m, CH.sub.2CH(CH.sub.3)O), 5.06 (s, COOCH.sub.2Ar), 4.20 (m, CH.sub.2OCO), 2.25 (s, CL CH.sub.2COO), 1.26 (m, CH.sub.2CH(CH.sub.3)O), 1.60 and 1.33 (all remaining hydrogens) ppm (see,
Example 8
Synthesis of Poly(-Caprolactone-b-Propylene Maleate)
[0170] Using standard Schlenk line techniques, an ampoule was filled with Mg(BHT).sub.2(THF).sub.2 (586.8 mg, 0.97 mmol), benzyl alcohol (0.1 mL, 0.97 mmol) and -caprolactone (5.35 mL, 48.3 mmol). The reagents were dissolved into toluene to a total monomer concentration of 2 M. The ampoule was sealed and heated at 80 C. for 24 h. 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 polymerization via cannula and heating continued at 80 C. for a further 120 h. The resultant polymer was recovered by precipitation in excess diethyl ether.
Example 9
Synthesis of Poly(-Heptalactone-b-Propylene Maleate)
[0171] Poly(-heptalactone-b-propylene maleate) was synthesized using the method set forth in Example 4 using -heptalactone as shown in Scheme 14, below and the using reaction parameters shown in Table 5, below.
##STR00018##
TABLE-US-00005 TABLE 5 mol. mol. mol. T Time Time M.sub.n, NMR M.sub.n, GPC Initiator eq. HL eq. PO eq. MA ( C.) 1 (h) 2 (h) (kDa) (kDa) .sub.M BnOH 50 50 50 80 24 120 9.6 13.5 1.27
[0172] The presence of a poly(-heptalactone-b-propylene maleate) product was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.32 (m, Ar), 6.23 (m, OC(O)HCH(O)O), 5.22 (m, CH.sub.2CH(CH.sub.3)O), 5.07 (s, COOCH.sub.2Ar), 4.85 (m, HL CH.sub.2OCO), 4.23 (m, PO CH.sub.2OCO), 2.23 (s, CH.sub.2COO), 1.16 (m, HL CH.sub.3), 1.63-1.22 (all remaining hydrogens) ppm (see,
Example 10
Synthesis of Poly(-Decalactone-b-Propylene Maleate)
[0173] Poly(-decalactone-b-propylene maleate) was synthesized using the method set forth in Example 4 using -decalactone as shown in Scheme 15, below and the using reaction parameters shown in Table 6, below.
##STR00019##
TABLE-US-00006 TABLE 6 mol. mol. mol. T Time Time M.sub.n, NMR M.sub.n, GPC Initiator eq. DL eq. PO eq. MA ( C.) 1 (h) 2 (h) (kDa) (kDa) .sub.M BnOH 50 50 50 80 24 120 10.7 10.8 2.10
[0174] The presence of a Poly(-decalactone-b-propylene maleate) product was confirmed by .sup.1H NMR (300 MHz, 303 K, CDCl.sub.3): =7.33 (m, Ar), 6.25 (m, OC(O)HCH(O)O), 5.25 (m, CH.sub.2CH(CH.sub.3)O), 5.09 (s, COOCH.sub.2Ar), 4.84 (m, DL CH.sub.2OCO), 4.24 (m, PO CH.sub.2OCO), 2.26 (s, CH.sub.2COO), 0.87 (m, DL CH.sub.3(CH.sub.2).sub.3), 1.65-1.20 (all remaining hydrogens) ppm (see,
Example 11
General Procedure for the Isomerization of Poly(Lactone-b-Propylene Maleate)
[0175] Poly(-caprolactone)-b-(propylene maleate) (1.0 g, 12 mol. eq. olefin) was dissolved into chloroform (50 mL) and diethylamine (0.01 mL, 0.15 mol. eq. olefin) was added. The solution was refluxed for 24 h under a nitrogen atmosphere. After cooling to room temperature, the organic solution was washed with a 0.5 M phosphate buffer solution (150 mL, pH=6) prior to removal of solvent via rotary evaporation.
[0176] In light of the foregoing, it should be appreciated that the present invention significantly advances the art by providing a poly(lactone-b-propylene fumarate) block copolymer that is structurally and functionally improved in a number of ways. While particular embodiments of the invention have been disclosed in detail herein, it should be appreciated that the invention is not limited thereto or thereby inasmuch as variations on the invention herein will be readily appreciated by those of ordinary skill in the art. The scope of the invention shall be appreciated from the claims that follow.