| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | * December 6, 1988 |
| PATENT TITLE |
Preparation of anhydride copolymers |
| PATENT ABSTRACT |
A method for preparation of very pure anhydride copolymers with high yield. The anhydride copolymers, consisting of aromatic and aliphatic diacids are formed by melt condensation of individually prepared, pure, isolated prepolymers. The method of preparation is characterized by high yield, reproducibility, polymer purity and controlled composition, and is a short and convenient procedure. The polyanhydrides produced by the disclosed method are particularly well suited to biomedical applications requiring low levels of toxic or inflammatory contaminants and physical and mechanical properties which closely conform to manufacturing specifications. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 17, 1986 |
| PATENT REFERENCES CITED |
John E. Bucher and W. Clifton Slade, The Anhydrides of Isophthalic and Terephthalic Acids, J. Amer. Chem. Soc. 32, 1319 (1909). Naoya Yoda, Synthesis of Polyanhydrides. XI., Makromol. Chem. 36 (1962). Naoya Yoda, Syntheses of Polyanhydrides, XII. Crystalline and High Melting Polyamidepolyanhydride of Methylenebis (p-Carboxyphenyl)amide, Journal of Polymer Science: Part A, vol. I, 1323 (1962). Naoya Yoda, Synthesis of Polyanhydrides. II. New Aromatic Polyanhydrides with High Melting Points and Fiber-Forming Properties, Makromol. Chem. 32, 1 (1959). Naoya Yoda, Synthesis of Polyanhydrides. X. Mixed Anhydrides of Aromatic and Five-Membered Heterocyclic Dibasic Acids, Makromol. Chem. 10 (1962). Naoya Yoda and Akihisa Miyake, Synthesis of Polyanhydride. I. Mixed Anhydride of Aromatic and Aliphatic Dibasic Acids, Makromol. Chem. 32 (10), 1120 (1959). Julian W. Hill and Wallace H. Carothers, Studies of Polymerization and Ring Formation. XIX. Many-Membered Cyclic Anhydrides, J. Amer. Chem. Soc. 55, 5023 (1933). A Conix, Poly[1,3-Bis(p-Carboxyphenoxy)-Propane Anhydride], Macromolecular Syntheses, vol. two, 95 (1966). Julian W. Hill and Wallace H. Carothers, Studies of Polymerization and Ring Formation. XIV. A Linear Superpolyanhydride and a Cyclic Dimeric Anhydride from Sebacic Acid, J. Amer. Chem. Soc. 54, 1969 (1932). Polyanhydrides, Ency. of Poly. Sci. & Tech. 10, 630 (1969). |
| PATENT GOVERNMENT INTERESTS | The United States Government has rights in this invention by virtue of National Institute of Health Grant No. 98000 |
| PATENT CLAIMS |
We claim: 1. A method for preparing highly pure anhydride copolymers comprising: providing at least two individually synthetized and purified diacids, reacting the individual diacids and acetic anhydride separately to form mixed anhydrides of the invididual diacids, separately removing the unreacted acetic anhydride and diacids from the individual mixed anhydrides formed by the reaction of the acetic anhydride with said diacids, combining said individual mixed anhydrides, and polymerizing said mixture of the purified mixed anhydrides of the individual diacids to form copolymers. 2. The method of claim 1 wherein the diacids are selected form the group consisting of sebacic acid, bis(p-carboxyphenoxy-propane, bis(p-carboxyphenoxy)hexane, isophthalic acid, 1,4 phenylene diporpionic acid, adipic acid and dodecanedioic acid. 3. A highly pure anhydride copolymer consisting essentially of individually synthetisized and purified monomers selected from the group consisting of mixed anhydrides of aliphatic and aromatic diacids, wherein said diacids were individually reacted with acetic anhydride and the unreacted diacid and acetic anhydride removed after the reaction. 4. The anhydride copolymer of claim 3 wherein said mixed anhydrides are formed by separately refluxing individual diacids with acetic anhydride to form individual mixed anhydrides, removing the excess acetic anhydride, and recrystallizing the individual mixed anhydrides. 5. The anhydride copolymer of claim 3 wherein the copolymers are further purified by recrystallization. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The present invention is in the area of organic synthesis and, in particular, methods of synthesizing high purity anhydride copolymers. Aromatic polyanhydrides were first synthesized in 1909 by Bucher and Slade, as reported in J. Am. Chem. Soc. 31, 1319 (1909). Aliphatic polyanhydrides were first prepared in 1932 by Hill and Carothers, as described in J. Am. Chem. Soc. 54, 1569 (1932) and 55, 5023 (1933). A number of aromatic and heterocyclic polyanhydrides, intended as substitutes for polyesters in textile applications, were further investigated over the next thirty years. Only a few papers have been published on the preparation of anhydride copolymers. In these studies anhydride copolymers were produced by mixing a calculated amount of two diacids, e.g., aromatic and aliphatic diacids, and treating with acetic anhydride to yield the mixed prepolymer. The mixed prepolymer was then polymerized by heating under vacuum. The reaction is shown in equation 1. The mixed prepolymer was not isolated nor purified prior to polymerization. ##STR1## Using this method of preparation, N. Yoda et al. prepared anhydride copolymers composed of terephthalic acid, sebacic acid, adipic acid and five membered heterocyclic diacids, as described in Makromol. Chem. 56, 32 (1962), and Bull. Chem. Soc. Japan 1120 (1959) 32, Another anhydride copolymer composed of methylene bis(p-carboxyphenyl)amide and adipic acid was reported by N. Yoda in Chem. High Polymers Japan 19, 613 (1962). Unpurified mixed prepolymers were used in all these studies. In a recent study by Leong et al., reported in J. Biomed Mat. Res., 19, 941 (1985), anhydride copolymers composed of bis(p-carboxyphenoxy)propane and sebacic acid were prepared. The copolymers were prepared from the mixed prepolymers obtained when the calculated amount of CPP and sebacic acid were treated with acetic anhydride. The mixed prepolymer was isolated after several weeks of crystallization at -20.degree. C. The composition of the final polymer was not controlled. Polymerization of the mixed prepolymers yielded polymers with molecular weights of 12,030. Unsuccessful attempts were made to obtain the copolymers by polycondensing the mixture of individually prepared prepolymers, especially sebacic acid prepolymers. It is therefore an object of the present invention to provide a method for preparation of highly pure anhydride copolymers having a controlled composition, especially for use in biomedical applications. It is a further object of the present invention to provide a method for preparation of highly pure anhydride copolymers with controlled composition which is reproducible, has a high yield and is quick. It is a still further object of the present invention to provide a method for preparation of highly pure anhydride copolymers wherein prepolymers of the diacids are produced which can be combined to yield a wide variety of copolymers having an actual composition which is close to the calculated composition. It is another object of the invention to provide a method for preparation of highly pure anhydride copolymers for use in preparing high molecular weight polyanhydrides. SUMMARY OF THE INVENTION The invention is a method of synthesis of highly pure anhydride copolymers of known composition wherein the key element is the use of individually prepared, pure prepolymers. Calculated amounts of the individual prepolymers, e.g. aromatic and alphatic prepolymers, are mixed together and polymerized to form copolymers. High molecular weight polyanhydrides are produced by polymerization of the prepolymers at a temperature between 150.degree. C. and 220.degree. C. for 10 to 240 minutes, preferably 180.degree. C. for 90 minutes, under high vacuum. Examples of anhydride copolymers composed of the following diacids: sebacic acid (SA), bis(p-carboxyphenoxy)propane (CPP), adipic acid, bis(p-carboxyphenoxy)hexane (CPH), isophthalic acid (Isoph.) 1,4 phenylene dipropionic acid and dodecanedioic acid (DD), are polymerized from pure isolated prepolymers by a melt polycondensation process. Polyanhydrides prepared from the very pure, isolated prepolymers are especially useful for biomedical applications because of the agreement between calculated and actual composition, reproducible molecular weights and degradation kinetics, lack of inflammatory or toxic contaminants, and mechanical properties such as film formation. Higher molecular weights can be generated by the addition of coordination catalysts to the copolymer mixture. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is the synthesis of a pure anhydride copolymer according to the present invention. FIG. 2 is the synthesis of ananhydride copolymer according to the prior art . DETAILED DESCRIPTION OF THE INVENTION Anhydride copolymers are synthesized by melt condensation from a mixture of individually synthesized and purified mixed anhydride prepolymers prepared by heating diacids and acetic anhydride as shown in FIG. 1. The prior art method of synthesis is shown in FIG. 2 wherein the diacids are first mixed together, then refluxed with acetic anhydride to form the prepolymers. The method according to the present invention is used in the following non-limiting examples to synthesize anhydride prepolymers which can then be combined and polymerized to form anhydride copolymers with controlled composition. Individually prepared, pure, isolated prepolymers are made and purified within two work days with 50 to 80% yield. Calculated amounts of the prepolymers, such as CPP prepolymers and sebacic acid prepolymers, are then mixed together and polymerized, for example, at 180.degree. C. for 90 minutes under high vacuum. The prepolymer data analysis is summarized in Table 1. The data for the copolymers prepared from these prepolymers is summarized in Table 2. High molecular weight anhydride copolymers with high reproducibility in polymer composition and molecular weight are obtained. TABLE 1 __________________________________________________________________________ Characterization of Prepolymers GPC Analysis NMR Analysis.sup.b Prepolymer of: Mp Mw Mn Dp.sup.a Dp IR.sup.c __________________________________________________________________________ Sebacic acid 67-69 1620 825 3.9 5 (2.22:1.32).sup.d 1810,1740 Dodecanedioic 76-77 2410 1250 4.7 9 (2.22:1.27).sup.d 1810,1740 acid Adipic acid 62-63 1765 694 4.0 6 (2.23:1.74).sup.d 1810,1740 1,4 Phenylene 74-75 1985 915 4.0 5 (2.18:7.11).sup.d 1800,1735 dipropionic acid Bis(p-Carboxy- 104-106 495 484 1.3 1.4 (2.30:7.1-8.1).sup.d 1800,1730 phenoxy) propane Bis(p-Carboxy- 92-94 573 490 1.1 1.3 (2.30:7.1-8.1).sup.d 1800,1735 phenoxy) hexane Isophthalic 56-58 484 376 1.9 1.6 (2.43:7.4-8.6).sup.d 1800,1735 acid __________________________________________________________________________ .sup.a Dp based on the Mn of the GPC analysis. .sup.b Determined from 'H--NMR analysis. .sup.c Characteristic for anhydride bonds. .sup.d Chemical shift in PPM of the methyl terminal and the representativ peak of the repeating unit. TABLE 2 ______________________________________ Characterization of Anyhdride Copolymers % Aliphatic Units (calculated) (found) ______________________________________ CPP:SA 80 80 .+-. 2 115,000 .+-. 5,000 70 70 .+-. 2 78,000 .+-. 4,500 50 50 .+-. 2 32,000 .+-. 3,000 Isoph:SA 80 81 .+-. 2 112,000 .+-. 5,400 50 49 .+-. 1 30,000 .+-. 2,900 CPP:DD 80 79 .+-. 2 122,000 .+-. 6,100 50 50 .+-. 2 31,000 .+-. 3,200 CPH SA 80 79 .+-. 2 76,400 .+-. 6,800 CPH:DD 80 80 .+-. 2 84,900 .+-. 5,600 50 51 .+-. 1 36,550 .+-. 3,420 CPP:adipic acid 80 82 .+-. 2 56,800 .+-. 3,800 ______________________________________ Copolymers prepared from individually prepared prepolymers in Table 1 wer polymerized at 180.degree. C. for 90 min. Results are an average of five separate polymerizations. The following materials and methods were used in the examples: Chemicals: Sebacic acid, dodecannedioic acid and adipic acid (99%, Aldrich Chemical Co., Milwaukee, Wis.) were recrystallized three times from ethanol and 1,4 phenylene dipropionaic acid (98%, Aldrich Chemical Co.) was recrystallized from acetone before use. Bis(p-carobxyphenoxy)alkanes were synthesized according to the method described by A. Conix in Marcomol. Synth. 2, 95 (1966) and cleaned by extraction with acetone and ether before use. Isophthalic acid (99%, Aldrich Chemical Co.) was recrystallized from ethanol. All solvents were analytical grade. Instrumentation: Infared spectroscopy was performed on a Perkin-Elmer Spectrophotometer Model 1430. Polymeric samples were film cast onto NaCl plates from solutions of the polymer in chloroform. Prepolymer samples were either pressed into KBr pellets or dispersed in nujol onto NaCl plates. Thermal analysis of polymers was performed on a Perkin Elmer DSC-2 differential Scanning Calorimeter employing a heating rate of 20.degree. C./min. The melting point of prepolymers was determined on a Fisher Johns melting point apparatus. The molecular weights of the polymers and prepolymers were estimated on a Perkin Elmer GPC system consisting of a series 10 pump, a 3600 Data Station with an LKB 214 - rapid spectral detector at 254 nm wavelength. Samples were eluted in chloroform through two Pl Gel columns (Polymer Laboratories; 100 Angstroms and 1000 Angstroms pore sizes) in series at a flow rate of 1.5 ml/min. Polystyrene (Polyscience) was used as the calibration standard. Viscosity of polymers was measured in an Ubbelohde Viscometer (cannon 75) at 23.degree. C. using 1, 0.5 and 0.25% w/v polymer in chloroform solution. 'H-NMR spectra were run on a Bruker AM-250 spectrometer in CHCl.sub.3. Determination of Prepolymer and Polymer Composition The composition of anhydride copolymers is determined by 'H-NMR from the ratio of the peaks integration of the copolymer units, for example, the composition of CPP:SA copolymers is determined by 'H-NMR from the ratio of the peaks integration at 1.3 PPM (8H, Sebacic acid) and 6.9-8.2 PPM (8H, CPP). General Method for Polymer Synthesis Polyanhydrides are synthesized by melt polycondensation of mixed anhydrides of diacids and acetic anhydride. Aliphatic mixed anhydride prepolymers are prepared by refluxing the dicarboxylic acid monomers (40 g) in acetic anhydride (200 ml) for 20 to 90 minutes. The excess acetic anhydride is removed to dryness under vacuum at 60.degree. C. The crude prepolymer is recrystallized from dry toluene. The crystals are then immersed in a 1:1 mixture of dry petroleum ether and ethyl ether overnight to extract traces of acetic anhydride and toluene. The pure crystals are dried under vacuum over calcium chloride (75-88% yield). Aromatic monomers are refluxed for 15 to 30 minutes, then the unreacted diacid (5 to 10%) removed by filtration. The solution is concentrated to 150 ml and allowed to crystallize overnight at 0.degree. C. The crystals are then immersed in dry ether (200 ml) overnight with stirring to extract traces of acetic anhydride. The purified prepolymer is washed with dry ether and dried under vacuum over calcium chloride (42-50% yield). The prepolymers are characterized by GPC, 'H-NMR and IR analysis. The amounts of prepolymers (as calculated below) then undergo melt polycondensation as follows: In a typical reaction, CPP prepolymer is mixed with sebacic acid prepolymer in a glass tube (2.times.20 cm) with a side arm equipped with a capillary nitrogen inlet. The tube is immersed in an oil bath at 180.degree. C. After the prepolymers are melted, approximately 1 minute, high vacuum (10-4 mm Hg) is applied through the side arm. The condensation product, acetic anhydride, is collected in an acetone/dry ice trap. During the polymerization, a strong nitrogen sweep with vigorous agitation of the melt is performed for 30 seconds every 15 minutes. The crude polymer is purified by precipitation in dry petroleum ether from a dichloromethane solution. The precipitate is then extracted with anhydrous ether for several hours at room temperature. Calculations The calculated amounts of prepolymers to be mixed for the synthesis of an x:y copolymer, where x:y is the molar ratio of copolymer units, is as follows: ##EQU1## wherein x and y are the molar ratios of prepolymers 1 and 2 in the copolymer, Mn is the number average molecular weight of the prepolymer as determined by GPC, and Dp is the number of units in the prepolymer as calculated from: ##EQU2## where 102 is the molecular weight of prepolymer end groups: ##STR2## and Ru is the molecular weight of the repeating unit in the prepolymer. For example: for sebacic acid, the repeating unit is: ##STR3## Ru=184 and for CPP, the repeating unit is: ##STR4## and Ru=308 |
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| PATENT PHOTOCOPY | Available on request |
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