U.S. patent application number 13/812604 was filed with the patent office on 2013-07-18 for functional biodegradable polymers.
This patent application is currently assigned to THE UNIVERSITY OF AKRON. The applicant listed for this patent is Abhishek Banerjee, Coleen Pugh, William Storms, Colin Wright. Invention is credited to Abhishek Banerjee, Coleen Pugh, William Storms, Colin Wright.
Application Number | 20130184429 13/812604 |
Document ID | / |
Family ID | 45530418 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130184429 |
Kind Code |
A1 |
Pugh; Coleen ; et
al. |
July 18, 2013 |
FUNCTIONAL BIODEGRADABLE POLYMERS
Abstract
Biodegradable polyesters are made by synthesizing copolymers
derived from biodegradable hydroxyacid monomers as well as from
hydroxyacid monomers containing a functional group such as an azide
group, a halogen group, a thioacetate group, and the like.
Preferably, the functionalized biodegradable polyester copolymers
are derived from a functionalized hydroxyacid such as a homolog of
lactic acid and/or glycolic acid with the copolyester thus
containing functional groups on the backbone thereof. These
biodegradable polyesters can be utilized wherever biodegradable
polyesters are currently used, and also serve as a polymer to which
various medical and drug delivery systems can be attached.
Inventors: |
Pugh; Coleen; (Akron,
OH) ; Banerjee; Abhishek; (Akron, OH) ;
Storms; William; (Akron, OH) ; Wright; Colin;
(Cuyahoga Falls, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pugh; Coleen
Banerjee; Abhishek
Storms; William
Wright; Colin |
Akron
Akron
Akron
Cuyahoga Falls |
OH
OH
OH
OH |
US
US
US
US |
|
|
Assignee: |
THE UNIVERSITY OF AKRON
Akron
OH
|
Family ID: |
45530418 |
Appl. No.: |
13/812604 |
Filed: |
July 28, 2011 |
PCT Filed: |
July 28, 2011 |
PCT NO: |
PCT/US11/01333 |
371 Date: |
March 8, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61368413 |
Jul 28, 2010 |
|
|
|
Current U.S.
Class: |
528/274 ;
528/302 |
Current CPC
Class: |
C08G 2230/00 20130101;
C08G 63/6822 20130101; C08G 63/06 20130101; C08G 63/914 20130101;
C08G 63/60 20130101; C08G 63/912 20130101 |
Class at
Publication: |
528/274 ;
528/302 |
International
Class: |
C08G 63/06 20060101
C08G063/06 |
Goverment Interests
GOVERNMENT RIGHTS
[0002] The Government may have certain rights in this invention
under National Science Foundation Contract No. DMR-0830301 and/or
under National Health Institute Contract No. ARRA Supplement for
Parent Grant 5RO1 GM86895-2.
Claims
1. A functionalized biodegradable copolyester, comprising; repeat
units derived from one or more diols containing from 2 to about 10
carbon atoms and one or more dicarboxylic acids containing from 2
to about 15 carbon atoms, or repeat units derived from one or more
hydroxyacids containing from 2 to about 20 carbon atoms, or both;
repeat units derived from one or more functionalized hydroxyacids;
and wherein said copolyester is a random, statistical copolymer and
is biodegradable.
2. The functionalized biodegradable copolyester of claim 1, wherein
the amount of said functionalized repeat units is from about 10 to
about 99 mole %; and wherein said hydroxyacid comprises glycolic
acid, galactaric acid, hydroxypropionic acid, lactic acid,
hydroxybutyric acid, hydroxyisobutyric acid, hydroxy methylbutyric
acid, bis(hydroxymethyl)propionic acid, gibberellic acid,
hydroxyoctadecanoic acid, di-tert-butyl hydroxybenzoic acid,
benzilic acid, hydroxyl fluorenecarboxylic acid, hydroxydecanoic
acid, hydroxynaphthalenecarboxylic acid, hydroxybenzenedicarboxylic
acid, hydroxymethylbenzoic acid, hydroxyphenylacetic acid, mandelic
acid, hydroxymethoxybenzoic acid, methoxysalicylic acid,
hydroxyoctanoic acid, hydroxycinnamic acid, dihydroxycinnamic acid,
dihydroxyhydrocinnamic acid, hydroxyphenylpropionic acid,
dihydroxytartaric acid, hydroxymethoxycinnamic acid, salicylic
acid, citrazinic acid, galacturonic acid, glucuronic acid,
hydroxypropanedioic acid, hydroxyphenyl propionic acid,
methoxysalicylic acid, tartaric acid, or trihydroxybenzoic acid, or
any combination thereof.
3. The functionalized biodegradable copolyester of claim 2, wherein
said functionalized hydroxyacid is HHPPA, chlorohydroxybenzoic
acid, chloromandelic acid, chlorosalicylic acid, dibromo
hydroxybenzoic acid, dichlorohydroxy benzoic acid,
dichlorosalicyclic acid, a hydroxyacid containing a halogen group
other than said preceding acids, a hydroxyacid containing an azide
group, or a hydroxyacid containing a thioacetate group, or any
combination thereof.
4. The functionalized biodegradable copolyester of claim 3, wherein
the amount of said functionalized repeat units is from about 30 to
about 80 mole %; wherein the number average molecular weight of
said copolyester is from about 2,000 to 40,000 Da; and wherein said
functionalized group is said halogen, said azide, or said
thioacetate.
5. The functionalized biodegradable copolyester of claim 4,
including repeat units derived from said lactic acid, or said
glycolic acid, or both.
6. The functionalized biodegradable copolyester of claim 5, wherein
said number average molecular weight of said copolyester is from
about 6,000 to about 25,000 Da; and wherein said functional group
exists on the backbone of said copolyester.
7. The functionalized biodegradable copolyester of claim 6, wherein
the amount of said functionalized monomer is from about 35 to about
50 mole %; including said repeat units derived from said lactic
acid and including said repeat units derived from said glycolic
acid, and wherein the amount of said lactic acid and said glycolic
repeat units is from about 20 to about 80 mole % based upon the
total number of said lactic acid and said glycolic acid repeat
units.
8. A process for synthesizing a functionalized biodegradable
copolyester comprising the steps of: reacting one or more diols
containing from 2 to about 10 carbon atoms with one or more
dicarboxylic acids containing from 2 to about 15 carbon atoms, or
reacting one or more hydroxyacids containing from 2 to about 20
carbon atoms, or both; with one or more functionalized hydroxyacids
at low pressure and elevated temperature in the presence of a
protonic acid catalyst or a Lewis acid catalyst.
9. The process of claim 8, wherein said pressure is about 50 mm Hg
or less; wherein said temperature is from about 50.degree. C. to
about 180.degree. C; and wherein said hydroxyacid comprises
glycolic acid, galactaric acid, hydroxypropionic acid, lactic acid,
hydroxybutyric acid, hydroxyisobutyric acid, hydroxy methylbutyric
acid, bis(hydroxymethyl)propionic acid, gibberellic acid,
hydroxyoctadecanoic acid, di-tert-butyl hydroxybenzoic acid,
benzilic acid, hydroxyl fluorenecarboxylic acid, hydroxydecanoic
acid, hydroxynaphthalenecarboxylic acid, hydroxybenzenedicarboxylic
acid, hydroxymethylbenzoic acid, hydroxyphenylacetic acid, mandelic
acid, hydroxymethoxybenzoic acid, methoxy salicylic acid,
hydroxyoctanoic acid, hydroxycinnamic acid, dihydroxycinnamic acid,
dihydroxyhydrocinnamic acid, hydroxyphenylpropionic acid,
dihydroxytartaric acid, hydroxymethoxycinnamic acid, salicylic
acid, citrazinic acid, galacturonic acid, glucuronic acid,
hydroxypropanedioic acid, hydroxyphenyl propionic acid, methoxy
salicylic acid, tartaric acid or trihydroxybenzoic acid or any
combination thereof.
10. The process of claim 9, wherein the amount of said
functionalized hydroxyacid is from about 30 to about 80 mole %
based upon the total number of moles of said one or more
functionalized hydroxyacids and said one or more non-functionalized
hydroxyacids; and wherein the number average molecular weight of
said functionalized biodegradable copolyester is from about 2,000
Da to about 40,000 Da.
11. The process of claim 10, wherein said pressure is about 10 mm
Hg or less; and wherein said functionalized hydroxyacid is HHPPA,
chlorohydroxybenzoic acid, chloromandelic acid, chlorosalicylic
acid, dibromo hydroxybenzoic acid, dichlorohydroxy benzoic acid,
dichlorosalicyclic acid, a hydroxyacid containing a halogen group
other than said preceding acids, a hydroxyacid containing an azide
group, or a hydroxyacid containing a thioacetate group, or any
combination thereof.
12. The process of claim 11, wherein said catalyst comprises
p-dimethylaminopyridinium toluenesulphonate (DPTS), p-toluidine
hydrochloride, dimethyl-p-phenylenediamine dihydrochloride,
p-toluenesulphonic acid, or SnCl.sub.2, or any combination
thereof.
13. The process of claim 12, wherein the amount of said one or more
functionalized hydroxyacids are from about 35 to about 50 mole %;
including said repeat units derived from said lactic acid or
including said repeat units derived from said glycolic acid, or
both, and wherein the amount of said lactic acid repeat units is
from about 20 to about 80 mole % based upon the total number of
said lactic acid and said glycolic acid repeat units; and wherein
catalyst is p-toluene sulphonic acid.
14. The process of claim 8, including further reacting said
biodegradable functionalized copolyester with a linking agent and a
protonic catalyst or a Lewis acid catalyst at ambient
temperature.
15. The process of claim 11, including further reacting said
biodegradable functionalized copolyester with a linking agent and a
protonic catalyst or a Lewis acid catalyst at ambient temperature.
Description
CROSS REFERENCE
[0001] This patent application claims the benefit and priority of
U.S. provisional application 61/368,413, filed Jul. 28, 2010 for
FUNCTIONAL BIODEGRADABLE POLYMERS, which is hereby fully
incorporated by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to biodegradable polyester
polymers or copolymers containing functionalities on their backbone
that are capable of being covalently attached to compounds such as
drugs or other therapeutic molecules for making drug delivery
medications, or other small molecules of interest. More
specifically, the invention relates to forming functionalized
biodegradable polyesters or copolyesters derived from biodegradable
hydroxyacid monomers and functional monomers.
BACKGROUND OF THE INVENTION
[0004] Traditional biodegradable polymers, like poly(lactic acid)
(PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA), see
FIG. 1, do not have functionalities on their backbones. Such
biodegradable polymer systems are therefore not able to covalently
attach drugs or other therapeutic molecules for making drug
delivery devices, or other functional molecules for a variety of
applications. Instead, the functional molecules, such as
therapeutic agents have to be physically entrapped into these
polymers, either by forming micelles or by nano-encapsulation.
[0005] Recently, much attention has focused on the development of
degradable and bioabsorbable polymers for biomaterials, and
disposable or non-recoverable polymer goods applications.
Biodegradable plastics we able to replace non-biodegradable
polymers like polystyrene and poly(ethylene terephthalate) (PET) in
a variety of applications. For example, Cargill Dow LLC under the
trade name Nature Works is using PLA to make biodegradable products
like dairy containers, food trays, cold drink cups, products for
packaging applications, bottles for fruit juices, sport drinks and
jams and jellies; poly(butylene succinate) is being used in
agricultural applications in the form of mulch films, bags for
seedlings and replanting pots; poly(butylene succinate) is also
being used for manufacturing packaging films, bags and flushable
feminine hygiene products because of its excellent mechanical
properties. Traditional biodegradable polymers have included
polyamides, polyanhydrides, polycarbonates, polyesters,
polyesteramides, and polyurethanes, which incorporate a degradable
linkage into the backbone that can be cleaved by hydrolytic,
enzymatic and oxidative processes. Of these, aliphatic polyesters,
specifically poly(lactic acid) (PLA), poly(lactic-co-glycolic acid)
(PLEA) and poly(.epsilon.-caprolactone) (PCL), have become the most
widespread biomedical soft materials, finding use in drug and gene
delivery, sutures, stents, dental implants and as tissue
engineering scaffolding. Aliphatic polyesters have found success
due to their ease of preparation, good mechanical properties and
relatively quick in vivo degradation to small molecules easily
absorbed or excreted by the body. However, PLA, PLGA and PCL lack
pendant functional groups, which is a major limitation for a large
number of applications. Pendant functionality is highly desirable
for the fine-tuning of properties such as rate of crystallization,
fire retardancy, color, hydrophobicity, bioadhesion,
biodegradability and the loading of therapeutics. Because of this,
it is of great importance that an efficient route to main-chain
functionalization of aliphatic polyesters and their random, graft,
or block copolymers be found.
[0006] Polyesters are generally prepared by polycondensation of
diols with diacids (A-A monomers+B-B monomers), self-condensation
of hydroxyacids (A-B monomers), or by ring-opening polymerization
of lactones. However, many useful functional groups, e.g. hydroxyl
thiol, amine and carboxylic acid, are incompatible with these types
of polymerization as they form cross-links, eliminating the
functionality. Protecting group chemistry, chemoselective
step-growth polymerization and ring-opening polymerization of
monomers with non-reactive functional groups have all been used to
address this problem to varying degrees of success to prepare
polyesters with hydroxyl, thiol, ketone, halogen, azido, alkyne and
poly(ethylene glycol) (PEG) pendant groups. However, no highly
versatile and general strategy for functionalizing aliphatic
polyesters has yet been developed.
[0007] 2-Halo-3-hydroxypropionic acid (HHPA) is a halogenated
constitutional isomer (C.sub.3H.sub.5XO.sub.3) of LA
(C.sub.3H.sub.6O.sub.3), with a primary alcohol like GA
(C.sub.2H.sub.4O.sub.3), and is therefore an ideal co-monomer for
incorporation of .alpha.-halo ester functionality into PLGA, PLA,
PGA and/or their copolymers with other classes of polymers,
including both condensation and addition polymers. Such polyesters
are potentially biodegradable, and can be further functionalized
post-polymerization, via nucleophilic substitution, radical
addition, radical-radical coupling and/or electrophilic
substitution.
[0008] .alpha.-Halo are activated to nucleophilic attack by three
mechanisms: inductive electron withdrawal by the adjacent carbonyl,
reduced steric bulk at the .sigma.* orbital of the carbon-halogen
bond due to the adjacent carbonyl and through-space electron
donation from the .sigma.-orbital of the carbon-halogen bond to the
.pi.* orbital of the carbonyl. Because of this activation,
.alpha.-halo esters undergo nucleophilic substitution by a number
of hard (e.g. alcohol, alkoxide, carboxylate and primary amine),
soft (e.g. cyanide, iodide, thio and thioalkoxide) and borderline
hard/soft nucleophiles (e.g. azide, nitroxide and pyridine) under
mild conditions. The major hurdle to this type of reaction is chain
scission due to attack at the carbonyl or .alpha.-elimination. For
these reasons, very reactive/hard nucleophiles such as alkoxide or
carbanions may not be suitable for this type of reaction.
[0009] .alpha.-Halo esters participate in electrophilic
substitution reactions via lithium metalation, Grignard and
Reformatsky chemistries. Of these, Reformatsky reactions are the
most mild and therefore, potentially of the most useful. The
classical Reformatsky reaction involves the coupling of an
.alpha.-haloester with an electrophile, via a zinc enolate
intermediate. First, zinc reacts with an .alpha.-haloester, by
insertion into the carbon-halogen bond, to form an enolate. This
enolate is then reacted with an electrophile, traditionally an
aldehyde or ketone but also an anhydride, phosphonate or
.alpha.,.beta.-unsaturated carbonyl.
[0010] .alpha.-Halo esters participate in radical reactions due to
the weakness of the carbon-halogen bond, which undergoes homolytic
cleavage under redox conditions to form a carbon centered radical.
Curran et al. [Synthesis 1988, 489-513] and Matyjaszewski et. al.
have shown that .alpha.-halo esters can add across the double bond
of an olefin in atom transfer radical coupling and polymerization
reactions, respectively. Depending on the structure of the olefin
this can impart new functional groups onto the polymer. Jerome et.
al. have used ring-opening of .alpha.-chloro lactones to prepare
chloro functional polyesters. They further derivatized these
polyesters by coupling with 3-butenyl benzoate to demonstrate
radical coupling and using them as macroinitiators for the atom
transfer radical polymerization (ATRP) of methacylate to prepare
graft copolymers. Depending on the location of the .alpha.-halogen
the architecture of the system can be controlled. If the halogen is
spread throughout the polymer backbone, grafting-to or
grafting-from structures can be made. If the halogen is at the
chain end then block copolymers can be readily made.
SUMMARY OF THE INVENTION
[0011] Biodegradable polyesters containing functional groups on
their, backbone are generally prepared by two different routes. One
route relates to the co-polyesterification of various hydroxyacid
monomers and other monomers containing functional groups therein
via a two-step route initially utilizing high temperature, low
pressure and a catalyst and subsequently a linking agent, a
different catalyst and ambient temperatures. The second route
relates to a co-polyesterification of various hydroxyacid monomers
and the functionalized monomers in the presence of an acid
catalyst, high temperatures, and low pressures.
[0012] The use of 2-halo-3-hydroxypropionic acid as a co-monomer
with a diol plus diacid system or a hydroxyacid, preferably GA
and/or LA, incorporates halogen functionality therein and produces
high molecular weight halogenated polyesters, by direct
polycondesation. The co-polycondensation is acid catalyzed and
driven by high temperature, e.g. from about 50.degree. C. to about
180.degree. C., and preferably from about 90.degree. C. to about
110.degree. C., and vacuum, e, g, from about 0 mm Hg to about 50 mm
Hg and preferably from about 0 mm Hg to about 3 mm Hg. A small
amount of high boiling solvent, preferably diphenylether (DPE) is
used to plasticize the bulk. Copolymers with various compositions
of LA, GA and 2-bromo-3-hydroxypropionic acid (BHPA) were prepared
with number-average molecular weights of 2,000 to 40,000 Da
relative to polystyrene (Da.sub.PSt), preferably about 8,000 to
about 20,000 Da.sub.PSt (FIG. 5, FIG. 9, Table 1). To investigate
potential reactions to functionalize the brominated polyester, a
small molecule model compound, methyl 3-acetoxy-2-bromopropanoate
(MABP), was synthesized and derivatized by nucleophilic
substitution with sodium azide, sodium iodide and sodium
thioacetate. Adapting from these conditions, the brominated
polyester was functionalized into azido, iodo and thioester derived
polyesters (FIG. 10). Further functionalization reactions were
performed on the iodinated polyester.
[0013] In one aspect of the invention, a functionalized
biodegradable copolyester is disclosed, comprising repeat units
derived from one or more diode containing from 2 to about 10 carbon
atoms and one or more dicarboxylic acids containing from 2 to about
15 carbon atoms, or repeat units derived from one or more
hydroxyacids containing from 2 to about 20 carbon atoms, or both;
repeat units derived from one or more functionalized hydroxyacids;
and wherein said copolyester is a random, statistical copolymer and
is biodegradable.
[0014] In another aspect of the invention, a process for
synthesizing a functionalized biodegradable copolyester is
disclosed comprising the steps of reacting one or more diols
containing from 2 to about 10 carbon atoms with 1 one or more
dicarboxylic acids containing from 2 to about 15 carbon atoms, or
reacting one or more hydroxyacids containing from 2 to about 20
carbon atoms, or both; with one or more functionalized hydroxyacids
at low pressure and elevated temperature in the presence of a
protonic acid catalyst or a Lewis acid catalyst.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 illustrates poly(lactic acid-co-glycolic acid)
copolymer;
[0016] FIG. 2 illustrates 2-halo-3-hydroxypropionic acid
(HHPPA);
[0017] FIG. 3 illustrates synthesis of 2-halo-3-hydroxypropionic
acid from DL-Serine;
[0018] FIG. 4 illustrates direct polycondensation of
2-halo-hydroxypropionic acid;
[0019] FIG: 5 illustrates co-polyesterification of
2-bromo-3-hydroxypropionic acid glycolic acid and/or lactice acid
via a multi-step process;
[0020] FIG. 6 illustrates N,N'-Diisopropylcarbodiimide;
[0021] FIG. 7 illustrates 4-(dimethylamino)pyridinium
4-toluenesulphonate
[0022] FIG. 8 illustrates N,N'-Diisopropylurea;
[0023] FIG. 9 illustrates direct polycondensation of glycolic acid,
lactic acid and 2-halo-3-hydroxypropionic acid;
[0024] FIG. 10 illustrates iodide, azide and thioacetate
functionalization reactions on the model small molecule; and
[0025] FIG. 11 illustrates a reaction of a rearranged copolyester
with sodium azide and with a thioacetate.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The invention is initially described with respect to
specific monomers and reaction conditions and then subsequently
with regard to overall reaction conditions and compounds.
[0027] Biodegradable polyesters are made by synthesizing copolymers
derived from biodegradable hydroxyacid monomers as well as from
hydroxyacid monomers containing a functional group such as an azide
group, a halogen group, a thioacetate group, and the like.
Alternatively, or in addition thereto, biodegradable polyesters can
be made from various diols having from 2 to about 10 carbon atoms
and desirably from about 2 to about 3 carbon atoms and dicarboxylic
acids having from about 2 to about 15 carbon atoms, desirably from
about 2 to about 10 carbon atoms and preferably from about 2 to
about 8 carbon atoms. Preferably, the functionalized biodegradable
polyester copolymers are derived from a functionalized hydroxyacid
such as a homolog of lactic acid and/or glycolic acid with the
copolyester thus containing functional groups on the backbone
thereof. Synthesized 2-halo-3-hydroxypropionic acids can be
utilized as the key intermediate for the synthesis of
acrylate-based inimers that can be polymerized by atom transfer
radical polymerization or functionalized and polymerized by
reversible addition-fragmentation chain transfer (RAFT)
polymerization to produce hyperbranched polyacrylates,
2-Halo-3-hydroxypropionic acid is essentially a functionalized
constitutional isomer of lactic acid (LA), and can therefore be
used to synthesize halogenated poly(lactic acid), poly(glycolic
acid), poly(lactic-co-glycolic acid) (PLGA), and other halogenated
polyesters and condensation polymers in which the halogen can be
used as a backbone attachment site for a compound such as a drug,
therapeutic compound, antibody, peptide, nucleating agent, fire
retardant, or other molecule of interest to the biodegradable,
FDA-approved PLGA backbone. 2-Halo-3-hydroxypropionic acid (FIG. 2)
is synthesized by a deaminohalogenation reaction of D-, L- or
D,L-serine (FIG. 3). This monomer is a hydroxyacid, which can
self-condense under acidic conditions to form
oligo(halohydroxypropionic acid) (FIG. 4). This reaction is driven
by applying heat and vacuum, to produce oligomers of number average
molecular weight, M.sub.n.gtoreq.1,500 Da. By a polyesterification
reaction, the halohydroxypropionic acid monomer is also
copolymerized with lactic acid, glycolic acid and other
hydroxyacids to form random, statistical copolymers. This
polyesterification (FIG. 5) can be performed at high temperature
and low pressure with subsequent polymerization occurring with a
linking agent at room temperature under dry conditions using
dichloromethane as a solvent, diisopropylcarbodiimide (DiPC) (FIG.
5) as the linking agent and dimethylaminopyridinium
toluenesulphonate (DPTS) (FIG. 7) as the catalyst, After the
reaction, the byproduct, diisopropylurea (DiPU) (FIG. 8) and the
catalyst, DPTS, are washed out with a methanol/water mixture and
the polymer is precipitated out in isopropyl alcohol (IPA) or in
hexane/methanol (95%, 5%, v %, v %) mixture. Typical M.sub.n of
about 8,000-10,000 Da are obtained.
[0028] The co-polyesterification of the halohydroxypropionic acid
with lactic acid and glycolic acid can also be performed in bulk
using p-toluenesulphonic acid (PTSA) as a catalyst (FIG. 9). This
reaction is driven by applying heat and vacuum and a typical
M.sub.n of .gtoreq.5,000 Da is observed.
[0029] The functionalized 2-halo-3-hydroxypropionic acid (HHPPA) is
produced by reacting serine with an alkali nitrite such as sodium
nitrite in the presence of an aqueous acid, preferably hydrobromic
acid or hydrochloric acid, and potassium bromide or potassium
chloride initially at low temperatures such as from about minus
35.degree. C. to about 0.degree. C. and preferably from about minus
15.degree. C. to about minus 5.degree. C. for short periods of
time, such as from about 1 to about 6 hours and desirably from
about 1.5 to about 2.5 hours until the addition of HX/KX to serine
is complete. Subsequently, the reaction is continued at from about
5.degree. C. to about 60.degree. C., and desirably from about
15.degree. C. to about 40.degree. C., and most preferably from
about 20.degree. C. to about 30.degree. C. for about 1 to about 48
hours and desirably from about 5 to about 24 hours, and most
preferably from about 10 to about 14 hours to produce the
halogenated hydroxyacid, i.e. HHPPA. Other hydroxy-containing amino
acids such as tyrosine can also be used in this reaction.
[0030] HHPPA can be polymerized under high temperature and low
pressure in the presence of a catalyst to produce a polymer as set
forth in FIG. 4. That is, under acidic conditions as in the
presence in p-toluenesulfonic acid, SnCl.sub.2, or SnO, HHPPA can
self-condense at temperatures of from about 50.degree. C. to about
180.degree. C. and desirably from about 80.degree. C. to about
150.degree. C., and most preferably from about 90.degree. C. to
about 110.degree. C. at low pressures of from about 0 mm Hg to
about 50 mm Hg and desirably from about 0 mm Hg to about 10 mm Hg,
and most preferably from about 0 mm Hg to about 3 mm Hg in the
presence of an acid catalyst such as p-toluenesulfonic acid,
SnCl.sub.2, or SnO, and the like. The resulting polymer generally
has a number average molecular weight of at least about 2,000
desirably from about 6,000 to about30,000, and most preferably from
about 20,000 to about 25,000 Da.
[0031] HHPPA and other functional-containing hydroxyacid monomers
can be utilized to form biodegradable copolyesters by two different
routes, for example co-polyesterification or by bulk polymerization
of hydroxyacid monomers.
[0032] Examples of hydroxyacids that are nitrogen free, have a
total of from 2 to about 20 carbon atoms and desirably 2 or 3
carbon atoms and contain at least 1 hydroxyl group include glycolic
acid, galactaric acid, hydroxypropionic acid, lactic acid,
hydroxybutyric acid, hydroxyisobutyric acid, hydroxy methylbutyric
acid bis(hydroxymethyl)propionic acid, gibberellic acid,
hydnoxyactadecanoic acid, di-tert-butyl hydroxybenzoic acid,
benzilic acid, hydroxyl fluorenecarboxylic acid, hydroxydecanoic
add, hydroxynaphthalenecarboxylic acid, hydroxybenzenedicarboxylic
acid, hydroxymethylbenzoic acid, hydroxyphenylacetic acid, mandelic
acid, hydroxymethoxybenzoic acid, methoxysalicylic acid
hydroxyoctanoic acid, hydroxycinnamic acid, dihydroxycinnamic acid,
dihydroxyhydrocinnamic acid, hydroxyphenylpropionic acid,
dihydroxytartaric acid, hydroxymethoxycinnamic acid, salicylic
acid, citrazinic acid, galacturonic acid, glucuronic acid,
hydroxypropanedioic acid, hydroxyphenyl propionic acid, lactic
acid, methoxysalicylic acid, tartaric acid, or trihydroxybenzoic
acid, or any combination thereof. Lactic acid and glycolic acid are
preferred. The above hydroxyacids that can be functionalized can be
utilized, of course, as functionalized monomers. Examples of such
functionalized mononers include chlorohydroxybenzoic acid,
chloromandelic acid, chlorosalicylic acid, dibromo hydroxybenzoic
acid, dichlorohydroxy-benzoic acid, dichlorosalicylic acid, or any
combination thereof.
[0033] The HHPPA monomer and other functionalized acids can be
reacted with various functional groups such as a halogen, an azide,
a thioacetate, and the like in a manner well known to the art and
to the literature. Upon reaction of the functionalized hydroxyacid,
copolyesters are produced wherein a functional group is located on
the backbone of the polymer.
[0034] The multi-step polyesterification route as set forth in FIG.
5 produces a statistical copolymer. The initial step is carried out
at high temperatures, generally from about 50.degree. C. to about
180.degree. C., desirably from about 80.degree. C. to about
150.degree. C. and preferably from about 90.degree. C. to about
110.degree. C. Low pressures are utilized such as from about 0 mm
Hg to about 50 mm Hg, desirably from about 0 mm Hg to about 10 mm
Hg and preferably from about 0 mm Hg to about 3 mm Hg. Protonic or
Lewis acids are utilized with specific compounds including
p-dimethylaminopyridinium toluenesulphonate (DPTS), p-toluidine
hydrochloride, dimethyl-p-phenylenediamine dihydrochloride,
p-toluenesulphonic acid, and the like with p-toluenesulphonic acid
being preferred. The amount of catalysts is generally small and
ranges from about 0.01 equivalents to about 1.0 or to about 5
equivalents and desirably from about 0.03 equivalents to about 0.5
equivalents, and most preferably from about 0.05 equivalents to
about 0.1 equivalents based upon the total equivalents of all
hydroxyacid monomers. These reaction conditions generally produce a
prepolymer, see FIG. 5. The prepolymer generally has the number
average molecular weight of from about 2,000 Da to about 20,000 Da,
desirably from about 4,000 Da to about 10,000 Da, and preferably
from about 6,000 Da to about 9,000 Da. The reaction times will vary
from about 2 hours to 48 hours, desirably from about 8 hours to 24
hours, and preferably from about 12 hours to 18 hours.
[0035] A subsequent step utilizes various solvents that include
halogenated solvents such as dichloromethane and chloroform, polar
solvents such as N,N-dimethylformamide, ether solvents such as
tetrahydrofuran and aromatic solvents such as toluene, see FIG. 5.
Dichloromethane and tetrahydrofuran are preferred. Suitable amounts
of solvents are generally such that the various monomers can be
readily dissolved and generally involve concentrations of from
about 0.1 M to about 2 M and desirably from about 0.2 M to about
1.5 M, and most preferably from about 0.7 M to about 1 M.
[0036] Activating and dehydrating linking agents generally include
carbodiimides with specific examples including
diisopropylcarbodiimide, dicyclohexylcarbodiimide and
ethyl-3-(3-dimethylaminopropyl)carbodiimide. Suitable amounts of
linking agents generally range from about 0.5 equivalents to about
10 equivalents and desirably from about 1 equivalent to about 5
equivalents, and most preferably from about 1.1 equivalents to
about 1.5 equivalents based upon the total equivalents of the
prepolymer. The linking agents are added to the reaction at a
temperature from about 0.degree. C. to about 50.degree. C. and
desirably from about 0.degree. C. to about 25.degree. C. and most
preferably from about 0.degree. C. to about 5.degree. C. The
subsequent reaction is generally carried out at an ambient
temperature of from about 10.degree. C. to about 50.degree. C.,
desirably from about 15.degree. C. to about 35.degree. C., and
preferably from about 20.degree. C. to about 30.degree. C. for
about 0.5 hours to about 24 hours and desirably from about 4 hours
to about 7 hours. Catalysts for the subsequent reaction generally
include protonic and latent protonic acids with specific compounds
including p-dimethylaminopyridinium toluenesulphonate (DPTS),
p-toluidine hydrochloride, dimethyl-p-phenylenediamine
dihydrochloride, and the like with p-dimethylaminopyridinium
toluenesulphonate being preferred. The amount of catalysts is
generally small and ranges from about 0.01 equivalents to about 1.0
or to about 5 equivalents and desirably from about 0.03 equivalents
to about 0.5 equivalents, and most preferably from about 0.05
equivalents to about 0.1 equivalents.
[0037] The reaction times are generally for about 30 minutes to 24
hours and desirably from about 2 hours to 12 hours, and most
preferably from about 4 hours to 7 hours.
[0038] The resultant statistical polyester copolymer generally has
a number average molecular weight of from about 2,000 Da to about
40,000 Da, desirably from about 5,000 Da to about 32,000 Da, more
desirably from about 6,000 to about 25,000 Da, and preferably from
about 8,000 Da to about 20,000 Da. After the reaction, various
byproducts such as diisopropylurea and the catalyst are washed out
of the reaction medium by utilizing a mixture of water and alcohol
such as methanol with the polymer being subsequently precipitated
as by utilizing a different alcohol such as isopropyl alcohol. The
yield of the above described process is generally high, such as
from at least about 10 mole %, generally at least about 50 mole %,
and preferably at least about 90 mole % of all of said hydroxyacid
monomers and functionalized monomers being incorporated into a
polymer.
[0039] The functionalized biodegradable polyester copolymers
derived utilizing the esterification route set forth in FIG. 5 will
have repeat units generally in proportion to the amount of monomers
utilized, with the repeat units derived from the functionalized
hydroxyacids containing a functional group on the backbone thereof.
If a biodegradable polyester copolymer having high functionality is
desired, the amount of the one or more functionalized hydroxyacid,
e.g. "n" is generally from about 10 or about 20 to about 99 mole %,
desirably from about 30 to about 80 mole %, and most preferably
from about 35 to about 60 mole %, with the amount of the one or
more biodegradable monomers, e.g "l" and "m" being the difference.
When lactic acid and glycolic acid are used, the amount of the
lactic and glycolic acid units is from about 1 to about 97 mole %,
desirably from about 20 to about 80 mole %, and preferably from
about 40 to about 60 mole % based upon the total moles of said
lactic acid and said glycolic acid.
[0040] The alternate bulk polymerization, high temperature, acid
catalyst, low pressure route as set forth in FIG. 9 also produces a
random, statistical biodegradable polyester copolymer and only
requires a catalyst since, of course, solvents are not required.
The polymerization temperature is generally from about 50.degree.
C. to about 180.degree. C., desirably from about 80.degree. C. to
about 150.degree. C., and preferably from about 90.degree. C. to
about 110.degree. C. In order to remove water generated by the
reaction, a vacuum or low pressures are utilized such as from about
0 mm Hg to about 50 mm Hg, desirably from about 0 mm Hg to about 10
mm Hg, and preferably from about 0 mm Hg to about 3 mm Hg. Suitable
catalysts include various protonic and Lewis acids such as those
set forth herein above with para-toluenesulphonic acid and
SnCl.sub.2 being preferred. The amount of the catalyst is generally
from about 0.01 to about 1.0 or to about 5.0 equivalents, desirably
from about 0.03 to about 0.5 equivalents, and preferably from about
0.05 to about 0.1 equivalents based upon the total equivalents of
all hydroxyacid monomers. The molecular weight of this route is
generally the same as that of the multi-step reaction route of FIG.
5, and thus copolymers are produced generally having a number
average molecular weight of from around 2,000 Da to about 40,000
Da, desirably around 5,000 kDa to preferably 32,000 Da, and more
desirably from about 6,000 Da to about 25,000 Da, and most
preferably from about 8,000 kDa to about 20,000 kDa. The yield of
the above described process is generally high, such as from at
least about 10 mole %, generally at least about 50 mole %, and
preferably at least about 90 mole % of all of said hydroxyacid
monomers and functionalized monomers being incorporated into a
polymer. The reaction time is generally from about 2 hours to about
72 hours, desirably from about 24 hours to about 60 hours, and
preferably from about 36 hours to about 48 hours.
[0041] If desired, the various biodegradable copolyesters can
contain conventional additives in conventional amounts known to the
art and to the literature such as light stabilizers, pigments, heat
stabilizers, anti static agents, UV absorbers, antioxidants, and
the like, as well as various inorganic fillers such as calcium
carbonate, clay, silica, and the like.
[0042] The statistical random polyester copolymers as set forth in
FIGS. 5 and 9 generally contain a halogen group that is bromo. The
repeat unit containing the halogen is set forth on the left side of
FIG. 10. This repeat bromo group can be reacted by three different
routes to yield the same copolyester but wherein the bromo group is
an iodo group, an azide group, or a thioacetate group, see right
side of FIG. 10. For example, if the copolyester of either FIGS. 5
and 9 are desired to have a pendant iodo functional group thereon,
a copolymer can be reacted with an alkali metal iodate compound
with any group one metal iodide salt such as sodium iodide or
potassium iodide, under an inert gas such as nitrogen and argon,
from temperatures that range from -40.degree. C. to 60.degree. C.,
ideally from 25.degree. C. to 30.degree. C. The amount of azide
relative to the brominated repeat unit can range from 1 to 5 but
preferably from 1.5 to 2.5 equivalences.
[0043] Similarly, if the bromine group set forth in FIGS. 5 and 9
of the copolyester are desired to be replaced by an azide group,
the following reaction can be utilized. Any group with one metal
azide salt such as sodium azide or potassium azide, can be reacted
under an inert gas such as nitrogen and argon, from temperatures
that range from -40.degree. C. to 60.degree. C., ideally from
0.degree. C. to 25.degree. C. The amount of azide relative to the
brominated repeat unit can range from 0.5 to 1.5 equivalences but
ideally is 0.75 to 0.95 equivalence.
[0044] If the bromo group on the copolyester polymers of FIGS. 5
and 9 are desired to be replaced with a thioacetate group, the
following reaction can be utilized. With any group one metal
thioacetate salt such as sodium thioacetate or potassium
thioacetate can be reacted, under an inert gas such as nitrogen and
argon, from temperatures that range from -20.degree. C. to
70.degree. C., ideally from 0.degree. C. to 30.degree. C. The
amount of thioacetate relative to the brominated repeat unit can
range from 0.5 to 1.5 equivalences but ideally is 0.75 to 1.5
equivalences.
[0045] The polymer system of the present invention has the
advantage of a good leaving group (halogen) attached to the main
chain of the biodegradable polymer. As noted above, the number of
functional groups on the main chain of this biodegradable polymer
can be varied by varying the feed ratio of the functionalized
monomer such as 2-halo-3-hydroxypropionic acid monomer. The
biodegradability of the polymer can also be tailored by varying the
biomonomers such as lactic acid and glycolic acid feed ratios.
Based an the ability of n-butylamine and pyridine to displace
bromine from methyl 2-bromopropionate, and 4-amino-1-butanol and
5-amino-1-pentanol to displace the bromine end group from
poly(methyl acrylate) (PMA), without reaction at the ester groups,
functionalized PLGAs and other polyesters should be synthesized by
reaction with the amine group of bioactive molecules. An example of
potential application of this system is the covalent attachment of
silver N-heterocyclic carbene (NHC) complexes developed by Youngs,
et al, [Chem. Rev. 2005, 105, 3978-4008] at the halogen sites of
the poly(halohydroxypropionic acid-co-lactic acid-co-glycolic acid)
copolymer system. Previous NHCs have been shown to have
antibacterial properties, and covalently attaching them would
potentially give us a drug delivery device with slow release
antibacterial properties,
[0046] The reference will be better understood by reference to the
following examples which serve to illustrate, but not to limit the
present invention.
EXAMPLES
[0047] Materials. 18-Crown-6 (Janssen 99%), diphenyl ether (Acros,
99%), glycolic acid (TCl, 98.0%), hydrobromic acid (Fluka,48 w/w %
aq), D,L-lactic acid (Acros, 85%), potassium bromide (Acros, 98%),
potassium thioacetate (Acros, 98%), D,L-serine (Alfa Aesar, 99%,
sodium azide (Aldrich, 99%), sodium iodide (J. T. Baker), sodium
nitrite (Sigma-Aldrich, 99.5%), succinonitrile (Sigma Aldrich, 99%)
and p-toluenesutfonic acid monohydrate (pTSA; Aldrich, 98%) were
used as received. Acetyl chloride (98%, Sigma-Aldrich) was
distilled from PCl.sub.5, Diethyl ether (ACS GR, MD) was distilled
from purple sodium benzophenone ketyl under N.sub.2.
N,N-Dimethytformamide (ACS GR, ENID) was vacuum distilled from
CaH.sub.2 and stored over MgSO.sub.4. Triethylamine (99.5%,
Aldrich) was distilled from and stored over KOH under N.sub.2. All
other reagents and solvents were commercially available and were
used as received.
[0048] Techniques. All reactions were performed under a N.sub.2
atmosphere using a Schlenk line unless noted otherwise. .sup.1H and
.sup.13C NMR spectra (.delta., ppm) were recorded on a Varian
Mercury 300 (300 MHz and 75 MHz, respectively). Unless noted
otherwise, all spectra were recorded in CDCl.sub.3, and the
resonances were measured relative to residual solvent resonances
and referenced to tetramethylsilane. Number--(M.sub.n) and weight
average (M.sub.w) molecular weights relative to linear polystyrene
(GPC.sub.PSt) and polydisperisties (pdi=M.sub.w/M.sub.n) were
determined by gel permeation chromatography (GPC) from calibration
curves of log M.sub.n vs. elution volume at 35.degree. C. using
tetrahydrofuran (THF) as solvent(1.0 mL/min), a set of 50 .ANG.,
100 .ANG., 500 .ANG., 10.sup.4 .ANG. and linear (50-10.sup.4 .ANG.)
Styragel 5 .mu.m columns, a Waters 486 tunable UV/Vis detector set
at 254 nm, a Waters 410 differential refractometer, and Millenium
Empower 2 software.
Example 1
[0049] Synthesis of 2-bromo-3-hydroxypropionic acid (FIG. 3).
NaNO.sub.2 (69 g, 1.0 mol) was added in 12 portions over three h to
a cooled (-13.degree. C.) solution of D,L-serine (53 g, 0.51 mol),
potassium bromide (180 g. 1.5 mol), and hydrobromic acid (120 mL,
48 wt %, 1.0 moi) in distilled water (400 mL) that had been sparged
with N.sub.2; the solution turned brown upon addition of
NaNO.sub.2. The solution was warmed to room temperature (23.degree.
C.) and stirred for 16 h. It was then salted out with NaCl and
extracted five tunes with ethyl acetate (100 mL ea). The aqueous
layer was acidified with concentrated HBr to pH<2 and extracted
five times with ethyl acetate (100 mL ea). The organic layers were
combined and dried over MgSO.sub.4. After filtration and removing
the solvent by rotary evaporation, followed by drying under vacuum
on a Schlenk line, the resulting yellow solid was recrystallized
from CH.sub.2Cl.sub.2 to yield 55 g (64%) of
2-bromo-3-hydroxypropionic acid as a white crystalline solid; mp
48-51.degree. C. .sup.1H-NMR (CDCl.sub.3/DMSO-d.sub.6): 3.58 (dd,
CHH, .sup.2J=11.6 Hz, .sup.3J=5.9 Hz), 3.71 (dd, CHH, .sup.2J=11.6,
.sup.3J=7.5 Hz), 3.99 (dd, CHBr, .sup.3J=7.3, .sup.3J=6.1 Hz).
.sup.13C NMR (CDCl.sub.3/DMSO-d.sub.6): 45.6 (CBr), 64.0 (COH),
171.0 (C.dbd.O).
[0050] Examples 2 and 3 relate to the preparation of a
bromopropionate compound wherein the end groups contain an
unreactable compound so that the a group therein can be replaced
with an iodo group or with an azido group as set forth
respectively, in Examples 5 and 6. Example 4 relates to the
rearrangement of the bromo group in the model compound. Thus,
Examples 4, 5, and 6 relate to actual reaction conditions, as
utilized in FIG. 10, so that the above-noted bromo group can be
replaced with either an iodo, an azide, or a thioacetate group.
Example 2
[0051] Synthesis of methyl 2-bromo-3-hydroxypropionate.
Concentrated hydrobromic acid (10 drops) was added to a solution of
2-bromo-3-hydroxypropionic acid (10 g, 60 mmol) in methanol (80 mL,
2.0 mol). After refluxing the solution for 17 h, the solvent was
removed using a rotary evaporator. The resulting oil was dissolved
in CH.sub.2Cl.sub.2 (150 mL), and washed twice with aq NaHCO.sub.3
(75 mL ea) and once with brine (100 mL). The organic layer was
dried over MgSO.sub.4. After filtration, the solvent was removed by
rotary evaporation, and the residue was distilled (105-110.degree.
C./4 mm Hg) to yield 8.7 g (79%) of methyl
2-bromo-3-hydroxypropionate as a yellow oil. .sup.1H NMR: 2.22 (br
s, OH), 3.83 (s, CH.sub.3), 3.95 (dd, CHHOH, .sup.2J=12.0 Hz,
.sup.3J=5.5 Hz), 4.06 (dd, CHHOH, .sup.2J=12.1 Hz, .sup.3J=7.4 Hz),
4.36 (dd, CHBr, .sup.3J=5.6 Hz, .sup.3J=7.4 Hz). .sup.13C NMR: 44.4
(CHBr), 53.4 (CH.sub.3), 63.8 (CH.sub.2OH), 169.6 (C.dbd.O).
Example 3
[0052] Synthesis of methyl 3-acetoxy-2-bromopropionate. A solution
(total volume 10 mL) of acetyl chloride (4.2 mL, 31 mmol) in dry
ether was added dropwise to an ice-cooled solution of methyl
2-bromo-3-hydroxypropionate (4.6 g, 25 mmol) and triethylamine (4.2
mL, 30 mmol) in dry ether (5 mL). The reaction was then warmed to
room temperature (23.degree. C.) and stirred for 16 h. The reaction
was poured into ice water (200 mL) and extracted four times with
ether (50 mL ea). The organic layers were combined and dried over
MgSO.sub.4. After filtration, the solvent was removed by rotary
evaporation, and the yellow residue was distilled (84-85.degree.
C./3 mm Hg) to yield 3.6 g (63%) of methyl
3-acetoxy-2-bromopropionate as a colorless oil. .sup.1H NMR: 2.08
(s, CH.sub.3CO.sub.2), 3.82 (s, CH.sub.3O.sub.2C), 4.50-4.38 (m,
CH.sub.2CHBr). .sup.13C NMR: 20.8 (CH.sub.3CO.sub.2), 40.4 (CHBr),
53.4 (CH.sub.3O.sub.2C), 64.2 (CH.sub.2), 168.3 (CH.sub.3CO.sub.2),
170.21 (CO.sub.2C H.sub.3).
Example 4
[0053] Synthesis of methyl 2-acetoxy-2-bromomethylethanoate. A
solution of methyl 3-acetoxy-2-bromopropionate (0.27 g, 1.2 mmol)
in succinionitrile (1.0 g, 12 mmol) was stirred and heated at
120.degree. C. in a pressure tube for 72 hours. The product was 64%
rearranged by .sup.1H NMR integration. .sup.1H NMR: 5.42 (t,
CHCH.sub.2Br), 4.46 (m, CH.sub.2CHBr), 3.80 (q, CO.sub.2CH.sub.3),
3.71 (t, CHCH.sub.2Br), 2.20 (s, CH.sub.3CO.sub.2). .sup.13C-NMR:
169.90 (C(O)OCH.sub.3), 167.56 (CH.sub.3C(O)), 71.31 (CH), 52.91
(OCH.sub.3), 29.61 (CH.sub.2Br) 20.51 (CH.sub.3C(O)).
Example 5
[0054] Synthesis of methyl 3-acetoxy-2-iodopropionate. A mixture of
methyl 3-acetoxy-2-bromopropionate (0.12 g, 0.52 mmol) and sodium
iodide (0.16 g, 1.1 mmol) in acetone (1 mL) was stirred at room
temperature (23.degree. C.) for 6 h. It was then poured into
H.sub.2O (10 mL) and extracted five times with CH.sub.2Cl.sub.2 (3
mL ea). The organic layers were combined, washed with aq
Na.sub.2S.sub.2O.sub.3 (10 mL), and dried over MgSO.sub.4. After
filtration, the solvent was removed by rotary evaporation to yield
0.12 g (86%) of methyl 3-acetoxy-2-iodopropionate as light yellow
oil. .sup.1H NMR: 2.00 (s, CH.sub.3CO.sub.2), 3.72 (s,
CH.sub.3O.sub.2C), 4.47-4.35 (m, CH.sub.2CHI). .sup.13C NMR: 14.3
(CHI), 20.8 (CH.sub.3CO.sub.2), 53.3 (s, CH.sub.3O.sub.2C), 65.7
(CH.sub.2), 170.0 (CO.sub.2CH.sub.3), 170 0 (CH.sub.3CO.sub.2).
Example 6
[0055] Synthesis of methyl 3-acetoxy.2-azidoprepionate. A solution
of methyl 3-acetoxy-2-bromopropionate (0.11 g, 0.49 mmol) and
sodium azide (32.0 mg, 0.49 mmol) in dry DMF (1 mL) was stirred at
room temperature (23.degree. C.) for 45 min, and then poured into
brine (10 mL) and extracted three times with CH.sub.2Cl.sub.2 (4 mL
ea). The combined organic layers were dried over Na.sub.2SO.sub.4.
After filtration, the solvent was removed by rotary evaporation to
yield 50 mg (54%) of methyl 3-acetoxy-2-azidopropionate as slightly
yellow oil. .sup.1H-NMR: 2.03 (s, CH.sub.3CO.sub.2), 3.77 (s,
CH.sub.3O.sub.2C), 4.06 (dd, CHN.sub.3, .sup.3J=5.6, .sup.3J=4.2
Hz), 4.32 (dd, CHH, .sup.2J=11.6 Hz, .sup.3J=5.8 Hz), 4.40 (dd,
CHH, .sup.2J=11.6, .sup.3J=4.1 Hz). .sup.13C NMR: 20.7
(CH.sub.3CO.sub.2), 53.2 (CH.sub.3O.sub.2C), 60.4 (CHN.sub.3), 63.6
(CH.sub.2), 168.3 (CO.sub.2CH.sub.3), 170.4 (CH.sub.3CO.sub.2).
Example 7
[0056] Synthesis of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic acid)] in solution using
carbodiimide coupling (FIG. 5). A mixture of D,L-lactio acid (0.69
g, 6.7 mmol), 2-bromo-3-hydroxypropionic acid (0.28 g, 1.7 mmol)
and pTSA (50 mg, 0.29 mmol) in a sealed Schlenk tube was stirred at
110.degree. C. under reduced pressure (.about.1-3 mm Hg) for 14 h
to create a prepolymer with M.sub.n=8.81.times.10.sup.3, pdi=2.15.
The Schlenk tube was removed from the oil bath, opened to the
atmosphere, and its contents were dissolved in CH.sub.2Cl.sub.2 (60
mL). Half of the contents were transferred to a 50 mL round bottom
flask. The solvent was refluxed over oven-dried 4 .ANG. molecular
sieves for 18 h to dehydrate the, polymer solution. After cooling
the polymerization solution to room temperature, DPTS (0.10 g, 0.34
mmol) was added, and the solution was further cooled to 0-5.degree.
C. using an ice bath and DIPC (0.20 g, 1.6 mmol) was added
dropwise. The reaction was performed for 7 h at room temperature.
The polymer was precipitated into methanol (50 mL). The methanol
was carefully decanted from the precipitate, and the polymers was
dried in vacuo. The polymer was reprecipitated four times from
CH.sub.2Cl.sub.2 (10 mL) into methanol (50 mL) to yield 0.23 g
(52%) of halogenated PLA as a white powder;
M.sub.n=1.53.times.10.sup.4, pdi=1.71. .sup.1H-NMR: 1.8-1.4 (m,
CH.sub.3), 4.7-4.4 (m, CHBrCH.sub.2), 5.30-5.10 (m, CHCH.sub.3).
.sup.13C NMR: 16.62 (CH.sub.3), 39.78 (CBr), 64.49 (CH.sub.2CHBr),
68.95 (CHCH.sub.3), 166.63 (CHBrCO.sub.2), 169.33
(C(CH.sub.3)COO).
Example 8
[0057] Synthesis of poly[(lactic acid)-co-(glycolic
acid)-co-(2-bromo-3-hydroxypropionic acid)]]by direct
polyesterification (FIG. 9). A solution of D,L-lactic acid (0.93 g,
9.0 mmol), glycolic acid (85 mg, 1.1 mmol),
2-bromo-3-hydroxypropionic acid (0.19 g, 1.1 mmol) and pTSA (51 mg,
0.29 mmol) in diphenyl ether (1 ml) in a Schlenk tube was stirred
at 95.degree. C. under reduced pressure (.about.1-3 mm Hg) for 48
h. The Schlenk tube was removed from the oil bath, opened to the
atmosphere, and its contents were dissolved in CH.sub.2Cl.sub.2 (10
mL). The Schlenk tube was cooled to -10.degree. C., and the
crystallized diphenyl ether was filtered off. The polymer was
precipitated into methanol (50 ml), the solvents decanted, and the
product was reprecipitated four times from CH.sub.2Cl.sub.2 (10 mL)
into methanol (50 ml) to yield 0.53 g (53%) of halogenated PLGA as
a white powder; M.sub.n=2.37.times.10.sup.4, pdi=2.51. .sup.1H-NMR:
1.4-1.8 (m, CH.sub.3), 4.4-4.7 (m, CHBrCH.sub.2), 4.7-4.9 (m,
CH.sub.2CO.sub.2), 5.10-5.30 (m, CHCH.sub.3). .sup.13C NMR: 16.6
(CH.sub.3), 39.4 (CBr), 60.7 (CH.sub.2CO.sub.2), 64.5
(CH.sub.2CHBr), 69.0 (CHCH.sub.3), 166.5 (CH.sub.2CO.sub.2), 166.5
(CHBrCO.sub.2), 169.0 (C(CH)COO).
Example 9
[0058] Partial isomerization of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic acid)] to poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic
acid)-co-(2-bromomethyl-2-hydroxyethanoic acid)]. A solution of
poly[(lactic acid)-co-(2-bromo-3-hydroxypropionic acid)
(M.sub.n=5.2.times.10.sup.4, pdi=1.66; 0.10 g, 0.42 mmol Br) in
acetonitrile (0.8 mL) in a Schlenk tube was degassed by three
freeze-pump-thaw (20 min pumping) cycles. The tube was backfilled
with nitrogen and placed in an oil bath at 105.degree. C. for 96
hours. .sup.1H NMR spectroscopy demonstrated that 25% of the
2-bromo-3-hydroxypropionate units rearranged to
2-brornomethyl-2-hydroxyethanoate units.
Example 10
[0059] Synthesis of poly[(lactic
acid)-co-(3-hydroxy-2-iodopropionic acid)] (see FIG. 10). A
solution of poly[(lactic acid)-co-(2-bromo-3-hydroxypropionic
acid)] (M.sub.n=9.50.times.10.sup.3, pdi=1.42; 0.40 g, 1.3 mmol Br)
and sodium iodide (0.17 g, 1.1 mmol) in acetone (1 mL) and stirred
at room temperature (23.degree. C.) for 48 h. The reaction mixture
was diluted with CH.sub.2Cl.sub.2 (10 mL), washed once with water
(10 mL), and precipitated into ice-cooled i-propanol (200 mL) to
yield 0.43 g (94%) of copolymer as a yellow solid;
M.sub.n=8.45.times.10.sup.3, pdi=1.41. .sup.1H NMR: 1.4-1.7 (m,
CH.sub.3), 4.4-4.6 (m, CH.sub.2CHI), 5.3-5.1 (m, CHCH.sub.3).
.sup.13C NMR: 13.2 (CHI), 16.6 (CH.sub.3), 66.0 (CH.sub.2), 69.0
(CHCH.sub.3), 168.3 (CHBrCO.sub.2), 168.8 (CHICO.sub.2), 169.2
(C(CH.sub.3)COO).
Example 11A
[0060] Synthesis of poly[(lactic
acid)-co-(3-hydroxy-2-azidopropionic acid)] (see FIG. 10) starting
from the brominated copolymers. A solution of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic acid)]
(M.sub.n=9.50.times.10.sup.3, pdi=1.42; 0.20 g , 0.62 mmol Br) and
sodium azide (36 mg, 0.56 mmol) in dry DMF (1 mL) and stirred at
room temperature (23.degree. C.) for 48 h. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 (10 mL), washed once with water (10
mL), and precipitated into ice-cooled i-propanol (200 mL) to yield
0.11 g (62%) of copolymer as a yellow solid;
M.sub.n=1.56.times.10.sup.3, pdi=1.71. .sup.1H NMR: 1.4-1.7 (m,
CH.sub.3), 4.2-4.3 (m, CHN.sub.3), 4.4-4.6 (m, CH .sub.2), 5.3-5.1
(m, CHCH.sub.3). .sup.13C NMR: 16.6 (CH.sub.3), 39.6 (CHBr), 60.0
(CHN.sub.3), 64.2 (CH.sub.2), 69.1 (CHCH.sub.3), 166.8
(CHBrCO.sub.2) 169.3 (C(CH.sub.3)COO), 173.2
(CHN.sub.3CO.sub.2).
Example 11B
[0061] Synthesis of poly[(lactic
acid)-co-(3-hydroxy-2-azidopropionic acid)] (see FIG. 10) starting
from the iodinated copolymer. A solution of poly[(lactic
acid)-co-(2-iodo-3-hydroxypropionic acid)]
(M.sub.n=8.45.times.10.sup.3, pdi=1.41; 0.11 g, 0.12 mmol l) and
sodium azide (13 mg, 0.21 mmol) in dry DMF (1 mL) and stirred at
roam temperature (23.degree. C.) for 48 h. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 (10 mL), washed once with water (10
mL), and precipitated into ice-cooled i-propanol (200 mL) to yield
0.13 g (87%) of copolymer as a yellow solid;
M.sub.n=1.97.times.10.sup.3, pdi=1.41.
Example 11C
[0062] Synthesis of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic
acid)-co-(2-acetylthiomethyl-2-hydroxyethanoic acid)] (see FIG. 10)
starting from the brominated copolymer. A solution of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic acid)]
(M.sub.n=9.50.times.10.sup.3, pdi=1.42; 0.20 g, 0.60 mmol Br),
potassium thioacetate (65 mg, 5.7 mmol) and 18-crown-6 (29 mg, 0.10
mmol) in acetonitrile (2 mL) was stirred at room temperature
(23.degree. C.) for 48 h. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (10 mL), washed one with water (10 mL), and,
precipitated into ice-cooled i-propanol (120 mL) to yield 58 mg
(30%) of copolymer as a transparent glassy solid;
M.sub.n=1.50.times.10.sup.3, pdi=1.28. .sup.1H NMR: 1.4-1.7 (m,
CH.sub.3), 2.3 (s, CH.sub.3COS), 3.2-3.4 (m, CHCH.sub.2S), m,
4.3-4.6 (CH.sub.2CHBr), 5.1-5.2 (m CHCH.sub.3). .sup.13C NMR: 16.6
(CH.sub.3), 30.0 (SCOCCH.sub.3), 39.7 (CBr), 45.0 (CS), 64.5
(CH.sub.2CHBr), 69.0 (CHCH.sub.3), 70.0 (CH.sub.2CHS), 166.5
(CHBrCO), 169.2 (C(CH)COO), 173.2 (SCO).
Example 11D
[0063] Synthesis of poly[(lactic
acid)-co-(2-iodo-3-hydroxypropionic
acid)-co-(2-acetylthiomethyl-2-hydroxyethanoic acid)] starting from
the iodinated copolymer. A mixture of poly[(lactic
acid)-co-(2-iodo-3-hydroxypropionic acid)]
(M.sub.n=8.45.times.10.sup.3, pdi=1.41; 0.10 g, 0.22 mmol l),
potassium thioacetate (22 mg, 0.22 mmol) and 18-crown-6 (10 mg, 40
.mu.mol) in acetonitrile (1 mL) was stirred at room temperature for
48 h. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (10
mL), washed once with water (10 mL), and precipitated into
ice-cooled i-propanol (120 mL) to yield 0.13 g of copolymer as a
yellow solid; M.sub.n=1.70.times.10.sup.3, pdi=1.35.
Example 11E
[0064] Synthesis of poly[(lactic
acid)-co-(2-bromo4-hydroxypropionic
acid)-co-(2-azidomethyl-2-hydroxyethanoic acid)] starting from the
isomerized brominated copolymer. A solution of sodium azide (17 mg,
0.26 mmol) in dry DMF (15 mL) was added dropwise over 30 minutes to
a solution of poly(lactic acid)-co-(2-bromo-3-hydroxypropionic
acid)-co-(2-bromomethyl-2-hydroxyethanoic acid)]
(M.sub.n=9.50.times.10.sup.3, pdi=1.42: 0.20 g, 0.21 mmol
CH.sub.2Br) in DMF (2 mL) and stirred at room temperature for 48 h.
The reaction was concentrated using a rotary evaporator and then
dissolved in CH.sub.2Cl.sub.2 (10 mL), washed once with water (10
mL), and the organic layer was concentrated using a rotary
evaporator to yield 0.11 g (58%) of copolymer as a white solid;
M.sub.n=3.93.times.10.sup.3, pdi1.86. .sup.1H NMR: 1.4-1.7 (m,
CH.sub.3), 2.4 (m, CHCH.sub.2N.sub.3), 3.6-3.7 (m,
CH.sub.2N.sub.3), m, 4.1-4.3 (m, CHCH.sub.2Br), 4.3-4.6 (CHBr),
5.1-5.2 (m CHCH.sub.3), 5.3-5.4 (m, CH.sub.2Br). .sup.13C NMR: 16.6
(CH.sub.3), 29.0 (CHCH.sub.2Br), 39.7 (CHBr), 60.0
(CHCH.sub.2N.sub.3), 64.4 (CH.sub.2CHBr), 66.6 (CHCH.sub.2N.sub.3)
70.0 (CHCH.sub.3), 165.5 (CHCH.sub.2CO), 166.7 (CHBrCO), 169.3
(C(CH.sub.3)COO).
Example 11F
[0065] Synthesis of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic
acid)-co-(2-acetylthiomethyl-2-hydroxyethanoic acid)] starting from
the isomerized brominated copolymer. A solution of poly[(lactic
acid)-co-(2-bromo-3-hydroxypropionic
acid)-co-(2-bromomethyl-2-hydroxyethanoic acid)] (M.sub.n=7.
06.times.10.sup.3, pdi=1.99; 0.20 g. 0.21 mmol CH.sub.2Br),
potassium thioacetate (23 mg, 0.20 mmol) and 18-crown-6 (8.5 mg, 32
.mu.mol) in acetonitrile (35 mL) was stirred at room temperature
(23.degree. C.) for 48 h. The reaction mixture was concentrated on
a rotary evaporator and then dissolved in CH.sub.2Cl.sub.2 (10 ml),
and washed once with water (10 mL), to yield 0.27 g of copolymer as
a yellow solid; M.sub.n=3.57.times.10.sup.3, pdi=2.24. .sup.1H NMR:
1.4-1.7 (m, CH.sub.3), 2.3 (s, CH.sub.3COS), 4.3-4.6 (m,
CHCH.sub.2S, CH.sub.2CHI), 5.1-5.2 (m CHCH.sub.3). .sup.13C NMR:
16.6 (CH.sub.3), 30.0 (SCOCCH.sub.3), 45.0 (CS), 66.0
(CH.sub.2CHI), 66.6 (Cl), 69.0 (CHCH3), 70.0 (CH.sub.2CHS), 166.5
(CHBrCO), 169.2 (C(CH.sub.3)COO), 173.2 (SCO).
[0066] Results and Discussion
[0067] Polyesterification: Direct polycondensations in bulk are
reversible reactions, and need extremely high extent of conversion
to achieve high molecular weight. At higher conversions, the
increase in the viscosity of the bulk, makes removal of the
by-product, water, by heat and vacuum more and more difficult.
Adding a small amount of high boiling solvent, like diphenylether
(DPE), plasticizes the bulk, permitting the bulk to be dehydrated
further. This shifts the equilibrium to the right, and affords
higher molecular weights. The number average molecular weights
obtained were around 20,000 Da, measured by GPC calibrated to
polystyrene standards. However, since the different co-polymer
compositions have different molecular weights, the
co-polymerizations may only be compared by their degree of
polymerizations. PLA had the highest DP. Upon introducing glycolic
acid, the PLGA copolymers formed with lower DP. Co-polymers of
lactic acid with 2-bromo-3-hydroxypropionic acid also formed
polymers with lower DP than that of PLA and PLGA. Increasing
content of 2-bromo-3-hydroxypropionic acid led to polymers with
decreasing DP. This could be attributed to the lower reactivity of
2-bromo-3-hydroxypropionic acid, as compared to LA. However, with
the tri-component co-polymers of LA, GA and
2-bromo-3-hydroxypropionic acid of varying ratios, their DP was
higher than the copolymers of just LA with
2-bromo-3-hydroxypropionic acid. This could be because of the
higher reactivity of GA units. The polydispersity was also higher
in the tri-component co-polymers.
[0068] Reactions on the model compound: (Table 2) To investigate
potential reactions to functionalized the brominated polyester, a
small molecule model, methyl 3-acetoxy-2-bromopropanoate, was
synthesized by esterifying the carboxylic acid and the hydroxyl
groups of 2-bromo-3-hydroxypropionic acid with methanol and acetyl
chloride respectively. This molecule and the brominated polyester
have very similar reactivity at the halogen, as the immediate
electronic environment of the carbon-halogen bond in the model and
the polymer is identical out to three bonds. The model molecule
underwent substitution at the halogen using sodium azide, sodium
iodide and sodium thioacetate as nucleophiles to prepare the azido,
iodo and thioester derivatives. These reactions were fast, less
than 1 hour in the case of azide, and quantitative. Highly
efficient functionalization reactions are necessary for
post-polymerization functionalization as bimolecular reactions with
macromolecules occur much slower than those with small molecules,
due to diffusion limitations, and non-reacted sites along the
backbone cannot be removed post reaction.
[0069] Potassium phenoxide and potassium acetate caused a competing
.alpha.-elimination reaction that makes them unsuitable for
substitution. Potassium phenoxide caused 95% elimination at room
temperature in less than one hour, Potassium acetate caused varying
amounts of elimination, 45-80%, depending on temperature and
solvent, with lower temperatures and more polar solvents favoring
substitution. Even a small amount of elimination makes these
nucleophiles unsuitable for polymer functionalization because the
elimination results in chain-scission. (scheme 4).
[0070] .alpha. to .beta.Halo Rearrangement: While conducting
substitution experiments using 3-methyl-4,5-dichloroimidazole, a
poor nucleophile, and MABP a product was formed that did not
correspond to substitution or elimination. Repeating this
experiment in the absence of a nucleophile it was observed that
MABP underwent a thermal rearrangement from the .alpha.-bromo
isomer to .beta.-bromo isomer, likely via a five-member ring
intermediate.
[0071] This rearrangement is supported by .sup.1H and .sup.13C NMR
spectroscopy, which shows the emergence of resonances corresponding
to the methine at 5.43 and 71.38 ppm and the methylene at 3.71 and
29.68 ppm in the 1H and .sup.13C spectra respectively, of the
.beta.-bromo isomer.
[0072] This rearrangement mechanism is further supported by an
experiment isomerizing a 5.2 kDa 58:42 poly[(lactic
acid)-co-(2bromo-3-hydroxypropionic acid)]. The polyester was
heated to 105.degree. C. in acetonitrile for 96 hours and observed
to isomerize 25% with very little loss in molecular weight, as
observed by a shift in GPC retention time from 39.9 to 40.9
minutes. This shift may be accounted for by a change in
hydrodynamic due to the different repeat unit and not actual
polymer degradation.
[0073] This rearrangement proceeds most efficiently upon heating in
polar solvent, acetonitrile, succinonitrile or DMF. The
rearrangement of the small molecule proceeded to an equilibrium
concentration of 60:40.beta. to .alpha., quantified by .sup.1H-NMR
at 120.degree. C. in succinonitrile in a pressure tube. This
thermal rearrangement offers a possible route to orthogonal
functionalization by providing two types of halogen functionality,
a primary halogen, which is more susceptible to nucleophilic
substitution due to reduced steric bulk at the .sigma.* orbital,
and an .alpha.-halo ester, capable of radical chemistry due to the
adjacent carbonyl, in the same polyester backbone utilizing one
functional monomer. Furthermore, this isomerization can be
accomplished in situ during the polycondensation and the amount of
each isomer repeat unit controlled by the temperature used during
the polymerization. Below 95.degree. C. almost no .beta.-halo
isomer is observed.
[0074] Reactions on the Polyester: (Table 2) The reactions on the
polyester all were ran for 48 hours at room temperature. Iodo and
azide both substituted quantitatively, while the thioaceate showed
substitution once the polymer had rearranged to the .beta. halogen
form. In the case of iodo substitution there was a loss of 1,000 Mn
when substitution occurred. When the thioacetate substitutes onto
the polymer there is a loss of 8,000 and 7,800 Da from the bromo
and iodo derivatives respectively. When sodium azide substitutes
onto the polymer 7,900 and 7,900 Da from the bromo and iodo
derivatives respectively. Looking at the molecular weight
differences the iodo polymer is better for functionalizing, which
corresponds with iodine being a better leaving group then
bromine.
[0075] In order to decrease the loss of molecular weight when
functionalizing the polyester a partially isomerized polymer was
used. By targeting the primary halide the favorability of
nucleophlic substitution is increased. For the sodium azide
substitution a slow dilute addition of sodium azide resulted in a %
M.sub.n loss of 33% which is an improvement from 84% when the alpha
bromine is targeted. The reason for this improvement is that there
is a primary halide that favors S.sub.n2 over E.sub.2. Another
reason is presumably that the polymer exists as a random coil in
solution and so the bromine in the center of the coil is shielded
from the azide. This causes a local concentration of azide on the
outside of the polymer to be in excess of 1.0 and increases the
chance of elimination. With the dilute addition the azide the
excess azide at the surface of the polymer is avoided, and
substitution is favored. When the partially isomerized polymer is
substituted with thioacetate the % M.sub.n loss decreases from 89%
to 47%. This is because the thioacetate does not have to wait for
the polymer to spontaneously rearrange before it substitutes. This
limits the amount of excess thioaceate in the system and again
promotes substitution over elimination.
TABLE-US-00001 TABLE 1 Feed Ratio GPC PSt by NMR calculation Sample
LA GA BrH Mn Mw PDI DP LA GA BrH PLA 100 0 0 3.16 .times. 10.sup.4
5.12 .times. 10.sup.4 1.62 438.9 100 0 0 PLGA9010 90 10 0 2.92
.times. 10.sup.4 3.49 .times. 10.sup.4 1.53 324.4 90.1 9.9 0
PLGA8020 80 20 0 2.01 .times. 10.sup.4 3.05 .times. 10.sup.4 1.51
290.5 80.3 19.7 0 PLBr9010 90 0 10 2.08 .times. 10.sup.4 4.13
.times. 10.sup.4 1.99 260.3 89.9 0 10.1 PLBr8020 80 0 20 1.80
.times. 10.sup.4 3.96 .times. 10.sup.4 2.2 205.0 80.3 0 19.7
PLBr7030 70 0 30 1.68 .times. 10.sup.4 3.67 .times. 10.sup.4 2.18
175.5 70.3 0 29.7 PLBr6040 60 0 40 1.71 .times. 10.sup.4 3.44
.times. 10.sup.4 2.01 165.1 59.7 0 39.3 PLBr5050 50 0 50 2.03
.times. 10.sup.4 3.91 .times. 10.sup.4 1.93 182.1 50 0 50
PLGBr801010 80 10 10 2.99 .times. 10.sup.4 7.49 .times. 10.sup.4
2.51 380.9 80.1 10 9.9 PLGBr701020 70 10 20 2.37 .times. 10.sup.4
9.45 .times. 10.sup.4 3.99 274.3 70 10.1 19.9 PLGBr601030 60 10 30
2.30 .times. 10.sup.4 1.00 .times. 10.sup.5 4.35 243.9 60.1 10 29.9
PLGBr702010 70 20 10 2.32 .times. 10.sup.4 5.87 .times. 10.sup.4
2.52 300.9 69.8 20.1 9.1 PLGBr602020 60 20 20 2.20 .times. 10.sup.4
9.10 .times. 10.sup.5 4.13 258.9 59.46 16.29 24.25 PLGBr502030 50
20 30 1.89 .times. 10.sup.4 7.28 .times. 10.sup.5 3.86 202.9 51.64
16.52 31.84
TABLE-US-00002 TABLE 2 Mn Mn pdi pdi Reactant Solvent Time Temp
Conversion before after before after Model sodium Acetone 6 h RT
quatitative iodide sodium DMF 45 min RT quatitative azide sodium
Acetonitrile 48 h RT re-arranged thioacetate substituted Brominated
sodium Acetone 48 h RT quatitative 9470 8450 1.42 1.41 iodide
Polyester sodium DMF 48 h RT quatitative 9470 1560 1.42 1.71 azide
sodium Acetonitrile 48 h RT re-arranged 9470 1500 1.42 1.28
thioacetate substituted Iodated sodium DMF 48 h RT quatitative 8450
1970 1.41 1.48 azide Polyester sodium Acetonitrile 48 h RT
re-arranged 8450 1700 1.41 1.35 thioacetate substituted Partially
sodium DMF 24 h RT quatitative 5850 3925 2.11 1.86 Isomerized azide
Brominated sodium Acetonitrile 48 h RT re-arranged 7060 3751 1.99
2.24 polyester thioacetate
[0076] The functionalized copolyesters of the present invention
have the same end uses of that of current commercial biodegradable
polyesters. For example, they can be utilized to make food trays,
cold drink cups, packaging applications, bottles, jars, pots,
films, bags, and so forth. They also can be utilized as a feedstock
for attachment of medical or drug delivery systems or compounds
thereto.
[0077] While in accordance with the patent statutes the best mode
and preferred embodiment have been set forth, the scope of the
invention is not intended to be limited thereto, but only by the
scope of the attached claims.
* * * * *