Alpha-angelicalactone polymerization product

FIELD: biodegradable polymers, medicine.

SUBSTANCE: claimed product is obtained by polymerization of alpha-angelicalactone in presence of sodium butylate at 18-25°C for 220-315 hours. Further product is purified with diethyl ether, volatile matters are removed by heating up to 80°C for 4 h under pressure of 14 Hg mm and product is exposed with gamma- or ultraviolet irradiation. Obtained product is characterized with two kinds of interunit bonds, namely carbon-carbon polyolefin bonds and carbon-carbon polyester bonds and contains polyester bonds in amount of 0.01-0.99 as calculated to monomer unit and cross-links between chains in amount of 0-1,94 as calculated to monomer unit. Polymers of present invention are useful in medicine in production of pharmaceutical preparations, surgery filaments, packing materials, etc.

EFFECT: polymer with controlled biodegradation.

7 ex

 

The claimed invention relates to the field of polymeric materials obtained by polymerization of cyclic lactones, and can be used for the production of biodegradable polymers used in medicine, for the production of packaging products, packaging and other More narrow scope of the claimed invention is a polyester polymer materials based on alpha angelicalactone (5-methyl-2(3H)-furanone), obtained by dehydration of levulinate (4-oxopentanoate) acid.

Known polymeric material obtained by copolymerization of alpha-angelicalactone with methyldiphenylamine, maleic anhydride, norbornene [US Pat 6537727]. The copolymerization is carried out by radical initiation. And leads to the polyolefin, and not polyester. Alpha angelicalactone has its two functional groups capable of polymerization: double bond and ester group. Therefore, it has the potential to polymerization by two routes, the polyol (1) and polyolefins (2):

Obtained in accordance with known invention, the olefinic polymer has the structure (2), and therefore, the disadvantage of this polymer is its inability to biodegradation, i.e. slow destruction under the action of various enzymatic systems.

Known copolymer alphagalileo with polyhydroxystearic [US Pat 6492087]. The polymer also has limonaire C-C-bonds formed during the opening of double bonds in the furan ring (2), and is not prone to biodegradation.

Closest to the proposed polymeric material is a homopolymer obtained by polymerization of pure alpha angelicalactone under the action of boron TRIFLUORIDE without comonomers [Marvel C.S., C.L. Levesque J. Am. Chem. Soc. - 1939. - V.61. - P.1682-1684]. To a solution of 15 g of alpha-angelicalactone in 40 ml of carbon disulfide was added 0.4 ml of epirate of boron TRIFLUORIDE. The solution was stirred for 5 hours. Then decantation surface layer of the solvent from the viscous layer of the polymer. The polymer was washed with diethyl ether and drove volatile substances. Finally got to 14.7 g of a dark red solid, sticky, but does not exhibit fluidity. Obtained in this way known substance has the structure of a polyolefin (2), consisting entirely of gidroturbinih links.

The main disadvantage of the known substance is its resistance to enzymatic degradation, i.e. lack of ability to biodegradation. A marked disadvantage of the known substance is due to its essential characteristic: the absence in the structure of the ester Misonix relations of type (1). It is known that the five-membered lactones in General are reticent to polymerization by transformation lactone communication polyester (1) [Saz is the new Y. USP - 1968. - T.XXXVII. - 6 - S.1084-1096] and such cycles are revealed only in the polymerization of mixtures of monomers.

The purpose of the claimed invention - a new polymer-based material alpha angelicalactone with adjustable capacity for biodegradation.

This objective is achieved in that the target product contains polyester bonds in its structure. We found that under the action of some of the main catalysts of the type alpha angelicalactone polymerized by disclosure of the cycle (1). This exceptional behavior of alpha-angelicalactone in a series of five-membered lactones be explained by the effect of double bonds on the ability of furan cycle to its revelation. In suitable conditions, polymerization is possible on both routes (1) and (2), and this allows you to get the homopolymers of alpha-angelicalactone with two types Misonix links - carbon-carbon (disclosure of double bonds) (2) and the carbon-oxygen, ester (1) (disclosure of the cycle). Since the molecule of the monomer has two functional groups capable of polymerization under certain conditions, the formation of cross-linked polymers in which some of the links are connected with three or four neighboring:

For these reasons, the claimed substance depending on the ratio of the amounts of polyester, lead-carbon bonds and links of the chains has a wide speed range of biochemical degradation, making it suitable for use in various fields: matrix for drugs prolonged action (the period of the destruction of a few days), surgical sutures (the period of the destruction of a few weeks), biodegradable packaging (the period of destruction from several months to several years).

The inventive substance (polymer material) is characterized by the following set of essential features.

The main distinctive feature of the present invention is that the proposed substance contains in its structure Messinia polyester ties, and their share in the total number of Misonix links ranges from 99% to 1%.

The second distinctive feature of the claimed matter is the presence in its structure of crosslinks between the polymer chains, the number of which ranges from zero to 1,94 per Monomeric unit of the polymer.

Called distinctive features contribute to the achievement of the technical result of the claimed invention: the Biodegradability of polymeric material, i.e. the claimed ability of a substance to undergo biological decomposition with a wide range of speeds, from several days to several years.

The mentioned technical result is a consequence of the specificity and molecular structure of the offer is the first substance, i.e. characteristics of the invention. This means that the technical results and features of the invention are the causal relationships between them.

The positive effects of the invention become apparent in the presented interval ratios of polyester and carbon-carbon Misonix links and crosslinks between polymer chains.

When the content of the polyester Misonix ties less than 1%, and when the content of crosslinks between the polymer chains more 1,95 in the calculation of a monomer technical result of the invention is lost, i.e. the resulting polymer is not prone to biodegradation.

The invention and its technical result is illustrated by the following examples.

Example 1.

Carefully drained alpha angelicalactone (17 g) was mixed with 0.5 g of freshly prepared butyl sodium. The mixture thermostatically at a temperature of 25°With over 220 hours. The obtained polymer was purified by washing with several portions of diethyl ether, and then volatiles were removed by heating to 80°C for 4 hours under a pressure of 14 mm Hg Obtained by 15.4 g of solids, adhesive exhibiting fluidity. Srednevekovaja molecular weight determined by viscometric method [ISO 1628-5:1998] and was 1320 Amu (n=13). The content of the polyester with the ides in the obtained polymer was determined according to the 1H NMR (chemical shift, ppm (integral intensity)): 2.22(43.59), 2.6(7.41), 2.63(7.60), 2.75(7.32), 2.78(7.06), 4.47(2.15), 5.2(12.64) according to the standard technique [Koenig J.L. Spectroscopy of Polymers. Washington, DC: American Chemical Society, 1992.] The calculated content of the polyester linkages in the resulting polymer is 0.6 per link monomer.

The ability to biodegradation was evaluated by the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis accounted for one week 124 and 52%, respectively. Reduction srednevekovoi molecular weight of the polymer was 80% for two weeks.

Example 2 (prototype).

To a solution of 10 g of alpha-angelicalactone in 30 ml of carbon disulfide was added with 0.27 ml of epirate of boron TRIFLUORIDE. The moderately solution was stirred for 5 hours. Then decantation colorless surface layer of the solvent from the viscous layer of the polymer. The polymer is washed several times with diethyl ether, then volatiles were removed by heating to 80°C for 4 hours under a pressure of 14 mm Hg Obtained 9.3 g of a dark red solid, sticky, does not exhibit fluidity. The molecular mass determined viscometric [ISO 1628-5:1998], is 690 u

According to the1The NMR of the obtained polymer (chemical shift, ppm (integral intensity)): 2.01(68.20), 2.05(64.31), 2.55(45.92), 2.58(41.51), 2.67(40.96), 2.70(47.25), 3.24(6.94), 3.27(at 13.92), 3.30(13.90), 3.33(6.95), as well as the description of the prototype [Marvel C.S., C.L. Levesque J. Am. Chem. Soc. - 1939. - V.61. - P.1682-1684], the obtained polymer has a polyester Misonix links. The ability to biodegradation was evaluated by the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer in the process of biodegradation. The obtained polymer (prototype) not amenable to biodegradation during the year.

Example 3.

Carefully drained alpha angelicalactone (19 g) was mixed with 0.1 g of freshly prepared butyl sodium and 0.1 g of benzoyl peroxide. The mixture thermostatically at a temperature of 25°With over 220 hours. The obtained polymer was purified by washing with several portions of diethyl ether, and then volatiles were removed by heating to 80°C for 4 hours under a pressure of 14 mm Hg Obtained 18,6 g solids, adhesive exhibiting fluidity. The content of the polyester linkages in the resulting polymer defined according to the1H NMR of the obtained polymer (chemical shift, ppm (integral intensity)): 2.01(68.20), 2.05(64.31), 2.55(45.92), 2.58(41.51), 2.67(40.96), 2.70(47.25), 3.24(6.94), 3.27(at 13.92), 3.30(13.90), 3.33(6.95), 5.02(0.72), is 0.01 per link monomer. The ability to biodegradation was determined is about the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis is not registered. Reduction srednevekovoi molecular weight of the polymer was 20% during the year.

Example 4.

Carefully drained alpha angelicalactone (19 g) was mixed with 0.9 g of freshly prepared butyl sodium. The mixture thermostatically at a temperature of 18°With over 315 hours. The obtained polymer was purified by washing with several portions of diethyl ether, and then volatiles were removed by heating to 80°C for 4 hours under a pressure of 14 mm Hg Received 17.3 g solids, adhesive exhibiting fluidity during N.U. The molecular mass was 16500 Amu (n=168). The content of the polyester linkages in the resulting polymer defined according to the1H NMR (chemical shift, ppm (integral intensity)): 2.25(32.18), 2.62(5.33), 2.65(5.42), 2.78(5.39), 2.81(5.36), 4.50(0.13), 5.13(9.26))is 0.99 per one link monomer.

The ability to biodegradation was determined by the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis accounted for a week 182 and 56%, respectively. Reduction srednevekovoi molecular weight of the polymer, determined by the method viscosity, decreased during the week s u up to 3300 u, which is 80%.

Example 5.

The polymer content of polyester ties 0,99 on the link, obtained as in example 4 were subjected to gamma irradiation (2,7·103roentgen/h) within ten days. The obtained solid substance that does not exhibit fluidity. Molecular weight ≈280000 u Content mismanaging links and crosslinks in the obtained polymer was determined according to the1H NMR (chemical shift, ppm (integral intensity)): 2.31(47.32), 2.68(8.21), 2.71(8.05), 2.84(8.16), 2.87(8.10), 4.50(0.19), 5.13(0.41), 5.64(12.83) according to the standard technique [Koenig J.L. Spectroscopy of Polymers. Washington, DC: American Chemical Society, 1992.].

The obtained polymer to the number of crosslinks of 1.94 per Monomeric unit of the polymer. The calculation of the values of the coefficients m and n gives the values of m≈5820 and n≈3000.

The ability to biodegradation was determined by the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis is not registered. Reduction srednevekovoi molecular weight of the polymer, determined by the method viscosity, decreased during the year with 280000 u 224000 to u, i.e. by 20% during the year.

Example 6.

The polymer content of polyester ties 0,99 on the link, obtained as in example 4, was subjected to ultraviolet irradiation of the structure (50 watts) during the day. The resulting substance with a molecular weight of 145,000 u Content mismanaging links and crosslinks in the obtained polymer was determined according to the1H NMR (ppm, (int) 2.28(38.52), 2.59(6.40), 2.62(6.39), 2.75(6.45), 2.78(6.42), 4.48(0.15), 5.20(8.71), 5.64(1.86)).

The obtained polymer to the number of crosslinks 0.3 per Monomeric unit of the polymer. The calculation of the values of the coefficients m and n gives the values of m≈450 and n≈1400.

The ability to biodegradation was determined by the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis is not registered. Reduction srednevekovoi molecular weight of the polymer was 70% during the year.

Example 7.

The polymer content of polyester ties 0,99 on the link, obtained as in example 4, was subjected to UV irradiation (50 watts) for 1 hour. The resulting substance with a molecular mass of 52840 u Content mismanaging links and crosslinks in the obtained polymer was determined according to the1H NMR (ppm, (int) 2.3(40,12), 2.61(6.60), 2.64(6.59), 2.77(6.55), 2.80(6.62), 4.51(0.15), 5.10(10.32)).

The obtained polymer to the number of crosslinks 0,01 per Monomeric unit of the polymer. The calculation of the values of the coefficients m and n, p.3) gives the values of m≈5 and n≈540.

The ability to biodegradation definition is ranged according to the method of determining the increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis (VSB-906) according to GOST 171-81 and change the rheological properties of the polymer. The increase in dry weight of the microorganism Sacharomices cerevisae and Candida parapsilosis accounted for a week 180 and 57%, respectively. Reduction srednevekovoi molecular weight of the polymer was 80% during the week.

The product of the polymerization of alpha-angelicalactone characterized by two types Misonix links - carbon-carbon polyolefin and carbon-oxygen polyester containing polyether Messinia communication number from 0.01 to 0.99 in the calculation of a monomer and crosslinking between chains in number from zero to 1,94 per Monomeric unit of the polymer obtained by the polymerization of alpha-angelicalactone in the presence of butyl sodium at 18-25°for 220-315 h, with further purification of diethyl ether, removal of volatiles by heating at 80°C for 4 h under a pressure of 14 mm Hg, and then subjected to gamma or UV radiation.



 

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