EP0991692A1 - Novel monomers with dilactonic cycle, and corresponding polymers - Google Patents
Novel monomers with dilactonic cycle, and corresponding polymersInfo
- Publication number
- EP0991692A1 EP0991692A1 EP98933753A EP98933753A EP0991692A1 EP 0991692 A1 EP0991692 A1 EP 0991692A1 EP 98933753 A EP98933753 A EP 98933753A EP 98933753 A EP98933753 A EP 98933753A EP 0991692 A1 EP0991692 A1 EP 0991692A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- acid
- copolymer
- monomer
- ose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 39
- 239000000178 monomer Substances 0.000 title claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- 229920001577 copolymer Polymers 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000006116 polymerization reaction Methods 0.000 claims description 13
- 238000007334 copolymerization reaction Methods 0.000 claims description 12
- 150000001261 hydroxy acids Chemical class 0.000 claims description 12
- 150000007513 acids Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000004005 microsphere Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 229920001519 homopolymer Polymers 0.000 claims description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- IWHLYPDWHHPVAA-UHFFFAOYSA-N 6-hydroxyhexanoic acid Chemical class OCCCCCC(O)=O IWHLYPDWHHPVAA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- APRRQJCCBSJQOQ-UHFFFAOYSA-N 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound OS(=O)(=O)C1=CC(O)=C2C(N)=CC(S(O)(=O)=O)=CC2=C1 APRRQJCCBSJQOQ-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 6
- 231100000252 nontoxic Toxicity 0.000 abstract description 4
- 230000003000 nontoxic effect Effects 0.000 abstract description 4
- 239000007943 implant Substances 0.000 abstract description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 1
- 229920006280 packaging film Polymers 0.000 abstract 1
- 239000000047 product Substances 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- -1 trialkylsilyl ethers Chemical class 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 229950006191 gluconic acid Drugs 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000174 gluconic acid Substances 0.000 description 6
- 239000003999 initiator Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OIYFAQRHWMVENL-UHFFFAOYSA-N 2-(4-oxopyran-3-yl)acetic acid Chemical compound OC(=O)CC1=COC=CC1=O OIYFAQRHWMVENL-UHFFFAOYSA-N 0.000 description 5
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 5
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000009477 glass transition Effects 0.000 description 5
- 235000012208 gluconic acid Nutrition 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 229960003681 gluconolactone Drugs 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 238000001542 size-exclusion chromatography Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 3
- JPIJQSOTBSSVTP-PWNYCUMCSA-N D-erythronic acid Chemical compound OC[C@@H](O)[C@@H](O)C(O)=O JPIJQSOTBSSVTP-PWNYCUMCSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000007306 functionalization reaction Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WMXFNCKPYCAIQW-UHFFFAOYSA-N 1,2-dimethoxy-3-methylbenzene Chemical compound COC1=CC=CC(C)=C1OC WMXFNCKPYCAIQW-UHFFFAOYSA-N 0.000 description 2
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 2
- OZGMODDEIHYPRY-UHFFFAOYSA-N 2-bromopropanoyl chloride Chemical compound CC(Br)C(Cl)=O OZGMODDEIHYPRY-UHFFFAOYSA-N 0.000 description 2
- QOBYJDJSRIKUPS-UHFFFAOYSA-N 4-(3,6-dioxo-1,4-dioxan-2-ylidene)-2-oxopentanal Chemical compound O=CC(=O)CC(C)=C1OC(=O)COC1=O QOBYJDJSRIKUPS-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 241000052343 Dares Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 229940061720 alpha hydroxy acid Drugs 0.000 description 2
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- ROBFUDYVXSDBQM-UHFFFAOYSA-N hydroxymalonic acid Chemical compound OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- XZZXKVYTWCYOQX-UHFFFAOYSA-J octanoate;tin(4+) Chemical compound [Sn+4].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O XZZXKVYTWCYOQX-UHFFFAOYSA-J 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
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- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical class COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 description 1
- 206010056474 Erythrosis Diseases 0.000 description 1
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- 238000004566 IR spectroscopy Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 238000012662 bulk polymerization Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 125000000422 delta-lactone group Chemical group 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- FLISWPFVWWWNNP-BQYQJAHWSA-N dihydro-3-(1-octenyl)-2,5-furandione Chemical compound CCCCCC\C=C\C1CC(=O)OC1=O FLISWPFVWWWNNP-BQYQJAHWSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000013365 molecular weight analysis method Methods 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000004172 nitrogen cycle Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CRHIAMBJMSSNNM-UHFFFAOYSA-N tetraphenylstannane Chemical compound C1=CC=CC=C1[Sn](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CRHIAMBJMSSNNM-UHFFFAOYSA-N 0.000 description 1
- 230000000930 thermomechanical effect Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003746 yttrium Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- New monomers with a dilactonic cycle and corresponding polymers.
- the invention relates to new monomers with a dilactonic cycle, as well as the corresponding polymers, their preparation and the materials containing them.
- Biocompatible and / or biodegradable polymers are also of great interest in the production of packaging products for products manufactured in industry, including the food industry, due to the ever increasing constraints linked to the Environmental Protection.
- biodegradable polymers based on non-toxic products it is desirable to use raw materials of agricultural, plant or animal origin, which present in particular the advantage of avoiding complex chemical syntheses, when it is desired obtain products degradable into non-toxic compounds, and in particular degradable into natural products.
- the products of agricultural origin the dares and their derivatives constitute an abundant and relatively inexpensive raw material.
- their use poses several problems, in particular the presence of numerous hydroxyl groups which are all capable of reacting and which therefore make it difficult to obtain defined products.
- R is the residue of an acid R-CHOH-C0 2 H derived from a ose, the functional groups contained in R being optionally substituted, and X represents a group -C (R 1 ) (R2) - or
- the invention also relates to polymers (homopolymers and copolymers) obtained using a monomer of formula III and optionally other comonomers. These polymers are those which contain units of formula I
- the aryl groups including those present in the aralkyl groups, denote in particular optionally substituted phenyl groups, and the alkyl groups denote in particular those having from 1 to 4 carbon atoms.
- the polymers of the invention are in particular linear polymers having average molar masses which can range, for example, from 1000 to 3 million approximately.
- the acids derived from an ose can be chosen, for example, from those derived from an ose having from 3 to 7 carbon atoms, and in particular from 4 to 6 carbon atoms, including glyceraldehyde, erythrosis, threose , lyxose, xylose, arabinose, ribose, glucose, galactose and mannose, in the form of their various isomers, and in particular those of the D series. aldonic, uronic and aldaric acids.
- aldonic acids mention may be made in particular of gluconic, mannonic, galactonic, ribonic, arabinonic, xylonic and erythronic acids.
- uronic acids mention may be made, for example, of glucuronic, galacturonic and mannuronic acids.
- aldaric acids tartronic acid and tartaric, glucaric, galactaric and xylaric acids are particularly mentioned.
- the acid derived from an ose is an aldonic acid, that is to say an acid of formula: H- (CHOH) m -C0 2 H in which m is an integer which can vary in particular from 2 to 6, the monomers of formula III are in particular those for which R represents an H- (CHOH) - t group or a corresponding group in which one or more hydroxyl groups are substituted;
- 0 CH- (CHOH) F-1 - or a corresponding group in which one or more hydroxyl groups are substituted;
- the monomer of formula Illa can also be, as is easily understood, in the form of a derivative comprising the dilactonic ring at each of its ends; in other words, in this case, R can represent a group of formula VI:
- q is an integer which can vary for example from 2 to 5.
- monomers of formula Illa comprising two dilactonic rings, have the advantage of constituting not only polymerization agents, but also, because of their bifunctional nature , crosslinking agents, which can crosslink in particular any polymer capable of reacting with a lactone, that is to say any polymer comprising mobile proton functions such as alcohol, acid functions (carboxylic, hemisulfate, monophosphate, diphosphate, sulfonic ) or primary or secondary amino functions.
- a protected group denotes a group which is reversibly or irreversibly modified, by substitution (in this sense, "protected” and “substituted” are here synonymous), the substituent being able to be a protective group in the usual sense or a group which, in addition to its protective role (temporary or not), is capable of bringing advantageous properties such as a pharmaceutical or cosmetological activity, a coloring power, a fluorescent activity cence, phytosanitary properties, in particular a pesticidal effect (for example insecticide), thermo-reversible properties, thermosensitive or photosensitive activity, etc.
- the expression “protecting group” therefore designates, in general, such substituents. Groups capable of temporarily or not protecting hydroxyl groups are known. We can quote for example:
- - ethers such as methyl, vinyl, benzyl, trityl, tetrahydrofuranyl, p-nitrobenzyl, 3, 4-dethmethoxybenzyl, 2-methoxyethoxymethyl ethers; or alternatively silyl ethers such as trialkylsilyl ethers, alkyldiphenylsilyl ethers, alkylphenylalkoxysilyl ethers, which can be obtained by the action on an alcohol of a corresponding silyl halide,
- esters in particular sulfonates, including alkylsulfonates, phosphates, including dialkylphosphates, borates, acetates, benzoates, pivalates, sulfates, nitrates, etc.,
- - cyclic acetals obtained by the action of a carbonyl compound or one of its derivatives (in particular acetone, benzaldehyde and formaldehyde) on two hydroxyl groups carried by two carbons located one relative to the other in the ⁇ or ⁇ position on the compound carrying the hydroxyls to be protected, which leads to cyclic acetals containing in particular an isopropyl group dene, benzylidene or methylene connecting the two hydroxyls considered; for example, by reaction of gluconic acid with paraformaldehyde, a diacetal is obtained 2.4-3.5 and by reaction with acetone, a diacetal is obtained 3.4-5.6.
- a carbonyl compound or one of its derivatives in particular acetone, benzaldehyde and formaldehyde
- the two hydroxyls in alpha of the carboxylic groups can be temporarily protected by formation of a cyclic acetal, for example with dimethoxytoluene.
- the remaining unprotected hydroxyl can then be protected using 2-methoxyethoxymethyl chloride to form the corresponding ether.
- the two hydroxyls can then be released into alpha by catalytic hydrogenation.
- the compound of formula Illa can be prepared (with R representing a group of formula VI) without having to carry out operations for protecting the hydroxyls.
- the monomers of formula Illa can be homopolymé ⁇ sés or copolymerized according to the usual methods.
- the polymerization reactions are carried out on compounds of formula III in which the hydroxyl groups, and the carboxylic group possibly present, are in protected form.
- the polymerization conditions are, for example, those described below in the particular case of the copolymerization.
- the protected functions can be totally or partially deprotected, then, if desired, functionalized (in particular by esterification, etherification, etc.) so as to introduce into the polymer chemical groups capable of imparting desired properties.
- tees for example biodegradab lite and / or biosorbability properties, or also solubility properties (in water or in other solvents), hydrophilicity or hydrophobicity properties, resistance properties mechanical, gas permeability properties, crosslinking properties, etc.
- the apolar character of the polymers can be increased by functionalizing them with fatty chains, in particular by esterification using anhydrides of acyl succinyl or alkenyl succinic acids, such as octenyl succinic anhydride .
- the solubility characteristics, as well as the glass transition temperature of the polymers of the invention can be modulated by crosslinking them, thanks to the reactivity of the protected hydroxyl groups, or by grafting the polymers onto multifunctional products such as silica or granular starch. It is possible to crosslink in particular using the products of formula Illa derived from an aldaric acid having two lactonic cycles, as mentioned previously.
- the monomers and polymers of the invention can be used in various fields such as agriculture, pharmacy, medicine, surgery, agrochemistry, stationery, packaging, etc. In these fields of application, the polymers of the invention can, depending on the case, be used in particular as rheology agents, bonding agents, suspending agents, binding agents, surfactants, crosslinking agents or packaging agents.
- the polymers of the invention can be used in particular in the field of packaging (in particular in the form of films possibly deposited on metal sheets or sheets of paper), in medicine and in surgery (pieces of osteosyn- these, implants or microspheres for the gradual release of drugs, sutures), the paper industry (paper lamination), agriculture (mulching using films), etc.
- the monomers of formula Illa can be copolymerized with any other monomer containing mobile proton groups, and in particular:
- - acids, and in particular diacids, of non-osidic structure in particular those containing five or more carbon atoms, such as itaconic acid;
- - lactones such as poly-epsilon-caprolactone, lactide or glycolide;
- hydroxy acids HO-L-C0 2 H capable of forming a dilactonic ring are for example the ⁇ -hydroxy acids of formula: HO-C (R 5 ) (R 6 ) -C0 2 H in which R 5 and R 6 independently represent - H, alkyl, aryl
- hydroxy acids are in particular those for which at least one of the substituents R 5 and Rg represents -H, for example glycolic acid or lactic, mandelic and malic acids.
- the units of formula II formed with these ⁇ -hydroxy acids are therefore units:
- the carboxylic groups optionally present in R 5 and / or Rg can be in free or protected form.
- the carboxylic groups can be protected in particular in the form of esters.
- the hydroxy acids HO-L-C0 2 H capable of forming a monolactone are in particular hydroxy carboxylic acids having a hydroxy group in the ⁇ , ⁇ or ⁇ position relative to the carboxyl. Mention will in particular be made of hydroxy acids capable of giving a mono- lactone forming a ring having at least 6 links.
- the hydroxy acids of formula HO-L-C0 2 H capable of giving a ring-forming lactone having at least six links can be chosen in particular from aldonic acids, such as those mentioned above, having at least 5 carbon atoms, of which the hydroxyl groups not involved in the formation of the lactone can be in free or protected form.
- hydroxy acids capable of forming a lactonic ring having at least 6 members mention may also be made of 5-hydroxypentanoic, 2, 3, 4-trimethoxy 5-hydroxypentanoic, 6-hydroxy hexanoic acids, etc.
- the subject of the invention is in particular a copolymer containing: from 1 to 99%, in number of units relative to the total number of units, of units of formula I:
- R is the residue of an acid R-CHOH-C0 2 H derived from a ose, the functional groups contained in R being optionally substituted
- X represents a group -C (R 1 ) (R 2 ) - or -C ( R ⁇ ) (R 2 ) -C (R 3 ) (R 4 ) - in which R ] _, R 2 , 3 and R 4 independently represent -H or an alkyl, allyl, aryl or aralkyl group, and at least 1 %, in number of units relative to the total number of units, of units of formula II:
- L is the remainder of a HO-L-C0 2 H hydroxy acid chosen from hydroxy acids capable of forming a dilactonic ring or a monolactone.
- a HO-L-C0 2 H hydroxy acid chosen from hydroxy acids capable of forming a dilactonic ring or a monolactone.
- homopolymers and copolymers of the invention can be used in particular in the form of various materials or of finished articles such as powders, microspheres, films, parts molded parts, extruded parts, etc., which can be prepared according to the usual techniques.
- the invention also relates to a process for preparing a monomer or a polymer as defined above, in which:
- R ' is the remainder of an acid derived from a ose, the hydroxyl groups possibly contained in R' being protected, with an acid chloride of formula:
- the said compound of formula III is polymerized, by homopolymerization or by copolymerization with a comonomer,
- the copolymer obtained is put in the form of a powder, of microspheres of a film, of a molded part or of an extruded part.
- the invention relates in particular to a process for the preparation of a copolymer or of a finished material or article as defined above.
- the invention relates in particular to a process in which: a) reacting, under conditions allowing the copolymerization: at least one monomer of formula III: in which :
- R ' is the remainder of an acid R'-CHOH-C0 H derived from an ose, whose hydroxyl groups possibly contained in R' are protected, and X, R ⁇ , R 2 , R 3 and R 4 are defined as before, and at least one monomer chosen from dilactones and monolactones deriving from a hydroxy acid H0-L-C0 2 H as defined above, b) if desired, at least part of the hydroxyl groups are deprotected and / or functionalized of R ', c) and, if desired, the copolymer obtained is put in the form of a powder, microspheres, a film, a molded part or an extruded part.
- the copolymerization process of the invention therefore consists in reacting a compound of formula III as defined above: a) with a compound of formula IV such as for example glycolide or D-, L- or DL -lactide and / or b) with a monolactone, and in particular a monolactone forming a ring having at least 6 links, in particular a lactone of an aldonic acid having 5 or 6 carbon atoms (for example ⁇ -gluconolactone), the ⁇ -valero-lactone or 1 ⁇ -caprolactone.
- a compound of formula IV such as for example glycolide or D-, L- or DL -lactide and / or b
- a monolactone and in particular a monolactone forming a ring having at least 6 links, in particular a lactone of an aldonic acid having 5 or 6 carbon atoms (for example ⁇ -gluconolactone), the ⁇ -valero-lactone or 1 ⁇ -caprol
- copolymerization of the compounds of formula III with the compounds of formula IV or the monolactones can be carried out either in bulk or in solution in a solvent, generally in the presence of a suitable catalyst or initiator.
- the temperature and the duration of the reaction depend in particular on the reagents used and on the average molecular weight desired for the copolymer prepared. These parameters can be easily determined by simple routine experiments. Generally, the operation is carried out at a temperature of 20 to 200 ° C. under an inert atmosphere or in a sealed reactor, for a time which can range, for example, from a few minutes to 30 days.
- the initiators or catalysts used in the reaction of copolymerization are of a type known for this kind of reaction; there may be mentioned in particular tin octanoate, tetraphenyl tin, powdered metallic zinc, zinc lactate, alkoxyaluminum, lanthanide or yttrium derivatives.
- the polymer obtained can be purified according to the usual methods.
- Functionalization makes it possible to provide the copolymers with specific properties, in particular pharmaceutical properties (using a substituent derived from a drug), physical properties (for example thermal properties, solubility), physicochemical properties (for example hydrophilic or hydrophobic properties), or a particular chemical reactivity, including biodegradability and / or bioresorbability properties.
- Functionalization using bi-functional reagents also makes it possible to crosslink.
- dicarboxylic derivatives such as itaconic acid make it possible to carry out crosslinking by reaction with hydroxyl groups of the polymer
- polyols for example oses or polyethylene glycols
- the starting product of formula III can be prepared by reaction of an acid R '-CHOH-C0 H, as defined above with an acid chloride of formula: YX-CO-Z, in which X is defined as above ,
- Y is a halogen, and in particular chlorine or, preferably bromine,
- Z is a halogen, and in particular bromine or, preferably, chlorine.
- a product of formula V is thus obtained: YX-CO-0-CH (R ') -C0 2 H (V) which is transformed into compound of formula III by intra-molecular cyclization, with elimination of hydrohalic acid YH.
- the copolymers of the invention may be random copolymers or block copolymers of type AB, ABA or BAB, A being for example a polymerization product composed of units of formula I and B a polymerization product composed of units derived from the comonomer used , for example units of formula II.
- block polymers can be obtained in particular when the polymerization of the compound of formula III is started before adding the comonomer, for example monolactone or dilactone.
- the properties of the copolymer can be modulated.
- the glass transition temperature of the copolymer increases, compared to the glass transition temperature of poly (lactic acid), when the proportion of units derived from compound III increases (see the experimental part below).
- Tf melting temperature
- PLA50 poly (D, L-lactide) ⁇ -gluconolactone: ⁇ -D-gluconolactone gluconic acid: D-gluconic acid EXAMPLE 1 Preparation of DIPAGYL (monomer derived from gluconic acid)
- the solvents are evaporated off under reduced pressure at 30 ° C.
- the residue is dissolved in ether and washed with water.
- the organic phase is dried over magnesium sulfate, then the solvent is evaporated.
- the product obtained is in the form of a colorless viscous oil, insoluble in water and in hexane and soluble in organic solvents such as ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF.
- [ ⁇ ] D -1.8 ° cm 2 g _1 (589 nm, dioxane).
- a white powder is obtained, soluble in organic solvents such as ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF, and soluble in water at basic pH. The product reprecipitates at acid pH. It is insoluble in hydrocarbon solvents.
- organic solvents such as ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF
- the product reprecipitates at acid pH. It is insoluble in hydrocarbon solvents.
- Mp 154 ° C.
- [ ⁇ ] D -1, 6 ° cm 2 g _1 (589 nm, dioxane).
- a product is obtained in the form of an oil soluble in ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF and methanol insoluble in water and partially soluble in hexane and in cyclohexane (hot).
- the product which is sensitive to hydrolysis, is stored in the freezer.
- the product is soluble in ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane, DMF, methanol, as well as in cyclohexane (hot).
- EXAMPLE 2 Preparation of 3- (1, 2-dioxoethyl-isopropylidene) - dioxane-2, 5-dione.
- a) An aqueous solution containing erythronic acid in equilibrium with erythronolactone is used as the starting product. This aqueous solution contains 29.4% by weight of erythonic acid and 30.4% by weight of erytronolactone. 20 grams of this solution are evaporated under reduced pressure at 60 ° C. A white powder is obtained which is redissolved in methanol and precipitated with ether. The precipitate is filtered and dried under reduced pressure.
- the 3- (1,2-dioxoethyl-isopropylidene) - dioxane -2,5-dione obtained is a solid melting at 92 ° C. It can be purified by sublimation at 80 ° C. under reduced pressure (10 " mm of mercury, ie 0.13 Pa). The IR and 1 H NMR spectra are in agreement with the structure indicated.
- step c) By replacing, in step c) above, the bromine chloride acetyl with 2-bromopropionyl chloride, a compound of formula III derived from erythronic acid is obtained, in which X represents -CH (CHj) -.
- the products obtained at the end of the polymerization reaction come in different aspects.
- sample 1 was purified by dissolution in dioxane and precipitation in ethanol.
- Table 2 Molar masses of the products obtained by polymerization of DIPAGYL, after purification.
- DIPAGYL and D, L-lactide are placed in a flask and subjected to degassing by performing 3 cycles including evacuation (10 -3 mbar) at 90 ° C, then passing a current of cold argon . Then the initiator (tin octanoate) is added. The initiator / comonomer molar ratio is 1/600.
- the flask is sealed under reduced pressure and placed in an oil bath. The flask is rotated about an inclined axis during the copolymerization reaction. The copolymerization reaction is carried out for 5 days under vacuum at a temperature of 120 ° C. At the end of the reaction, the reaction mixture is allowed to cool and the ambient pressure is restored.
- the copolymerization yields are close to 90%.
- Poly (DIPAGYL-co-D, L-lactide) are film-forming and moldable polymers. Films can be obtained in particular by evaporation of a solution of the copolymer in a solvent such as acetone or dioxane.
- Molded parts can be obtained for example under the following molding conditions:
- the poly (DIPAGYL-co-D, L-lactide) obtained in Example 4 contain alcohol functions protected by acetal protecting groups. By elimination of the protective groups in an acid medium, the corresponding polyhydroxylated polymers can be obtained.
- the mass-average molar mass of the partially deprotected copolymer represents approximately 75% of that of the starting copolymer.
- Dimethoxytoluene and methanol are made to act on xylaric acid in the presence of p-tolene sulfonic acid. After three days of stirring at room temperature, the solvents are evaporated in the cold under reduced pressure. After purification, methyl 2,4-benzylidene xylarate is obtained.
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Abstract
The invention concerns monomers with dilactonic cycle and the corresponding polymers, their preparation, and materials containing these polymers. The monomers are of formula (IIIa) in which R is the residue of a acid derived from an ose such as glyconic, gylcuronic or glycaric acid and X represents in particular a methylene or ethylene group optionally substituted by at least an alkyl, allyl, aryl or aralkyl. The corresponding polymers are in the form of degradable non-toxic products and are used for example for packaging (films) or in medicine (implants).
Description
Nouveaux monomères à cycle dilactonique, et polymères correspondants. New monomers with a dilactonic cycle, and corresponding polymers.
L'invention concerne de nouveaux monomères à cycle dilacto- nique, ainsi que les polymères correspondants, leur préparation et les matériaux les contenant.The invention relates to new monomers with a dilactonic cycle, as well as the corresponding polymers, their preparation and the materials containing them.
On sait que dans le domaine médical et chirurgical, on utilise actuellement, et on recherche aussi, des polymères biocompatibles et biorésorbables pour réaliser par exemple des pièces d'ostéo- synthèse, des implants capables de libérer progressivement des médicaments, des fils de suture, etc.We know that in the medical and surgical field, biocompatible and bioresorbable polymers are currently used, and research is also being carried out, for example for producing osteosynthesis pieces, implants capable of progressively releasing medicaments, sutures, etc.
Les polymères biocompatibles et/ou biodégradables présentent également un grand intérêt dans la réalisation de produits d'emballage pour les produits fabriqués dans l'industrie, y compris 1 ' in- dustrie agro-alimentaire, en raison des contraintes sans cesse croissantes liées à la protection de l'environnement.Biocompatible and / or biodegradable polymers are also of great interest in the production of packaging products for products manufactured in industry, including the food industry, due to the ever increasing constraints linked to the Environmental Protection.
Il est donc important de pouvoir disposer d'une gamme de polymères qui soient dégradables en produits non toxiques et qui présentent des propriétés (notamment des propriétés mécaniques, thermo- mécaniques, physico-chimiques, etc.) variées.It is therefore important to be able to have a range of polymers which are degradable into non-toxic products and which have varied properties (in particular mechanical, thermo-mechanical, physico-chemical properties, etc.).
On a maintenant découvert de nouveaux monomères conduisant à des polymères qui présentent un grand intérêt dans les domaines qui viennent d'être évoqués.We have now discovered new monomers leading to polymers which are of great interest in the fields which have just been mentioned.
Pour réaliser des polymères biodégradables à base de pro- duits non toxiques, il est souhaitable d'utiliser des matières premières d'origine agricole, végétales ou animales, qui présentent notamment l'intérêt d'éviter des synthèses chimiques complexes, lorsqu'on souhaite obtenir des produits dégradables en composés non toxiques, et en particulier dégradables en produits naturels. Parmi les produits d'origine agricole, les oses et leurs dérivés constituent une matière première abondante et relativement bon marché. Toutefois, leur utilisation pose plusieurs problèmes, en particulier la présence de nombreux groupes hydroxyle qui sont tous susceptibles de réagir et qui rendent donc difficile l'obtention de produits définis.To produce biodegradable polymers based on non-toxic products, it is desirable to use raw materials of agricultural, plant or animal origin, which present in particular the advantage of avoiding complex chemical syntheses, when it is desired obtain products degradable into non-toxic compounds, and in particular degradable into natural products. Among the products of agricultural origin, the dares and their derivatives constitute an abundant and relatively inexpensive raw material. However, their use poses several problems, in particular the presence of numerous hydroxyl groups which are all capable of reacting and which therefore make it difficult to obtain defined products.
Ces problèmes peuvent parfois être résolus en protégeant sélectivement certains hydroxyles, temporairement ou définitivement, à
l'aide de groupements protecteurs appropries, de façon connue. Cependant, l'utilisation de groupements protecteurs ne suffit pas à résoudre tous les problèmes rencontres. Ainsi, lors de leurs recherches, les auteurs de la présente invention ont constate que, bien que les δ-lactones soient réputées polymérisables, la δ-gluconolactone, dont les groupements hydroxyle non impliqués dans la formation du cycle lactonique sont protèges, ne forme au mieux que des oligomères de faible masse moléculaire.These problems can sometimes be resolved by selectively protecting certain hydroxyls, temporarily or permanently, to with the aid of appropriate protective groups, in known manner. However, the use of protective groups is not enough to solve all the problems encountered. Thus, during their research, the authors of the present invention have found that, although δ-lactones are reputed to be polymerizable, δ-gluconolactone, whose hydroxyl groups not involved in the formation of the lactonic cycle are protected, does not form at better than low molecular weight oligomers.
On a maintenant découvert un nouveau type de monomères qui possèdent un cycle dilactonique et qui permettent notamment d'obtenir des polymères ayant des degrés de polymérisation qui, si on le désire, peuvent être suffisamment élevés. On peut ainsi disposer par exemple de toute une gamme de copolymères dont on peut facilement ajuster les propriétés en agissant notamment sur les proportions respectives des comonomères. Le composé à cycle dilactonique constituant le monomère de l'invention répond à la formule Illa :We have now discovered a new type of monomer which has a dilactonic ring and which makes it possible in particular to obtain polymers having degrees of polymerization which, if desired, can be sufficiently high. It is thus possible, for example, to have a whole range of copolymers whose properties can easily be adjusted by acting in particular on the respective proportions of the comonomers. The compound with a dilactonic cycle constituting the monomer of the invention corresponds to the formula Illa:
R dans laquelle : R est le reste d'un acide R-CHOH-C02H dérivé d'un ose, les groupes fonctionnels contenus dans R étant éventuellement substitués, et X représente un groupe -C(R1) (R2)- ouR in which: R is the residue of an acid R-CHOH-C0 2 H derived from a ose, the functional groups contained in R being optionally substituted, and X represents a group -C (R 1 ) (R2) - or
-C(R1) (R2)-C(R3) (R4)- dans lequel Rχ, R2, R3 et R représentent îndé- pendamment -H ou un groupement alkyle, allyle, aryle ou aralkyle.-C (R 1 ) (R 2 ) -C (R 3 ) (R 4 ) - in which R χ , R 2 , R 3 and R independently represent -H or an alkyl, allyl, aryl or aralkyl group.
L'invention concerne également des polymères (homopolymères et copolymères) obtenus à l'aide d'un monomère de formule III et éventuellement d'autres comonomères. Ces polymères sont ceux qui contiennent des motifs de formule IThe invention also relates to polymers (homopolymers and copolymers) obtained using a monomer of formula III and optionally other comonomers. These polymers are those which contain units of formula I
—FÔ-CH (R) -CO-0-X-CO~ - : D dans laquelle R et X sont définis comme précédemment.—FÔ-CH (R) -CO-0-X-CO ~ -: D in which R and X are defined as above.
Dans la présente demande, les groupements aryle, y compris ceux présents dans les groupes aralkyle, désignent notamment des
groupements phényle éventuellement substitués, et les groupements alkyle désignent notamment ceux ayant de 1 à 4 atomes de carbone.In the present application, the aryl groups, including those present in the aralkyl groups, denote in particular optionally substituted phenyl groups, and the alkyl groups denote in particular those having from 1 to 4 carbon atoms.
Les polymères de 1 ' invention sont notamment des polymères linéaires ayant des masses molaires moyennes pouvant aller par exem- pie de 1000 à 3 millions environ.The polymers of the invention are in particular linear polymers having average molar masses which can range, for example, from 1000 to 3 million approximately.
Les acides dérivés d'un ose peuvent être choisis par exemple parmi ceux dérivés d'un ose ayant de 3 à 7 atomes de carbone, et en particulier de 4 à 6 atomes de carbone, y compris le glycéraldéhyde, l'érythrose, le thréose, le lyxose, le xylose, l'arabinose, le ri- bose, le glucose, le galactose et le mannose, sous la forme de leurs divers isomères, et en particulier ceux de la série D. Les acides dérivés d'osés sont notamment les acides aldoniques, uroniques et aldariques .The acids derived from an ose can be chosen, for example, from those derived from an ose having from 3 to 7 carbon atoms, and in particular from 4 to 6 carbon atoms, including glyceraldehyde, erythrosis, threose , lyxose, xylose, arabinose, ribose, glucose, galactose and mannose, in the form of their various isomers, and in particular those of the D series. aldonic, uronic and aldaric acids.
Parmi les acides aldoniques, on citera en particulier les acides gluconiques, mannoniques, galactoniques , riboniques, arabino- niques, xyloniques et érythroniques .Among the aldonic acids, mention may be made in particular of gluconic, mannonic, galactonic, ribonic, arabinonic, xylonic and erythronic acids.
Parmi les acides uroniques, on citera par exemple les acides glucuroniques, galacturoniques et mannuroniques .Among the uronic acids, mention may be made, for example, of glucuronic, galacturonic and mannuronic acids.
Parmi les acides aldariques, on citera notamment l'acide tartronique et les • acides tartriques, glucariques, galactariques et xylariques .Among aldaric acids, tartronic acid and tartaric, glucaric, galactaric and xylaric acids are particularly mentioned.
Il résulte de ce qui précède que :It follows from the above that:
- lorsque l'acide dérivé d'un ose est un acide aldonique, c'est-à-dire un acide de formule : H-(CHOH)m-C02H dans laquelle m est un nombre entier pouvant varier notamment de 2 à 6, les monomères de formule III sont notamment ceux pour lesquels R représente un groupement H-(CHOH)— t ou un groupement correspondant dans lequel un ou plusieurs groupes hydroxyles sont substitués ;- when the acid derived from an ose is an aldonic acid, that is to say an acid of formula: H- (CHOH) m -C0 2 H in which m is an integer which can vary in particular from 2 to 6, the monomers of formula III are in particular those for which R represents an H- (CHOH) - t group or a corresponding group in which one or more hydroxyl groups are substituted;
- lorsque l'acide dérivé d'un ose est un acide uronique, c'est-à-dire un acide de formule : 0=CH-(CHOH)p-C02H dans laquelle p est un nombre entier pouvant varier notamment de 1 à 5,
les monomères de formule Illa sont notamment ceux pour lesquels R représente un groupement- when the acid derived from an ose is a uronic acid, that is to say an acid of formula: 0 = CH- (CHOH) p -C0 2 H in which p is an integer which can vary in particular 1 to 5, the monomers of formula Illa are especially those for which R represents a group
0=CH- (CHOH)F-1- ou un groupement correspondant dans lequel un ou plusieurs groupes hydroxyle sont substitués ;0 = CH- (CHOH) F-1 - or a corresponding group in which one or more hydroxyl groups are substituted;
- lorsque l'acide dérivé d'un ose est un acide aldarique, c'est-à-dire un acide de formule- when the acid derived from a dare is an aldaric acid, that is to say an acid of formula
H0C- (CHOH)q-C02H dans laquelle q est un nombre entier pouvant varier notam- ment de 1 à 5, les monomères de formule Illa sont notamment ceux pour lesquels R représente un groupement de formuleH0C- (CHOH) q -C0 2 H in which q is an integer which can vary in particular from 1 to 5, the monomers of formula Illa are in particular those for which R represents a group of formula
H02C-(CHOH)q-1- ou un groupement correspondant dans lequel un ou plusieurs groupes hydroxyles sont substitués et/ou dans lequel le groupement carboxylique est modifié, par exemple salifié ou estérifié ; en outre, lorsque q représente un nombre au moins égal à 2, le monomère de formule Illa peut également se présenter, comme on le comprend aisément, sous la forme d'un dérivé comprenant le cycle dilactonique à chacune de ses extrémités ; autrement dit, dans ce cas, R peut représenter un groupement de formule VI :H0 2 C- (CHOH) q - 1 - or a corresponding group in which one or more hydroxyl groups are substituted and / or in which the carboxylic group is modified, for example salified or esterified; in addition, when q represents a number at least equal to 2, the monomer of formula Illa can also be, as is easily understood, in the form of a derivative comprising the dilactonic ring at each of its ends; in other words, in this case, R can represent a group of formula VI:
dans laquelle q est un nombre entier pouvant varier par exemple de 2 à 5. Ces derniers monomères de formule Illa, comportant deux cycles dilactoniques, présentent l'intérêt de constituer non seulement des agents de polymérisation, mais aussi, en raison de leur caractère bifonctionnel, des agents de réticulation, pouvant réticuler notamment tout polymère capable de réagir avec une lactone, c'est-à- dire tout polymère comportant des fonctions à proton mobile telles que des fonctions alcool, acide (carboxylique, hémisulfate, monophosphate, diphosphate, sulfonique) ou encore des fonctions aminé primaire ou secondaire. in which q is an integer which can vary for example from 2 to 5. These latter monomers of formula Illa, comprising two dilactonic rings, have the advantage of constituting not only polymerization agents, but also, because of their bifunctional nature , crosslinking agents, which can crosslink in particular any polymer capable of reacting with a lactone, that is to say any polymer comprising mobile proton functions such as alcohol, acid functions (carboxylic, hemisulfate, monophosphate, diphosphate, sulfonic ) or primary or secondary amino functions.
Les procédés d'obtention de groupes hydroxyles protégés ou
plus généralement substitues sont connus.Processes for obtaining protected hydroxyl groups or more generally substitutes are known.
La protection, et la déprotection éventuelle, des groupes hydroxyles sont connues et ne seront donc pas décrites en détail ici ; on peut citer par exemple T. .GREEN, Protective groups m Or- ganic Synthesis, PGM Wuts, Wiley-Interscience Publication, USAThe protection, and possible deprotection, of the hydroxyl groups are known and will therefore not be described in detail here; we can quote for example T.. GREEN, Protective groups m Organic Synthesis, PGM Wuts, Wiley-Interscience Publication, USA
(1991) .(1991).
De façon plus générale, dans la présente demande, un groupement (ou une fonction) protégé désigne un groupement modifié de façon réversible ou irréversible, par substitution (dans ce sens, "protégé" et "substitué" sont ici synonymes) , le substituant pouvant être un groupe protecteur au sens usuel ou un groupe qui, en plus de son rôle protecteur (temporaire ou non), est susceptible d'apporter des propriétés intéressantes telles qu'une activité pharmaceutique ou cosmétologique, un pouvoir colorant, une activité de fluores- cence, des propriétés phytosanitaires, notamment un effet pesticide, (par exemple insecticide), des propriétés thermo-réversibles, une activité thermosensible ou photosensible, etc. Dans la présente demande, l'expression "groupe protecteur" désigne donc, de façon générale, de tels substituants. Les groupements capables de protéger, temporairement ou non les groupes hydroxyles sont connus. On peut citer par exemple :More generally, in the present application, a protected group (or function) denotes a group which is reversibly or irreversibly modified, by substitution (in this sense, "protected" and "substituted" are here synonymous), the substituent being able to be a protective group in the usual sense or a group which, in addition to its protective role (temporary or not), is capable of bringing advantageous properties such as a pharmaceutical or cosmetological activity, a coloring power, a fluorescent activity cence, phytosanitary properties, in particular a pesticidal effect (for example insecticide), thermo-reversible properties, thermosensitive or photosensitive activity, etc. In the present application, the expression “protecting group” therefore designates, in general, such substituents. Groups capable of temporarily or not protecting hydroxyl groups are known. We can quote for example:
- des éthers tels que les éthers de méthyle, de vinyle, de benzyle, de trityle, de tétrahydrofuranyle, de p-nitrobenzyle, de 3, 4-dιméthoxybenzyle, de 2-méthoxyéthoxyméthyle ; ou encore des éthers silylés tels que les éthers de trialkylsilyle, les éthers d' alkyldiphénylsilyle, les éthers d' alkylphénylalcoxysilyle, qui peuvent être obtenus par l'action sur un alcool d'un halogénure de silyle correspondant,- ethers such as methyl, vinyl, benzyl, trityl, tetrahydrofuranyl, p-nitrobenzyl, 3, 4-dethmethoxybenzyl, 2-methoxyethoxymethyl ethers; or alternatively silyl ethers such as trialkylsilyl ethers, alkyldiphenylsilyl ethers, alkylphenylalkoxysilyl ethers, which can be obtained by the action on an alcohol of a corresponding silyl halide,
- des esters, notamment les sulfonates, y compris les al- kylsulfonates, les phosphates, y compris les dialkylphosphates, borates, acétates, benzoates, pivalates, sulfates, nitrates, etc.,- esters, in particular sulfonates, including alkylsulfonates, phosphates, including dialkylphosphates, borates, acetates, benzoates, pivalates, sulfates, nitrates, etc.,
- des acétals cycliques obtenus par l'action d'un composé carbonylé ou d'un de ses dérivés (notamment l'acétone, le benzaldé- hyde et le formaldéhyde) sur deux groupements hydroxyles portés par deux carbones situés l'un par rapport à l'autre en position α ou β sur le composé portant les hydroxyles à protéger, ce qui conduit a des acétals cycliques contenant notamment un groupement isopropyli-
dène, benzylidène ou méthylène reliant les deux hydroxyles considérés ; par exemple, par réaction de l'acide gluconique avec le para- formaldéhyde, on obtient un diacetal 2,4-3,5 et par réaction avec l'acétone, on obtient un diacetal 3,4-5,6. Pour protéger temporairement l' hydroxyle en alpha du car- boxyle de l'acide dérivé d'osé utilise comme produit de départ, protection qui peut s'avérer nécessaire avant de mettre en œuvre les étapes de protection des autres groupes hydroxyle, on peut procéder par formation d'un complexe métallique. On sait en effet que les acides aldoniques et aldariques forment des complexes avec divers métaux (notamment cuivre, fer, étain, baryum) .- cyclic acetals obtained by the action of a carbonyl compound or one of its derivatives (in particular acetone, benzaldehyde and formaldehyde) on two hydroxyl groups carried by two carbons located one relative to the other in the α or β position on the compound carrying the hydroxyls to be protected, which leads to cyclic acetals containing in particular an isopropyl group dene, benzylidene or methylene connecting the two hydroxyls considered; for example, by reaction of gluconic acid with paraformaldehyde, a diacetal is obtained 2.4-3.5 and by reaction with acetone, a diacetal is obtained 3.4-5.6. In order to temporarily protect the alpha hydroxyl from the carboxyl of the acid derived from oste used as starting material, protection which may prove necessary before implementing the steps for protecting the other hydroxyl groups, it is possible to proceed by forming a metal complex. We know that aldonic and aldaric acids form complexes with various metals (especially copper, iron, tin, barium).
A titre d'exemple, dans le cas de l'acide xylarique, les deux hydroxyles en alpha des groupes carboxyliques peuvent être protégés temporairement par formation d'un acetal cyclique, par exemple avec le diméthoxytoluene . On peut alors protéger 1 'hydroxyle non protégé restant à l'aide du chlorure de 2-méthoxyéthoxyméthyle pour former l'éther correspondant. On peut ensuite libérer les deux hydroxyles en alpha par hydrogénation catalytique.For example, in the case of xylaric acid, the two hydroxyls in alpha of the carboxylic groups can be temporarily protected by formation of a cyclic acetal, for example with dimethoxytoluene. The remaining unprotected hydroxyl can then be protected using 2-methoxyethoxymethyl chloride to form the corresponding ether. The two hydroxyls can then be released into alpha by catalytic hydrogenation.
On remarquera que dans le cas de l'acide tartrique, on peut préparer le composé de formule Illa (avec R représentant un groupe de formule VI) sans avoir a effectuer des opérations de protection des hydroxyles.It will be noted that in the case of tartaric acid, the compound of formula Illa can be prepared (with R representing a group of formula VI) without having to carry out operations for protecting the hydroxyls.
Comme indiqué précédemment, les groupes fonctionnels contenus dans le reste R des motifs de formule I sont éventuellement substitués, par exemple par des groupes protecteurs tels que définis ci-dessus .As indicated above, the functional groups contained in the remainder R of the units of formula I are optionally substituted, for example by protective groups as defined above.
Les monomères de formule Illa peuvent être homopolyméπsés ou copolymérisés selon les méthodes usuelles. De préférence, les réactions de polymérisation sont effectuées sur des composés de for- mule III dont les groupes hydroxyles, et le groupe carboxylique éventuellement présent, sont sous forme protégée. Les conditions de polymérisation sont par exemple celles décrites ci-après dans le cas particulier de la copolymérisation. Après polymérisation, les fonctions protégées peuvent être totalement ou partiellement déproté- gées, puis, si désiré, fonctionnalisées (notamment par estérifica- tion, éthérification, etc. ) de façon à introduire dans le polymère des groupes chimiques capables de conférer des propriétés souhai-
tees, par exemple des propriétés de biodegradab lite et/ou de biore- sorbabilite, ou encore des propriétés de solubilité (dans l'eau ou dans d'autres solvents), des propriétés d' hydrophilie ou d' hydrophobie, des propriétés de résistance mécanique, des propriétés de per- meabilite au gaz, des propriétés d'aptitude à la reticulation, etc.The monomers of formula Illa can be homopolyméπsés or copolymerized according to the usual methods. Preferably, the polymerization reactions are carried out on compounds of formula III in which the hydroxyl groups, and the carboxylic group possibly present, are in protected form. The polymerization conditions are, for example, those described below in the particular case of the copolymerization. After polymerization, the protected functions can be totally or partially deprotected, then, if desired, functionalized (in particular by esterification, etherification, etc.) so as to introduce into the polymer chemical groups capable of imparting desired properties. tees, for example biodegradab lite and / or biosorbability properties, or also solubility properties (in water or in other solvents), hydrophilicity or hydrophobicity properties, resistance properties mechanical, gas permeability properties, crosslinking properties, etc.
A titre d'exemple, on peut augmenter le caractère apolaire des polymères en les fonctionnalisant par des chaînes grasses, en particulier par estérification à l'aide d'anhydrides d'acides acyl- succinyles ou alcénylsuccmyles, tels que l'anhydride octenylsucci- nique.By way of example, the apolar character of the polymers can be increased by functionalizing them with fatty chains, in particular by esterification using anhydrides of acyl succinyl or alkenyl succinic acids, such as octenyl succinic anhydride .
On peut moduler les caractères de solubilité, ainsi que la température de transition vitreuse des polymères de l'invention en les reticulant, grâce à la reactivite des groupes hydroxyles depro- teges, ou encore en greffant les polymères sur des produits multi- fonctionnels tels que de la silice ou un amidon granulaire. On peut reticuler notamment à l'aide des produits de formule Illa dérivés d'un acide aldarique possédant deux cycles lactoniques, comme mentionné précédemment. Les monomères et polymères de l'invention sont utilisables dans des domaines varies tels que l'agriculture, la pharmacie, la médecine, la chirurgie, 1 ' agrochimie, la papeterie, l'emballage, etc. Dans ces domaines d'application, les polymères de l'invention peuvent, selon les cas, être utilises notamment comme agents de rhéologie, agents de collage, agents de suspension, agents liants, agents tensioactifs, agents de reticulation ou agents d'emballage.The solubility characteristics, as well as the glass transition temperature of the polymers of the invention can be modulated by crosslinking them, thanks to the reactivity of the protected hydroxyl groups, or by grafting the polymers onto multifunctional products such as silica or granular starch. It is possible to crosslink in particular using the products of formula Illa derived from an aldaric acid having two lactonic cycles, as mentioned previously. The monomers and polymers of the invention can be used in various fields such as agriculture, pharmacy, medicine, surgery, agrochemistry, stationery, packaging, etc. In these fields of application, the polymers of the invention can, depending on the case, be used in particular as rheology agents, bonding agents, suspending agents, binding agents, surfactants, crosslinking agents or packaging agents.
Les polymères de l'invention peuvent être utilisés notamment dans le domaine de l'emballage (en particulier sous forme de films éventuellement déposés sur des feuilles métalliques ou des feuilles de papier), de la médecine et de la chirurgie (pièces d'ostéosyn- these, implants ou microsphères pour la libération progressive de médicaments, fils de suture), de l'industrie papetière (pelliculage du papier), de l'agriculture (paillage à l'aide de films), etc.The polymers of the invention can be used in particular in the field of packaging (in particular in the form of films possibly deposited on metal sheets or sheets of paper), in medicine and in surgery (pieces of osteosyn- these, implants or microspheres for the gradual release of drugs, sutures), the paper industry (paper lamination), agriculture (mulching using films), etc.
Les monomères de formule Illa peuvent être copolymérisés avec tout autre monomère contenant des groupements à proton mobile, et notamment :The monomers of formula Illa can be copolymerized with any other monomer containing mobile proton groups, and in particular:
- des oses ou dérives d'osés, en particulier des dérives de
pentoses et d'hexoses ;- dares or daring drifts, in particular daggerboards pentoses and hexoses;
- des acides, et notamment des diacides, de structure non osidique, en particulier ceux comportant cinq atomes de carbone ou davantage, comme l'acide itaconique ; - des lactones tels que la poly-epsilon-caprolactone, le lactide ou le glycolide ;- acids, and in particular diacids, of non-osidic structure, in particular those containing five or more carbon atoms, such as itaconic acid; - lactones such as poly-epsilon-caprolactone, lactide or glycolide;
- des polymères tels que ceux décrits dans le brevet européen EP 735104, par exemple les amidons et leurs dérivés, les celluloses et leurs dérivés, les protéines et leurs dérivés, les polymè- res vinyliques ou acryliques, etc. ;- polymers such as those described in European patent EP 735104, for example starches and their derivatives, celluloses and their derivatives, proteins and their derivatives, vinyl or acrylic polymers, etc. ;
- les hydroxyacides H0-L-C02H capables de former un cycle dilactonique ou une monolactone.- hydroxy acids H0-L-C0 2 H capable of forming a dilactonic cycle or a monolactone.
Les hydroxyacides HO-L-C02H capables de former un cycle dilactonique sont par exemple les α-hydroxyacides de formule : HO-C(R5) (R6)-C02H dans laquelle R5 et R6 représentent indépendamment -H, alkyle, aryleThe hydroxy acids HO-L-C0 2 H capable of forming a dilactonic ring are for example the α-hydroxy acids of formula: HO-C (R 5 ) (R 6 ) -C0 2 H in which R 5 and R 6 independently represent - H, alkyl, aryl
(notamment phényle) ou carboxyalkyle (notamment carboxyméthyle) , qui sont capables de former des dilactones de formule IV :(in particular phenyl) or carboxyalkyl (in particular carboxymethyl), which are capable of forming dilactones of formula IV:
Ces hydroxyacides sont notamment ceux pour lesquels l'un au moins des substituants R5 et Rg représente -H, par exemple l'acide glycolique ou les acides lactiques, mandéliques et maliques. Les motifs de formule II formés avec ces α-hydroxyacides sont donc des motifs : These hydroxy acids are in particular those for which at least one of the substituents R 5 and Rg represents -H, for example glycolic acid or lactic, mandelic and malic acids. The units of formula II formed with these α-hydroxy acids are therefore units:
-£CH C(R (R,)-CO 3-- £ CH C (R (R,) - CO 3-
Les groupements carboxyliques éventuellement présents dans R5 et/ou Rg peuvent être sous forme libre ou protégée. Les groupements carboxyliques peuvent être protégés notamment sous forme d'esters . Les hydroxyacides HO-L-C02H capables de former une monolactone sont en particulier des hydroxyacides carboxyliques possédant un groupement hydroxy en position γ, δ ou ε par rapport au carboxyle . On citera notamment les hydroxyacides capables de donner une mono-
lactone formant un cycle ayant au moins 6 chaînons.The carboxylic groups optionally present in R 5 and / or Rg can be in free or protected form. The carboxylic groups can be protected in particular in the form of esters. The hydroxy acids HO-L-C0 2 H capable of forming a monolactone are in particular hydroxy carboxylic acids having a hydroxy group in the γ, δ or ε position relative to the carboxyl. Mention will in particular be made of hydroxy acids capable of giving a mono- lactone forming a ring having at least 6 links.
Les hydroxyacides de formule HO-L-C02H capables de donner une lactone formant un cycle ayant au moins six chaînons peuvent être choisis notamment parmi les acides aldoniques, tels que ceux mentionnés ci-dessus, ayant au moins 5 atomes de carbone, dont les groupes hydroxyles non impliqués dans la formation de la lactone peuvent être sous forme libre ou protégée.The hydroxy acids of formula HO-L-C0 2 H capable of giving a ring-forming lactone having at least six links can be chosen in particular from aldonic acids, such as those mentioned above, having at least 5 carbon atoms, of which the hydroxyl groups not involved in the formation of the lactone can be in free or protected form.
Parmi les hydroxyacides capables de former un cycle lactonique ayant au moins 6 chaînons, on peut citer également les acides 5-hydroxypentanoïque, 2, 3, 4-triméthoxy 5-hydroxypentanoïque, 6-hydroxy hexanoïque, etc.Among the hydroxy acids capable of forming a lactonic ring having at least 6 members, mention may also be made of 5-hydroxypentanoic, 2, 3, 4-trimethoxy 5-hydroxypentanoic, 6-hydroxy hexanoic acids, etc.
L'invention a notamment pour objet un copolymère contenant : de 1 à 99 S, en nombre de motifs par rapport au nombre total de motifs, de motifs de formule I :The subject of the invention is in particular a copolymer containing: from 1 to 99%, in number of units relative to the total number of units, of units of formula I:
dans laquelle : in which :
R est le reste d'un acide R-CHOH-C02H dérivé d'un ose, les groupes fonctionnels contenus dans R étant éventuellement substitués, X représente un groupe -C(R1)(R2)- ou -C (Rχ) (R2 ) -C (R3) (R4 ) - dans lequel R]_, R2, 3 et R4 représentent indépendamment -H ou un groupement alkyle, allyle, aryle ou aralkyle, et au moins 1 % , en nombre de motifs par rapport au nombre total de motifs, de motifs de formule II :R is the residue of an acid R-CHOH-C0 2 H derived from a ose, the functional groups contained in R being optionally substituted, X represents a group -C (R 1 ) (R 2 ) - or -C ( R χ ) (R 2 ) -C (R 3 ) (R 4 ) - in which R ] _, R 2 , 3 and R 4 independently represent -H or an alkyl, allyl, aryl or aralkyl group, and at least 1 %, in number of units relative to the total number of units, of units of formula II:
dans laquelle : in which :
L est le reste d'un hydroxyacide HO-L-C02H choisi parmi les hydroxyacides capables de former un cycle dilactonique ou une mono- lactone. Parmi les copolymères de l'invention, on citera en particulier ceux qui contiennent au moins 5 % de motifs de formule II, et notamment ceux qui contiennent de 5 à 95 % de motifs de formule II.L is the remainder of a HO-L-C0 2 H hydroxy acid chosen from hydroxy acids capable of forming a dilactonic ring or a monolactone. Among the copolymers of the invention, mention will be made in particular of those which contain at least 5% of units of formula II, and in particular those which contain from 5 to 95% of units of formula II.
Les homopolymères et copolymères de l'invention peuvent être mis notamment sous la forme de matériaux divers ou d'articles finis tels que des poudres, des microsphères, des films, des pièces
moulées, des pièces extrudées, etc., qui peuvent être préparés selon les techniques usuelles.The homopolymers and copolymers of the invention can be used in particular in the form of various materials or of finished articles such as powders, microspheres, films, parts molded parts, extruded parts, etc., which can be prepared according to the usual techniques.
L'invention concerne également un procédé de préparation d'un monomère ou d'un polymère tel que défini précédemment, dans le- quel :The invention also relates to a process for preparing a monomer or a polymer as defined above, in which:
- on fait réagir un acide- an acid is reacted
R'-CHOH-C02H dans lequel R' est le reste d'un acide dérivé d'un ose, les groupements hydroxyles éventuellement contenus dans R' étant proté- gés, avec un chlorure d'acide de formule :R'-CHOH-C0 2 H in which R 'is the remainder of an acid derived from a ose, the hydroxyl groups possibly contained in R' being protected, with an acid chloride of formula:
Y-X-CO-Z, dans laquelle X est défini comme la revendication 1, et Y et Z représentent indépendamment un halogène, pour obtenir un produit de formule V :Y-X-CO-Z, in which X is defined as claim 1, and Y and Z independently represent a halogen, to obtain a product of formula V:
Y-X-CO-0-CH(R' ) -C02H (V) que l'on transforme en composé de formule III :YX-CO-0-CH (R ') -C0 2 H (V) which is transformed into compound of formula III:
par cyclisation intramoléculaire, - si désiré, on polymérise ledit composé de formule III, par homopolymérisation ou par copolymérisation avec un comonomère, by intramolecular cyclization, - if desired, the said compound of formula III is polymerized, by homopolymerization or by copolymerization with a comonomer,
- si désiré, on déprotège et/ou fonctionnalise au moins une partie des groupes hydroxyles de R',- if desired, at least part of the hydroxyl groups of R 'are deprotected and / or functionalized,
- et, si désiré, on met le copolymere obtenu sous la forme d'une poudre, de microsphères d'un film, d'une pièce moulée ou d'une pièce extrudée.- And, if desired, the copolymer obtained is put in the form of a powder, of microspheres of a film, of a molded part or of an extruded part.
L'invention concerne notamment un procédé de préparation d'un copolymere ou d'un matériau ou article fini tel que défini précédemment. L'invention concerne notamment un procédé dans lequel : a) on fait réagir, dans des conditions permettant la copolymérisation : au moins un monomère de formule III :
dans laquelle :The invention relates in particular to a process for the preparation of a copolymer or of a finished material or article as defined above. The invention relates in particular to a process in which: a) reacting, under conditions allowing the copolymerization: at least one monomer of formula III: in which :
R' est le reste d'un acide R'-CHOH-C0 H dérivé d'un ose, dont les groupements hydroxyles éventuellement contenus dans R' sont protégés, et X, R^, R2, R3 et R4 sont définis comme précédemment, et au moins un monomère choisi parmi les dilactones et les monolactones dérivant d'un hydroxyacide H0-L-C02H tel que défini précédemment, b) si désiré, on déprotège et/ou fonctionnalise au moins une partie des groupes hydroxyles de R', c) et, si désiré, on met le copolymere obtenu sous la forme d'une poudre, de microsphères, d'un film, d'une pièce moulée ou d'une pièce extrudée. Le procédé de copolymérisation de l'invention consiste donc à faire réagir un composé de formule III tel que défini ci-dessus : a) avec un composé de formule IV tel que par exemple le glycolide ou le D-, le L- ou le DL-lactide et/ou b) avec une monolactone, et en particulier une monolactone formant un cycle ayant au moins 6 chaînons, notamment une lactone d'un acide aldonique ayant 5 ou 6 atomes de carbone (par exemple la δ-gluconolactone) , la δ-valéro- lactone ou encore 1 'ε-caprolactone .R 'is the remainder of an acid R'-CHOH-C0 H derived from an ose, whose hydroxyl groups possibly contained in R' are protected, and X, R ^, R 2 , R 3 and R 4 are defined as before, and at least one monomer chosen from dilactones and monolactones deriving from a hydroxy acid H0-L-C0 2 H as defined above, b) if desired, at least part of the hydroxyl groups are deprotected and / or functionalized of R ', c) and, if desired, the copolymer obtained is put in the form of a powder, microspheres, a film, a molded part or an extruded part. The copolymerization process of the invention therefore consists in reacting a compound of formula III as defined above: a) with a compound of formula IV such as for example glycolide or D-, L- or DL -lactide and / or b) with a monolactone, and in particular a monolactone forming a ring having at least 6 links, in particular a lactone of an aldonic acid having 5 or 6 carbon atoms (for example δ-gluconolactone), the δ-valero-lactone or 1 ε-caprolactone.
La copolymérisation des composés de formule III avec les composés de formule IV ou les monolactones peut être effectuée soit en masse, soit en solution dans un solvant, généralement en présence d'un catalyseur ou d'un amorceur approprié.The copolymerization of the compounds of formula III with the compounds of formula IV or the monolactones can be carried out either in bulk or in solution in a solvent, generally in the presence of a suitable catalyst or initiator.
La température et la durée de la réaction dépendent notamment des réactifs employés et de la masse moléculaire moyenne souhaitée pour le copolymere préparé. Ces paramètres peuvent être aisé- ment déterminés par de simples expériences de routine. Généralement, on opère à une température de 20 à 200 °C sous atmosphère inerte ou dans un réacteur scellé, pendant un temps pouvant aller par exemple de quelques minutes à 30 jours.The temperature and the duration of the reaction depend in particular on the reagents used and on the average molecular weight desired for the copolymer prepared. These parameters can be easily determined by simple routine experiments. Generally, the operation is carried out at a temperature of 20 to 200 ° C. under an inert atmosphere or in a sealed reactor, for a time which can range, for example, from a few minutes to 30 days.
Les amorceurs ou catalyseurs utilisés dans la réaction de
copolymérisation sont de type connu pour ce genre de réaction ; on peut citer notamment l'octanoate d'étain, le tétraphényl étain, le zinc métallique en poudre, le lactate de zinc, les alcoxyaluminium, les dérivés de lanthanides ou d'yttrium. Le polymère obtenu peut être purifié selon les méthodes usuelles .The initiators or catalysts used in the reaction of copolymerization are of a type known for this kind of reaction; there may be mentioned in particular tin octanoate, tetraphenyl tin, powdered metallic zinc, zinc lactate, alkoxyaluminum, lanthanide or yttrium derivatives. The polymer obtained can be purified according to the usual methods.
Il est possible de déprotéger, totalement ou partiellement, les groupements protégés du copolymere obtenu, et/ou de fonctionnaliser les groupements déprotégés on non protégés. La fonctionnalisa- tion consiste en particulier à substituer lesdits groupements déprotégés ou non protégés à l'aide d'autres groupements protecteurs tels que définis ci-dessus.It is possible to deprotect, totally or partially, the protected groups of the copolymer obtained, and / or to functionalize the unprotected or unprotected groups. Functionalization consists in particular in replacing said deprotected or unprotected groups using other protective groups as defined above.
La fonctionnalisation permet d'apporter aux copolymères des propriétés particulières, notamment des propriétés pharmaceutiques (à l'aide d'un substituant dérivé d'un médicament), des propriétés physiques (par exemple propriétés thermiques, solubilité), des propriétés physico-chimiques (par exemple des propriétés d' hydrophilie ou d ' hydrophobie ) , ou une réactivité chimique particulière, y compris des propriétés de biodégradabilité et/ou de biorésorbabilité. La fonctionnalisation à l'aide de réactifs bi-fonctionnels permet également d'effectuer des réticulations . Par exemple des dérivés di- carboxyliques comme l'acide itaconique, permettent d'effectuer une reticulation par réaction avec des groupements hydroxyles du polymère, et des polyols (par exemple des oses ou des polyéthylènegly- cols) permettent d'effectuer une reticulation par réaction avec des groupements carboxyliques, préalablement activés du polymère.Functionalization makes it possible to provide the copolymers with specific properties, in particular pharmaceutical properties (using a substituent derived from a drug), physical properties (for example thermal properties, solubility), physicochemical properties ( for example hydrophilic or hydrophobic properties), or a particular chemical reactivity, including biodegradability and / or bioresorbability properties. Functionalization using bi-functional reagents also makes it possible to crosslink. For example, dicarboxylic derivatives such as itaconic acid make it possible to carry out crosslinking by reaction with hydroxyl groups of the polymer, and polyols (for example oses or polyethylene glycols) make it possible to carry out crosslinking by reaction. with carboxylic groups, previously activated from the polymer.
Le produit de départ de formule III peut être préparé par réaction d'un acide R' -CH0H-C0 H, tel que défini précédemment avec un chlorure d'acide de formule : Y-X-CO-Z, dans laquelle X est défini comme précédemment,The starting product of formula III can be prepared by reaction of an acid R '-CHOH-C0 H, as defined above with an acid chloride of formula: YX-CO-Z, in which X is defined as above ,
Y est un halogène, et en particulier le chlore ou, de préférence le brome,Y is a halogen, and in particular chlorine or, preferably bromine,
Z est un halogène, et en particulier le brome ou, de préférence, le chlore.Z is a halogen, and in particular bromine or, preferably, chlorine.
On obtient ainsi un produit de formule V: Y-X-CO-0-CH(R' ) -C02H (V)
qui est transformé en composé de formule III par cyclisation intra- moléculaire, avec élimination d'acide halohydrique YH.A product of formula V is thus obtained: YX-CO-0-CH (R ') -C0 2 H (V) which is transformed into compound of formula III by intra-molecular cyclization, with elimination of hydrohalic acid YH.
Les copolymères de l'invention peuvent être des copolymères statistiques ou des copolymères séquences de type A-B, A-B-A ou B-A-B, A étant par exemple un produit de polymérisation composé de motifs de formule I et B un produit de polymérisation composé de motifs dérivant du comonomère utilisé, par exemple des motifs de formule II. Comme on le comprend aisément, on peut obtenir des polymères séquences notamment dans le cas où l'on commence la polymérisation du composé de formule III avant d'ajouter le comonomère, par exemple la monolactone ou dilactone.The copolymers of the invention may be random copolymers or block copolymers of type AB, ABA or BAB, A being for example a polymerization product composed of units of formula I and B a polymerization product composed of units derived from the comonomer used , for example units of formula II. As is easily understood, block polymers can be obtained in particular when the polymerization of the compound of formula III is started before adding the comonomer, for example monolactone or dilactone.
En faisant varier les proportions respectives des motifs dérivés de III et des motifs dérivés du comonomère, notamment des motifs dérivés de IV (ou des motifs dérivés de la monolactone) , on peut moduler les propriétés du copolymere. Par exemple, lorsque le composé III est un dérivé d'acide gluconique et le composé IV est le lactide, on a constaté que la température de transition vitreuse du copolymere augmente, par rapport à la température de transition vitreuse du poly (acide lactique), lorsque la proportion des motifs dé- rivés du composé III augmente (voir la partie expérimentale ci- après) .By varying the respective proportions of the units derived from III and of the units derived from the comonomer, in particular units derived from IV (or units derived from monolactone), the properties of the copolymer can be modulated. For example, when compound III is a derivative of gluconic acid and compound IV is lactide, it has been found that the glass transition temperature of the copolymer increases, compared to the glass transition temperature of poly (lactic acid), when the proportion of units derived from compound III increases (see the experimental part below).
Les exemples suivants illustrent l'invention.The following examples illustrate the invention.
EXEMPLESEXAMPLES
Dans la partie expérimentale ci-après on utilise les abréviations et sigles suivants : Tf : température de fusionIn the experimental part below, the following abbreviations and acronyms are used: Tf: melting temperature
Tv : température de transition vitreuseTv: glass transition temperature
DMF : diméthylformamideDMF: dimethylformamide
Ether : éther éthyliqueEther: ethyl ether
PLA50 : poly(D,L-lactide) δ-gluconolactone : δ-D-gluconolactone acide gluconique : acide D-gluconique
EXEMPLE 1 : Préparation du DIPAGYL (monomère dérivé de l'acide gluconique)PLA50: poly (D, L-lactide) δ-gluconolactone: δ-D-gluconolactone gluconic acid: D-gluconic acid EXAMPLE 1 Preparation of DIPAGYL (monomer derived from gluconic acid)
A. Préparation du 3, 4-5, 6-diisopropylidène-gluconate de méthyle (MPIPAG)A. Preparation of methyl 3, 4-5, 6-diisopropylidene gluconate (MPIPAG)
On mélange 20 g de δ-gluconolactone, 34 cm3 de20 g of δ-gluconolactone, 34 cm 3 of
2, 2-diméthoxypropane, 20 cm3 d'acétone, 6 cm3 de méthanol et 0,24 g d'acide p-toluène sulfonique. Le mélange hétérogène obtenu est agité à température ambiante pendant 48 h et devient homogène au cours de la réaction.2, 2-dimethoxypropane, 20 cm 3 of acetone, 6 cm 3 of methanol and 0.24 g of p-toluene sulfonic acid. The heterogeneous mixture obtained is stirred at room temperature for 48 h and becomes homogeneous during the reaction.
On évapore les solvants sous pression réduite à 30°C. On dissout le résidu dans l'éther et on lave à l'eau. On sèche la phase organique sur sulfate de magnésium, puis on évapore le solvant.The solvents are evaporated off under reduced pressure at 30 ° C. The residue is dissolved in ether and washed with water. The organic phase is dried over magnesium sulfate, then the solvent is evaporated.
Le produit obtenu se présente sous la forme d'une huile visqueuse incolore, insoluble dans l'eau et dans l'hexane et soluble dans les solvants organiques tels que l'éther, le toluène, le tétra- hydrofurane, le chloroforme, l'acétone, le dioxane et le DMF. [α]D = -l,8°cm2g_1 (589 nm, dioxane).The product obtained is in the form of a colorless viscous oil, insoluble in water and in hexane and soluble in organic solvents such as ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF. [α] D = -1.8 ° cm 2 g _1 (589 nm, dioxane).
Les spectres IR et RMN ^H et 13C sont en accord avec la structure indiquée.The IR and 1 H and 13 C NMR spectra are in agreement with the structure indicated.
B. Préparation du 3, 4-5, 6-diisopropylidène-acide gluconique (DIPAG)B. Preparation of 3, 4-5, 6-diisopropylidene-gluconic acid (DIPAG)
On dissout 29,3 g de MDIPAG dans 80 cm3 d'une solution aqueuse 1M de NaOH. On chauffe la solution à 80°C, en agitant, pendant 10 min. On refroidit ensuite à 0°C et ajuste le pH à 2 en ajou- tant unes solution aqueuse 2M d'acide chlorhydrique refroidi à 0°C. On extrait par le dichlorométhane. La phase organique obtenue est séchée sur sulfate de magnésium, filtrée et évaporée sous pression réduite.29.3 g of MDIPAG are dissolved in 80 cm 3 of a 1M aqueous NaOH solution. The solution is heated to 80 ° C, with stirring, for 10 min. It is then cooled to 0 ° C. and the pH is adjusted to 2 by adding a 2M aqueous solution of hydrochloric acid cooled to 0 ° C. Extraction is carried out with dichloromethane. The organic phase obtained is dried over magnesium sulfate, filtered and evaporated under reduced pressure.
On obtient une poudre blanche, soluble dans les solvants or- ganiques tels que l'éther, le toluène, le tétrahydrofurane, le chloroforme, l'acétone, le dioxane et le DMF, et soluble dans l'eau à pH basique. Le produit reprécipite à pH acide. Il est insoluble dans
les solvants hydrocarbonés . Tf = 154°C. [α]D = -1, 6° cm2g_1 (589 nm, dioxane).A white powder is obtained, soluble in organic solvents such as ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF, and soluble in water at basic pH. The product reprecipitates at acid pH. It is insoluble in hydrocarbon solvents. Mp = 154 ° C. [α] D = -1, 6 ° cm 2 g _1 (589 nm, dioxane).
C. Préparation du 2-bromoacétyl-3, 4-5, 6-diisopropylidène- acide gluconique (BDIPAG)C. Preparation of 2-bromoacetyl-3, 4-5, 6-diisopropylidene-gluconic acid (BDIPAG)
On dissout 25,1 g de DIPAG dans 300 cm3 d'éther éthylique sous atmosphère d'azote. On ajoute 8 cm3 de chlorure de bromoacétyle en agitant, à température ambiante, pendant 30 min. Après 15 min de réaction, on refroidit la solution entre 0 et 5°C et on ajoute 15 cm3 de triéthylamine, sans que la température ne dépasse 5°C. On laisse sous agitation pendant 4 heures à 5°C. On ajoute ensuite 450 cm3 d'éther. La phase organique est lavée avec une solution aqueuse d'acide chlorhydrique, séchée sur sulfate de magnésium et filtrée, puis on évapore le solvant.25.1 g of DIPAG are dissolved in 300 cm 3 of ethyl ether under a nitrogen atmosphere. 8 cm 3 of bromoacetyl chloride are added while stirring, at room temperature, for 30 min. After 15 min of reaction, the solution is cooled to 0 to 5 ° C and 15 cm 3 of triethylamine are added, without the temperature exceeding 5 ° C. The mixture is left stirring for 4 hours at 5 ° C. Then 450 cm 3 of ether are added. The organic phase is washed with an aqueous hydrochloric acid solution, dried over magnesium sulfate and filtered, then the solvent is evaporated.
On obtient un produit se présentant sous la forme d'une huile soluble dans l'éther, le toluène, le tétrahydrofurane, le chloroforme, l'acétone, le dioxane et le DMF et le méthanol insolu- ble dans l'eau et partiellement soluble dans l'hexane et dans le cy- clohexane (à chaud). Le produit, qui est sensible à l'hydrolyse, est conservé au congélateur.A product is obtained in the form of an oil soluble in ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane and DMF and methanol insoluble in water and partially soluble in hexane and in cyclohexane (hot). The product, which is sensitive to hydrolysis, is stored in the freezer.
[α]D = +14, l0cm2g_1 (589 nm, dioxane).[α] D = +14, l 0 cm 2 g _1 (589 nm, dioxane).
Les spectres IR et RMN 1H et 13C sont en accord avec la structure indiquée.The 1 H and 13 C IR and NMR spectra are in agreement with the indicated structure.
D. Préparation de la 3- (1, 2-3, 4-tétraoxobutyl- diisopropylidène) -1, 4-dioxane-2, 5-dione (DIPAGYL)D. Preparation of 3- (1, 2-3, 4-tetraoxobutyl-diisopropylidene) -1, 4-dioxane-2, 5-dione (DIPAGYL)
On dissout 31,8 g de BDIPAG dans 100 cm3 de DMF. On ajoute la solution obtenue pendant 5 heures, sous forte agitation à 40°C, à un mélange comprenant 11,4 g de NaHC03 et 1,1 litre de DMF, puis on poursuit l'agitation pendant 4 heures après la fin de l'addition. On évapore le solvant sous pression réduite et on extrait le résidu à l'éther. On lave l'extrait à l'eau et le sèche sur sulfate de magnésium, puis on évapore le solvant sous pression réduite. On purifie
le résidu par chromatographie sur colonne de silice, en éluant avec un mélange dichlorométhane/heptane 4:1 (v:v).31.8 g of BDIPAG are dissolved in 100 cm 3 of DMF. The solution obtained is added for 5 hours, with vigorous stirring at 40 ° C., to a mixture comprising 11.4 g of NaHCO 3 and 1.1 liters of DMF, then stirring is continued for 4 hours after the end of the 'addition. The solvent is evaporated off under reduced pressure and the residue is extracted with ether. The extract is washed with water and dried over magnesium sulfate, then the solvent is evaporated off under reduced pressure. We purify the residue by chromatography on a silica column, eluting with a dichloromethane / heptane 4: 1 mixture (v: v).
On rassemble les fractions contenant le produit attendu, et on évapore les solvants. Le résidu est recristallisé dans un mélange cyclohexane/heptane 3:1 (v:v) .The fractions containing the expected product are combined, and the solvents are evaporated. The residue is recrystallized from a 3: 1 (v: v) cyclohexane / heptane mixture.
Le produit peut être purifié par sublimation à 85 °C sous pression réduite (0,1 Pa) . On obtient des cristaux blancs (Tf = 87°C), que l'on conserve sous atmosphère inerte (argon).The product can be purified by sublimation at 85 ° C under reduced pressure (0.1 Pa). White crystals are obtained (Tf = 87 ° C), which is stored under an inert atmosphere (argon).
Les spectres IR et RM :H sont en accord avec la structure indiquée.The IR and RM : H spectra are in agreement with the indicated structure.
Le produit est soluble dans l'éther, le toluène, le tétrahy- drofurane, le chloroforme, l'acétone, le dioxane, le DMF, le méthanol, ainsi que dans le cyclohexane (à chaud) .The product is soluble in ether, toluene, tetrahydrofuran, chloroform, acetone, dioxane, DMF, methanol, as well as in cyclohexane (hot).
[α]D = -29,2°cm2g_1 (589 nm, dioxane). De façon analogue, en remplaçant, à l'étape C) ci-dessus, le chlorure de bromoacetyle par le chlorure de 2-bromopropionyle, on obtient un composé de formule III, dérivé de l'acide gluconique, dans lequel X représente -CH(CH3)-[α] D = -29.2 ° cm 2 g _1 (589 nm, dioxane). Similarly, by replacing, in step C) above, bromoacetyl chloride with 2-bromopropionyl chloride, a compound of formula III is obtained, derived from gluconic acid, in which X represents -CH (CH 3 ) -
EXEMPLE 2 : Préparation de la 3- (1, 2-dioxoéthyl-isopropylidène) - dioxane-2, 5-dione. a) On utilise, comme produit de départ une solution aqueuse contenant de l'acide érythronique en équilibre avec l' érythronolac- tone. Cette solution aqueuse contient 29,4% en poids d'acide éry- thronique et 30,4% en poids d' érytronolactone. 20 grammes de cette solution sont évaporés sous pression réduite à 60° C. On obtient une poudre blanche que l'on redissout dans le méthanol et précipite à l'éther. Le précipité est filtré et séché sous pression réduite. On obtient 9,5 g d' érythronolactone que l'on solubilise dans 50 cm3 de méthanol additionné de 50 mg d'acide p-toluène sulfonique. On chauffe au reflux pendant trois heures. On peut suivre l'ouverture du cycle lactonique et la formation de l'ester méthylique par spec- trométrie infra-rouge. Après trois heures de réaction, aucune évolution n'est observée. On refroidit le milieu réactionnel et on ajoute 30 ml de 2, 2-diméthoxypropane. On agite pendant 24 heures à 20°C. On ajoute ensuite 1,5 g de résine échangeuse d'ions OIT . Après deux minutes de réaction, on filtre et évapore le solvant. On obtient le
3, -isopropylidène érythronate de méthyle. b) On dissout 8,7 g de ce produit dans 45 cm3 d'une solution d'hydroxyde de sodium 1,2M. Après dix minutes d'agitation, on refroidit la solution à 0°C et on ajoute une solution aqueuse IM d'acide chlorhydrique, refroidie à 0°C, jusqu'à obtention d'un pH 7. La solution est concentrée par evaporation jusqu'à un volume de 20 cm3 et est refroidie à 0°C. On ajoute une quantité suffisante de chlorure de sodium pour obtenir une solution saturée... Le pH de la solution est ajusté à 2 par addition d'une solution IM d'acide chlorhydrique refroidie à 0°C, et on procède à une extraction avec un litre de dichloromethane refroidi à 0°C. La phase organique est séchée, filtrée et évaporée. On obtient ainsi l'acide 3,4- isopropylidène érythronique. Le spectre infra-rouge est en accord avec la structure indiquée. c) On dissout 3,2 g d'acide 3, 4-isopropylidène érythronique dans 60 cm3 de dichloromethane. On ajoute 1, 9 cm de chlorure de bromoacetyle en agitant, sous atmosphère d'azote. On refroidit à 0°C et on ajoute goutte à goutte 4,2 cm3 de triéthylamine, sans que la température dépasse 5°C. On laisse sous agitation pendant trois heures, puis on extrait au dichloromethane. On lave l'extrait à l'eau et on le sèche avec du sulfate de magnésium. On filtre et évapore le solvant. On obtient le 2-bromoacétate de l'acide 3, 4-isopropylidène érythronique . d)On dissout 4,2 g de ce produit dans du diméthylformamide . On ajoute cette solution, en agitant, à un mélange de 1,9 g de NaHC03 et de 100 cm3 de diméthylformamide, puis on poursuit l'agitation pendant 4 heures. On évapore le solvant, extrait le résidu à l'éther et le lave à l'eau. On évapore l'éther. On purifie le produit obtenu par chromatographie sur colonne de silice, en éluant avec un mélange dichlorométhane/heptane 9:1 (v:v) . On rassemble les fractions contenant le produit attendu et on évapore les solvants. Le résidu est recristallisé dans le cyclohexane. La 3- (1, 2-dioxoéthyl- isopropylidène) - dioxane -2,5-dione obtenue est un solide fondant à 92 °C. Il peut être purifié par sublimation à 80°C sous pression ré- duite (10 " mm de mercure, soit 0,13 Pa) . Les spectres IR et RMN1?! sont en accord avec la structure indiquée.EXAMPLE 2 Preparation of 3- (1, 2-dioxoethyl-isopropylidene) - dioxane-2, 5-dione. a) An aqueous solution containing erythronic acid in equilibrium with erythronolactone is used as the starting product. This aqueous solution contains 29.4% by weight of erythonic acid and 30.4% by weight of erytronolactone. 20 grams of this solution are evaporated under reduced pressure at 60 ° C. A white powder is obtained which is redissolved in methanol and precipitated with ether. The precipitate is filtered and dried under reduced pressure. 9.5 g of erythronolactone are obtained which are dissolved in 50 cm 3 of methanol supplemented with 50 mg of p-toluene sulfonic acid. The mixture is heated at reflux for three hours. We can follow the opening of the lactonic cycle and the formation of the methyl ester by infrared spectrometry. After three hours of reaction, no change is observed. The reaction medium is cooled and 30 ml of 2,2-dimethoxypropane are added. The mixture is stirred for 24 hours at 20 ° C. 1.5 g of OIT ion exchange resin are then added. After two minutes of reaction, the solvent is filtered and evaporated. We get the 3, -isopropylidene methyl erythronate. b) 8.7 g of this product are dissolved in 45 cm 3 of a 1.2M sodium hydroxide solution. After ten minutes of stirring, the solution is cooled to 0 ° C. and an aqueous IM solution of hydrochloric acid, cooled to 0 ° C., is added until a pH of 7 is obtained. The solution is concentrated by evaporation until 'to a volume of 20 cm 3 and is cooled to 0 ° C. Sufficient sodium chloride is added to obtain a saturated solution ... The pH of the solution is adjusted to 2 by addition of a 1M solution of hydrochloric acid cooled to 0 ° C, and extraction is carried out with one liter of dichloromethane cooled to 0 ° C. The organic phase is dried, filtered and evaporated. 3,4-isopropylidene erythronic acid is thus obtained. The infrared spectrum is in agreement with the indicated structure. c) 3.2 g of 3,4-isopropylidene erythronic acid are dissolved in 60 cm 3 of dichloromethane. 1.9 cm of bromoacetyl chloride are added with stirring, under a nitrogen atmosphere. The mixture is cooled to 0 ° C. and 4.2 cm3 of triethylamine are added dropwise, without the temperature exceeding 5 ° C. The mixture is left stirring for three hours and then extracted with dichloromethane. The extract is washed with water and dried with magnesium sulfate. The solvent is filtered and evaporated. 3,4-isopropylidene erythronic acid 2-bromoacetate is obtained. d) 4.2 g of this product are dissolved in dimethylformamide. This solution is added, with stirring, to a mixture of 1.9 g of NaHCO 3 and 100 cm 3 of dimethylformamide, then stirring is continued for 4 hours. The solvent is evaporated, the residue is extracted with ether and washed with water. The ether is evaporated. The product obtained is purified by chromatography on a silica column, eluting with a dichloromethane / heptane mixture 9: 1 (v: v). The fractions containing the expected product are combined and the solvents are evaporated. The residue is recrystallized from cyclohexane. The 3- (1,2-dioxoethyl-isopropylidene) - dioxane -2,5-dione obtained is a solid melting at 92 ° C. It can be purified by sublimation at 80 ° C. under reduced pressure (10 " mm of mercury, ie 0.13 Pa). The IR and 1 H NMR spectra are in agreement with the structure indicated.
En remplaçant, à l'étape c) ci-dessus, le chlorure de bromo-
acétyle par le chlorure de 2-bromopropionyle, on obtient un composé de formule III dérivé de l'acide érythronique, dans lequel X représente -CH(CHj)-.By replacing, in step c) above, the bromine chloride acetyl with 2-bromopropionyl chloride, a compound of formula III derived from erythronic acid is obtained, in which X represents -CH (CHj) -.
EXEMPLE 3 : Homopolymérisation de la 3- (1,2-3, 4 -tétraoxobutyl- diisopropylidène) -1,4 -dioxane-2, 5-dione (DIPAGYL)EXAMPLE 3 Homopolymerization of 3- (1,2-3,4-tetraoxobutyl- diisopropylidene) -1,4 -dioxane-2,5-dione (DIPAGYL)
1 g de DIPAGYL est introduit dans un tube à sceller. Le monomère est amené à l'état fondu et dégazé par des cycles successifs vide-azote. L'amorceur est ensuite introduit sous atmosphère d'azote. Le tube est scellé sous vide pour les essais de polymérisation en masse. Les tubes sont placés à 110° C pendant 7 jours sous agitation. Les conditions expérimentales sont rassemblées dans le tableau 1.1 g of DIPAGYL is introduced into a sealing tube. The monomer is brought to the molten state and degassed by successive vacuum-nitrogen cycles. The initiator is then introduced under a nitrogen atmosphere. The tube is vacuum sealed for mass polymerization tests. The tubes are placed at 110 ° C for 7 days with stirring. The experimental conditions are collated in Table 1.
Tableau 1 Conditions de polymérisation du 3- (1,2-3, 4)- tétraoxo- butyl-diisopropylidène) -1, 4-dioxane-2, 5-dione.Table 1 Conditions for polymerization of 3- (1,2-3,4) - tetraoxobutyl-diisopropylidene) -1,4-dioxane-2,5,5-dione.
* [A/M] = rapport molaire Amorceur/Monomère (DIPAGYL)* [A / M] = initiator / monomer molar ratio (DIPAGYL)
Les produits obtenus à la fin de la réaction de polymérisation se présentent sous différents aspects.The products obtained at the end of the polymerization reaction come in different aspects.
Afin de déterminer la masse molaire des produits obtenus, des analyses ont été effectuées par chromatographie d'exclusion de taille (SEC), en milieu organique dans le dioxane.In order to determine the molar mass of the products obtained, analyzes were carried out by size exclusion chromatography (SEC), in an organic medium in dioxane.
Afin d'isoler les fractions ayant des masses molaires différentes, l'échantillon 1 a été purifié par dissolution dans le dioxane et précipitation dans l'éthanol.In order to isolate the fractions having different molar masses, sample 1 was purified by dissolution in dioxane and precipitation in ethanol.
Les résultats de l'analyse des masses molaires par SEC après
purification sont regroupés dans le tableau 2.The results of the molecular weight analysis by SEC after purification are grouped in Table 2.
Tableau 2 : Masses molaires des produits obtenus par polymérisation du DIPAGYL, après purification.Table 2: Molar masses of the products obtained by polymerization of DIPAGYL, after purification.
EXEMPLE 4 : Copolyméri sa ti on de la 3- (1 , 2-3 , 4 -tétraoxobutyl - di i sopropylidène ) -1 , 4 -di oxane-2 , 5-di one (DIPAGYL) avec le D, L -lactideEXAMPLE 4 Copolymerization of 3- (1, 2-3, 4 -tetraoxobutyl - di i sopropylidene) -1, 4 -di oxane-2, 5-di one (DIPAGYL) with D, L -lactide
La copolymérisation du DIPAGYL avec le D,L-lactide permet d'aboutir à une famille de copolymères du type polyester dont les propriétés physico-chimiques et mécaniques peuvent être ajustées par la proportion des comonomères de départ.The copolymerization of DIPAGYL with D, L-lactide makes it possible to arrive at a family of copolymers of the polyester type whose physico-chemical and mechanical properties can be adjusted by the proportion of the starting comonomers.
Le DIPAGYL et le D,L-lactide sont placés dans un ballon et soumis à un dégazage en effectuant 3 cycles comprenant une mise sous vide (10-3 mbar) à 90°C, puis on fait passer un courant d'argon à froid. On ajoute ensuite l'amorceur (octanoate d'étain). Le rapport molaire amorceur/comonomeres est de 1/600. On scelle le ballon sous pression réduite et on le place dans un bain d'huile. Le ballon est soumis à une rotation autour d'un axe incliné pendant la réaction de copolymérisation. La réaction de copolymérisation est effectuée pendant 5 jours sous vide à la température de 120°C. A la fin de la réaction, on laisse refroidir le mélange réactionnel et on rétablit la pression ambiante. Le mélange réactionnel est dissous dans l'acétone. On filtre pour éliminer la fraction insoluble, et on reprécipite le copolymere dans le méthanol. On obtient un copolymere brut qui peut être purifié par chromatographie d'exclusion de taille. Trois copolymères ont été synthétisés au départ d'un mélange de monomères contenant, en mole, 50 %, 30 % et 15 % de DIPAGYL, respectivement. Les résultats sont résumés dans le tableau suivant :
DIPAGYL and D, L-lactide are placed in a flask and subjected to degassing by performing 3 cycles including evacuation (10 -3 mbar) at 90 ° C, then passing a current of cold argon . Then the initiator (tin octanoate) is added. The initiator / comonomer molar ratio is 1/600. The flask is sealed under reduced pressure and placed in an oil bath. The flask is rotated about an inclined axis during the copolymerization reaction. The copolymerization reaction is carried out for 5 days under vacuum at a temperature of 120 ° C. At the end of the reaction, the reaction mixture is allowed to cool and the ambient pressure is restored. The reaction mixture is dissolved in acetone. Filtered to remove the insoluble fraction, and the copolymer is reprecipitated in methanol. A crude copolymer is obtained which can be purified by size exclusion chromatography. Three copolymers were synthesized from a mixture of monomers containing, by mole, 50%, 30% and 15% of DIPAGYL, respectively. The results are summarized in the following table:
(1) % en mole évalué par RJMN(1)% in moles evaluated by RJMN
(2) masse molaire moyenne en masse(2) mass average molar mass
(produit obtenu avant précipitation dans le méthanol)(product obtained before precipitation in methanol)
(3) indice de polymolécularité(3) polymolecularity index
Les rendements de la copolymérisation sont voisins de 90 %.The copolymerization yields are close to 90%.
Les spectres de RMN ^-H et 13C sont en accord avec la structure indiquée. Les copolymères obtenus sont amorphes. L'incorporation des motifs DIPAGYL dans le PLA fait considérablement varier la température de transition vitreuse, qui augmente avec la proportion de DIPAGYL dans les copolymères, comme le montre le tableau suivant :1 H and 13 C NMR spectra are in agreement with the indicated structure. The copolymers obtained are amorphous. The incorporation of the DIPAGYL units in the PLA considerably varies the glass transition temperature, which increases with the proportion of DIPAGYL in the copolymers, as shown in the following table:
Les poly (DIPAGYL-co-D, L-lactide) sont des polymères filmogè- nes et moulables . Des films peuvent être obtenus notamment par evaporation d'une solution du copolymere dans un solvant tel que l'acétone ou le dioxane.Poly (DIPAGYL-co-D, L-lactide) are film-forming and moldable polymers. Films can be obtained in particular by evaporation of a solution of the copolymer in a solvent such as acetone or dioxane.
Des pièces moulées peuvent être obtenues par exemple dans les conditions de moulage suivantes :Molded parts can be obtained for example under the following molding conditions:
• préchauffage du moule à 150°C pendant 30 mm,• preheating the mold at 150 ° C for 30 mm,
• dépôt du polymère sous forme de poudre,• deposition of the polymer in powder form,
• chauffage pendant 3 mm sans appliquer de pression,• heating for 3 mm without applying pressure,
• moulage avec augmentation de la pression (5 MPa/min) usqu'à 20 MPa,• molding with pressure increase (5 MPa / min) up to 20 MPa,
• arrêt de la compression et refroidissement à température
ambiante .• compression stop and temperature cooling ambient.
Exemple 5 : Déprotection des fonctions al coolExample 5: Deprotection of al cool functions
Les poly (DIPAGYL-co-D, L-lactide ) obtenus à l'exemple 4 contiennent des fonctions alcool protégées par des groupes protecteurs acétal. Par élimination des groupes protecteurs en milieu acide, on peut obtenir les polymères polyhydroxylés correspondants .The poly (DIPAGYL-co-D, L-lactide) obtained in Example 4 contain alcohol functions protected by acetal protecting groups. By elimination of the protective groups in an acid medium, the corresponding polyhydroxylated polymers can be obtained.
Par exemple, on dissout 1 g du copolymere 3 , obtenu à l'exemple 4, dans 10 cm3 de dichloromethane. On ajoute 1,5 cm3 d'eau et 10 cm3 d'acide trifluoroacétique à 5°C. On agite le mélange pendant 5 min. puis ajoute 100 cm3 d'éther. Le polymère polyhydroxylé précipite. On le sépare par décantation et le sèche sous pression réduite. Le taux de déprotection des fonctions alcool, déterminé parFor example, 1 g of copolymer 3, obtained in Example 4, is dissolved in 10 cm 3 of dichloromethane. 1.5 cm 3 of water and 10 cm 3 of trifluoroacetic acid are added at 5 ° C. The mixture is stirred for 5 min. then add 100 cm 3 of ether. The polyhydroxylated polymer precipitates. It is separated by decantation and dried under reduced pressure. The deprotection rate of alcohol functions, determined by
RMN 1H, est de l'ordre de 50 %. 1 H NMR, is of the order of 50%.
La masse molaire moyenne en masse du copolymere partiellement déprotégé représente environ 75 % de celle du copolymere de départ.The mass-average molar mass of the partially deprotected copolymer represents approximately 75% of that of the starting copolymer.
EXEMPLE 6 : Préparation d'un composé de formule III, dérivé de l'acide xylarique.EXAMPLE 6 Preparation of a compound of formula III, derived from xylaric acid.
On fait agir le diméthoxytoluène et le méthanol sur l'acide xylarique en présence d'acide p-tolène sulfonique. Après trois jours d'agitation à température ambiante, on évapore les solvants à froid sous pression réduite. Après purification, on obtient le 2,4- benzylidène xylarate de méthyle.Dimethoxytoluene and methanol are made to act on xylaric acid in the presence of p-tolene sulfonic acid. After three days of stirring at room temperature, the solvents are evaporated in the cold under reduced pressure. After purification, methyl 2,4-benzylidene xylarate is obtained.
On dissout le produit obtenu dans le chloroforme et ajoute 2,4 équivalents de diisopropyléthylamine, à 0°C, sous atmosphère d'azote. Après dix minutes de réaction, on ajoute, dans les mêmes conditions, du chlorure de méthoxyéthoxyméthyle . On porte à 60°C pendant quatorze heures. On refroidit à température ambiante et extrait au dichloromethane. L'extrait est lavé avec une solution aqueuse très diluée d'acide chlorhydrique, puis à l'eau. La phase organique est séchée et le solvant est évaporé. On obtient le 3 mé- thoxyéthoxyméthyl 2, 4-benzylidène xylarate de méthyle.
En procédant de façon analogue à celle décrite à l'étape B de l'exemple 1, on hydrolyse le diester éthylique en diacide car-" boxylique correspondant.The product obtained is dissolved in chloroform and 2.4 equivalents of diisopropylethylamine are added, at 0 ° C., under a nitrogen atmosphere. After ten minutes of reaction, methoxyethoxymethyl chloride is added under the same conditions. It is brought to 60 ° C for fourteen hours. Cool to room temperature and extract with dichloromethane. The extract is washed with a very dilute aqueous solution of hydrochloric acid, then with water. The organic phase is dried and the solvent is evaporated. 3 methyl methoxyethoxymethyl 2,4-benzylidene xylarate is obtained. By proceeding in a similar manner to that described in step B of Example 1, the ethyl diester is hydrolyzed to the diacid car- "boxylique corresponding.
Le groupe 2, 4-benzylidène est ensuite éliminé par hydrogéna- tion en présence de palladium déposé sur charbon actif. On obtient le 3-méthoxyéthoxyméthyl éther de l'acide xylarique.The 2,4-benzylidene group is then removed by hydrogenation in the presence of palladium deposited on activated carbon. 3-methoxyethoxymethyl ether of xylaric acid is obtained.
En opérant de façon analogue à celle décrite aux étapes C et D de l'exemple 1, on obtient le dérivé d'acide xylarique correspondant, contenant à chaque extrémité le cycle représenté à la formule III (avec X représentant -CH2-), ces deux cycles étant reliés par le groupementBy following a procedure analogous to that described in steps C and D of Example 1, the corresponding xylaric acid derivative is obtained, containing at each end the cycle represented in formula III (with X representing -CH2-), these two cycles being linked by the group
-CH(0-CH2-0-C2H4-OCH3)-.
-CH (0-CH 2 -0-C 2 H 4 -OCH 3 ) -.
Claims
1. Monomères de formule :1. Monomers of formula:
R dans laquelle :R in which:
R est le reste d'un acide R-CHOH-C02H dérivé d'un ose, les groupes fonctionnels contenus dans R étant éventuellement substitués,R is the remainder of an acid R-CHOH-C0 2 H derived from an ose, the functional groups contained in R being optionally substituted,
X représente un groupe -C(R1) (R2)_ ou -C (Rχ) (R2) -C(R3) (R ) - dans lequel R2, R2, R3 et R4 représentent indépendamment -H ou un groupement alkyle, allyle, aryle ou aralkyle ; et polymères obtenus au départ d'au moins un desdits monomères, comprenant des motifs de formule I :X represents a group -C (r 1 ) (r 2 ) _ or -c (r χ ) (r 2 ) -c (r 3 ) (r) -in which r 2 , r 2 , r 3 and r 4 represent independently -H or an alkyl, allyl, aryl or aralkyl group; and polymers obtained from at least one of said monomers, comprising units of formula I:
—Fθ-CH(R)-CO-0-X-Cθ"4— (I) dans laquelle R et X sont définis comme ci-dessus.—Fθ-CH(R)-CO-0-X-Cθ “ 4— (I) in which R and X are defined as above.
2. Monomère ou polymère selon la revendication 1, dans lequel ledit ose contient de 3 à 7 atomes de carbone.2. Monomer or polymer according to claim 1, wherein said ose contains from 3 to 7 carbon atoms.
3. Monomère ou polymère selon la revendication 1 ou 2, dans lequel ledit acide dérivé d'un ose est choisi parmi les acides aldoniques, uroniques et aldariques.3. Monomer or polymer according to claim 1 or 2, wherein said acid derived from an ose is chosen from aldonic, uronic and aldaric acids.
4. Monomère ou polymère selon l'une quelconque des revendications précédentes, dans lequel ledit acide dérivé d'un ose est un acide aldonique.4. Monomer or polymer according to any one of the preceding claims, wherein said acid derived from an ose is an aldonic acid.
5. Polymère résultant de la polymérisation d'au moins un monomère tel que défini dans l'une quelconque des revendications 1 à5. Polymer resulting from the polymerization of at least one monomer as defined in any one of claims 1 to
4.4.
6. Copolymere résultant de la polymérisation d'au moins un monomère tel que défini dans l'une quelconque des revendications 1 à 4, et d'au moins un comonomère. 6. Copolymer resulting from the polymerization of at least one monomer as defined in any one of claims 1 to 4, and at least one comonomer.
7. Copolymere selon la revendication 6 dans lequel ledit comonomère contient des groupements à proton mobile.7. Copolymer according to claim 6 wherein said comonomer contains mobile proton groups.
8. Copolymere selon la revendication 7, contenant des motifs de formule II :
dans laquelle :8. Copolymer according to claim 7, containing units of formula II: in which :
L est le reste d'un hydroxyacide H0-L-C02H choisi parmi les hydroxyacides capables de former un cycle dilactonique ou une monolactone.L is the remainder of a hydroxyacid H0-L-C0 2 H chosen from hydroxyacids capable of forming a dilactonic ring or a monolactone.
9. Copolymères selon la revendication 8 contenant de 1 à9. Copolymers according to claim 8 containing from 1 to
99 %, en nombre de motifs par rapport au nombre total de motifs, de motifs de formule I, et au moins 1 %, en nombre de motifs par rapport au nombre total de motifs, de motifs de formule II.99%, in number of patterns relative to the total number of patterns, of patterns of formula I, and at least 1%, in number of patterns relative to the total number of patterns, of patterns of formula II.
10. Copolymere selon la revendication 9, contenant au moins 5 % de motifs de formule II.10. Copolymer according to claim 9, containing at least 5% of units of formula II.
11. Copolymere selon l'une quelconque des revendications 8 à 10, dans lequel ledit motif de formule II est un motif :
dans lequel R5 et R6 représentent indépendamment -H ou un groupement alkyle, aryle ou carboxyalkyle.11. Copolymer according to any one of claims 8 to 10, in which said unit of formula II is a unit: in which R 5 and R 6 independently represent -H or an alkyl, aryl or carboxyalkyl group.
12. Copolymere selon la revendication 11, dans lequel ledit motif de formule II. dérive d'un acide HO-L-C02H capable de former une monolactone dont le cycle lactonique possède au moins 6 chaînons.12. Copolymer according to claim 11, wherein said unit of formula II. derives from an acid HO-L-C0 2 H capable of forming a monolactone whose lactonic ring has at least 6 members.
13. Copolymere selon la revendication précédente, dans lequel ledit motif de formule II dérive d'un acide HO-L-C02H choisi parmi les acides aldoniques, 5-hydroxy pentanoique et 6-hydroxy hexanoique . 13. Copolymer according to the preceding claim, in which said unit of formula II derives from an HO-L-C0 2 H acid chosen from aldonic, 5-hydroxy pentanoic and 6-hydroxy hexanoic acids.
14. Matériau ou article fini contenant un homopolymère ou un copolymere tel que défini dans l'une quelconque des revendications précédentes, ledit matériau se présentant sous la forme d'une poudre, de microsphères, d'un film ou d'une pièce moulée ou extru- dée. 14. Material or finished article containing a homopolymer or a copolymer as defined in any one of the preceding claims, said material being in the form of a powder, microspheres, a film or a molded part or extruded.
15. Procédé de préparation d'un monomère ou d'un polymère tel que défini dans l'une quelconque des revendications 1 à 13, dans lequel :15. Process for preparing a monomer or a polymer as defined in any one of claims 1 to 13, in which:
- on fait réagir un acide- we react an acid
R'-CHOH-C02H dans lequel R' est le reste d'un acide dérivé d'un ose, les groupements hydroxyles éventuellement contenus dans R' étant
protégés, avec un chlorure d'acide de formule :R'-CHOH-C0 2 H in which R' is the remainder of an acid derived from an ose, the hydroxyl groups possibly contained in R' being protected, with an acid chloride of formula:
Y-X-CO-Z, dans laquelle X est défini comme la revendication 1, et Y et Z représentent indépendamment un halogène, pour obtenir un pro- duit de formule V :Y-X-CO-Z, in which X is defined as claim 1, and Y and Z independently represent a halogen, to obtain a product of formula V:
Y-X-CO-0-CH(R' )-C02H (V) que l'on transforme en composé de formule III :YX-CO-0-CH(R')-C0 2 H (V) which is transformed into a compound of formula III:
par cyclisation intramoléculaire, - si désiré, on polymérise ledit composé de formule by intramolecular cyclization, - if desired, said compound of formula is polymerized
III, par homopolymérisation ou par copolymérisation avec un comonomère,III, by homopolymerization or by copolymerization with a comonomer,
- si désiré, on déprotège et/ou fonctionnalise au moins une partie des groupes hydroxyles de R', - et, si désiré, on met le copolymere obtenu sous la forme d'une poudre, de microsphères d'un film, d'une pièce moulée ou d'une pièce extrudée.- if desired, we deprotect and/or functionalize at least part of the hydroxyl groups of R', - and, if desired, we put the copolymer obtained in the form of a powder, of microspheres of a film, of a molded part or an extruded part.
16. Procédé selon la revendication 15, dans lequel le comonomère est choisi parmi les dilactones et les monolactones dérivant d'un hydroxyacide tel que défini dans l'une quelconque des revendications 8 et 11 à 13.16. Process according to claim 15, in which the comonomer is chosen from dilactones and monolactones deriving from a hydroxy acid as defined in any one of claims 8 and 11 to 13.
17. Procédé selon la revendication 16, dans laquelle ladite dilactone répond à la formule :17. Method according to claim 16, in which said dilactone corresponds to the formula:
dans laquelle R5 et Rg représentent indépendamment -H ou un groupe alkyle, aryle ou carboxyalkyle. in which R 5 and Rg independently represent -H or an alkyl, aryl or carboxyalkyl group.
18. Procédé selon la revendication 17, dans lequel ladite dilactone est choisie parmi le glycolide et le D-, le L- ou le18. Method according to claim 17, wherein said dilactone is chosen from glycolide and D-, L- or
DL-lactide.
DL-lactide.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9708146 | 1997-06-27 | ||
| FR9708145 | 1997-06-27 | ||
| FR9708146A FR2765224B1 (en) | 1997-06-27 | 1997-06-27 | MODIFIED BONES OR DERIVATIVES OF MODIFIED BONES COMPRISING A DILACTONIC CYCLE, THEIR INTERMEDIATES OF SYNTHESIS, AND POLYMERS OBTAINED BY OPENING THE DILACTONIC CYCLE |
| FR9708145A FR2765228B1 (en) | 1997-06-27 | 1997-06-27 | NOVEL COPOLYMERS DERIVED FROM HYDROXYACIDS, THEIR PREPARATION AND MATERIALS CONTAINING THEM |
| PCT/FR1998/001386 WO1999000441A1 (en) | 1997-06-27 | 1998-06-29 | Novel monomers with dilactonic cycle, and corresponding polymers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0991692A1 true EP0991692A1 (en) | 2000-04-12 |
Family
ID=26233644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98933753A Withdrawn EP0991692A1 (en) | 1997-06-27 | 1998-06-29 | Novel monomers with dilactonic cycle, and corresponding polymers |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US6156429A (en) |
| EP (1) | EP0991692A1 (en) |
| JP (1) | JP2002511113A (en) |
| CA (1) | CA2295952A1 (en) |
| WO (1) | WO1999000441A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19829305A1 (en) * | 1998-06-30 | 2000-01-05 | Schnell Chemie Gmbh Dr | One step preparation of alpha-hydroxycarboxylic acid sugar monoesters and also of novel lactides useful as surfactants or emulsifiers |
| JP3450810B2 (en) | 2000-01-31 | 2003-09-29 | キヤノン株式会社 | Aliphatic polyester, method for producing aliphatic polyester and method for recycling cellulose |
| JP4455413B2 (en) * | 2004-06-11 | 2010-04-21 | キヤノン株式会社 | Polyhydroxyalkanoic acid having vinyl group, ester group, carboxyl group and sulfonic acid group and method for producing the same |
| WO2009127009A1 (en) * | 2008-04-18 | 2009-10-22 | Commonwealth Scientific And Industrial Research Organisation | Condensation polymers |
| JP6894604B2 (en) * | 2016-03-30 | 2021-06-30 | 国立大学法人 東京大学 | New polymer with aldaric acid as a structural unit and manufacturing method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0407617B1 (en) * | 1989-01-27 | 1997-05-28 | MITSUI TOATSU CHEMICALS, Inc. | Process for the preparation of a biocompatible polyester |
| FR2693734B1 (en) * | 1992-07-15 | 1994-10-07 | Roquette Freres | Thermoformable-biodegradable composition based on a starchy compound and a biodegradable polyester. |
-
1998
- 1998-06-29 CA CA002295952A patent/CA2295952A1/en not_active Abandoned
- 1998-06-29 EP EP98933753A patent/EP0991692A1/en not_active Withdrawn
- 1998-06-29 US US09/446,607 patent/US6156429A/en not_active Expired - Fee Related
- 1998-06-29 JP JP50534899A patent/JP2002511113A/en active Pending
- 1998-06-29 WO PCT/FR1998/001386 patent/WO1999000441A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9900441A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999000441A1 (en) | 1999-01-07 |
| US6156429A (en) | 2000-12-05 |
| JP2002511113A (en) | 2002-04-09 |
| CA2295952A1 (en) | 1999-01-07 |
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