WO2010061025A1 - Functionalization of 1-vinyl-2-pyrrolidone at position 3, comprising the opening of cyclic precursors - Google Patents
Functionalization of 1-vinyl-2-pyrrolidone at position 3, comprising the opening of cyclic precursors Download PDFInfo
- Publication number
- WO2010061025A1 WO2010061025A1 PCT/ES2009/070521 ES2009070521W WO2010061025A1 WO 2010061025 A1 WO2010061025 A1 WO 2010061025A1 ES 2009070521 W ES2009070521 W ES 2009070521W WO 2010061025 A1 WO2010061025 A1 WO 2010061025A1
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- WIPO (PCT)
- Prior art keywords
- vinyl
- pyrrolidone
- group
- compound according
- formula
- Prior art date
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 239000002243 precursor Substances 0.000 title claims abstract description 13
- 238000007306 functionalization reaction Methods 0.000 title abstract description 10
- 125000004122 cyclic group Chemical group 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- 229920001577 copolymer Polymers 0.000 claims abstract description 11
- 150000001412 amines Chemical class 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 150000003573 thiols Chemical class 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- -1 alkylsultone Chemical class 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000000178 monomer Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 150000002596 lactones Chemical class 0.000 claims description 6
- XROWRWSZVHOXIG-UHFFFAOYSA-N 1-ethenyl-3-(2-hydroxyethyl)pyrrolidin-2-one Chemical compound OCCC1CCN(C=C)C1=O XROWRWSZVHOXIG-UHFFFAOYSA-N 0.000 claims description 5
- OYUQWSJNFQATSI-UHFFFAOYSA-N 1-ethenyl-3-(2-sulfanylethyl)pyrrolidin-2-one Chemical compound SCCC1CCN(C=C)C1=O OYUQWSJNFQATSI-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- MXVJGQYHICXLEV-UHFFFAOYSA-N 1-ethenyl-3-(5-hydroxypentanoyl)pyrrolidin-2-one Chemical compound OCCCCC(=O)C1CCN(C=C)C1=O MXVJGQYHICXLEV-UHFFFAOYSA-N 0.000 claims description 4
- ALXRSVWYPAAPLE-UHFFFAOYSA-N 1-ethenyl-3-(6-hydroxyhexanoyl)pyrrolidin-2-one Chemical compound OCCCCCC(=O)C1CCN(C=C)C1=O ALXRSVWYPAAPLE-UHFFFAOYSA-N 0.000 claims description 4
- HJONEXSLLOKKPB-UHFFFAOYSA-N 1-ethenyl-3-[2-(methylamino)benzoyl]pyrrolidin-2-one Chemical compound CNC1=CC=CC=C1C(=O)C1C(=O)N(C=C)CC1 HJONEXSLLOKKPB-UHFFFAOYSA-N 0.000 claims description 4
- RRGXGQRMTVKFAQ-UHFFFAOYSA-N 3-(1-ethenyl-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCC1CCN(C=C)C1=O RRGXGQRMTVKFAQ-UHFFFAOYSA-N 0.000 claims description 4
- SCFHMZQKPZAIPN-UHFFFAOYSA-N 3-(2-aminobenzoyl)-1-ethenylpyrrolidin-2-one Chemical compound NC1=CC=CC=C1C(=O)C1C(=O)N(C=C)CC1 SCFHMZQKPZAIPN-UHFFFAOYSA-N 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 150000008064 anhydrides Chemical group 0.000 claims description 3
- 150000003951 lactams Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001174 sulfone group Chemical group 0.000 claims description 3
- WDSJUMIWHPJLLU-UHFFFAOYSA-N 3-(1-ethenyl-2-oxopyrrolidin-3-yl)-3-oxopropanoic acid Chemical compound O=C(CC(=O)O)C1C(N(CC1)C=C)=O WDSJUMIWHPJLLU-UHFFFAOYSA-N 0.000 claims description 2
- GPUOFPNFYDKSPC-UHFFFAOYSA-N 3-(2-aminoethyl)-1-ethenylpyrrolidin-2-one Chemical compound NCCC1C(N(CC1)C=C)=O GPUOFPNFYDKSPC-UHFFFAOYSA-N 0.000 claims description 2
- OTOOZNXQUIAIGQ-UHFFFAOYSA-N 3-(2-aminopropanoyl)-1-ethenylpyrrolidin-2-one Chemical compound O=C(C(C)N)C1C(N(CC1)C=C)=O OTOOZNXQUIAIGQ-UHFFFAOYSA-N 0.000 claims description 2
- FGJNEEZJRZCZAR-UHFFFAOYSA-N 3-[2-(dimethylamino)ethyl]-1-ethenylpyrrolidin-2-one Chemical compound CN(C)CCC1C(N(CC1)C=C)=O FGJNEEZJRZCZAR-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- BQGLBMHIBYAMGC-UHFFFAOYSA-N NCCS(=O)(=O)C1C(N(CC1)C=C)=O Chemical compound NCCS(=O)(=O)C1C(N(CC1)C=C)=O BQGLBMHIBYAMGC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 230000005595 deprotonation Effects 0.000 claims description 2
- 238000010537 deprotonation reaction Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 125000000524 functional group Chemical group 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 10
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000007334 copolymerization reaction Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000003857 carboxamides Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FSSPGSAQUIYDCN-UHFFFAOYSA-N 1,3-Propane sultone Chemical compound O=S1(=O)CCCO1 FSSPGSAQUIYDCN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 150000001923 cyclic compounds Chemical class 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 3
- 150000008053 sultones Chemical class 0.000 description 3
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000012223 aqueous fraction Substances 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 150000003950 cyclic amides Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- QFZHSSIDYCSXKQ-UHFFFAOYSA-N 1-ethenyl-3-(2-hydroxypropyl)pyrrolidin-2-one Chemical compound OC(CC1C(N(CC1)C=C)=O)C QFZHSSIDYCSXKQ-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- GRMFETDPTVZGCA-UHFFFAOYSA-N CCC(N(CCC1)C1=O)[I](C)C Chemical compound CCC(N(CCC1)C1=O)[I](C)C GRMFETDPTVZGCA-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- KJMRWDHBVCNLTQ-UHFFFAOYSA-N N-methylisatoic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)N(C)C2=C1 KJMRWDHBVCNLTQ-UHFFFAOYSA-N 0.000 description 1
- 229920001007 Nylon 4 Polymers 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940064804 betadine Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- QDXBVEACAWKSFL-UHFFFAOYSA-N ethenethiol Chemical group SC=C QDXBVEACAWKSFL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229920000831 ionic polymer Polymers 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 235000020939 nutritional additive Nutrition 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003058 plasma substitute Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
- C08F226/10—N-Vinyl-pyrrolidone
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F26/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F26/06—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
- C08F26/10—N-Vinyl-pyrrolidone
Definitions
- the present invention relates to a process for the functionalization of 1-vinyl-2-pyrrolidone in position 3 by opening cyclic precursors and in a single step reaction.
- the present invention relates to functionalized VP compounds and polymers or copolymers that include them, as well as their different uses.
- Poly-1-vinyl-2-pyrrolidone is a non-ionic and water soluble polymer that is used in many applications. It is used for example in cosmetics, personal hygiene items, paints, adhesives, contact lenses as well as in the medical area. PVP has even been used as a blood plasma substitute due to its known biocompatibility. It is also used as a nutritional additive, stabilizer (E1201), excipient of pharmacological compounds or, in combination with iodine, for the preparation of betadine®.
- the PVP is, due to its water solubility and biocompatibility, a very interesting polymer. It can serve as a carrier of bioactive or pharmacological compounds or to prepare water soluble and pharmacologically active polymeric compounds.
- a modification of the side chain a certain group of monomer units carries the functional group in the side chain.
- the modifications in the side chain are multifunctional and allow the control of the number of functional groups since it is controlled by the degree of modification of the monomer units.
- PVP is a polymer that contains cyclic amide groups that can be opened, for example, by hydrolysis with which multifunctional side chain copolymers are obtained in which, however, the integrity of the rings is not maintained.
- the bromination of PVP at high temperatures has also been described, which leads to a polymer with a rather little specific modification.
- the best alternative for the preparation of multifunctional side chain PVP derivatives with a versatile control of the number of functional groups and of the composition and which also have a random distribution of functional groups is the modification of the VP monomer followed by homo- or copolymerization with unmodified VP (strategy B2).
- substrategy B2 unmodified VP
- main chains made of pure PVP can be obtained while maintaining the integrity of the pyrrolidone rings.
- the reactivities of the original VP and modified VP will be very similar and thus the inconveniences in copolymerization caused by differential reactivities mentioned above can be avoided.
- the VP contains a strongly polarized carbon-hydrogen bond in the ⁇ position of the carbonyl group. With strong bases this hydrogen can be abstracted, forming the anion of the enolato of the carboxamide.
- This intermediate compound can be used to attack alkyl halides in a nucleophilic manner.
- This reaction can be used to connect groups consisting of pure hydrocarbons to the VP and it has been used to rent the monomer or to synthesize alkyl crosslinkers carrying two VP units (Engstrom JUA, Helgee B. Macromol. Chem. Phvs. 2006, 207 : 536-544; White, LA, Jonson, S, Hoyle, CE, et al., Polvmer, 1999, 40 (23): 6597-6605 or even to connect a biomolecule such as cholesterol (Cho, I, Jeong, Sw ., Macromol Chem Phvsic.
- the present invention provides a method for synthesizing VP containing functional groups, such as carboxylic, hydroxy, mercapto, amino or sulfo, in its side chain. This procedure gives rise to functional groups in a one-step reaction by opening rings of appropriate cyclic compounds. These functionalized compounds can, in a second stage, react under mild conditions with an active compound to obtain conjugates of different nature.
- functional groups such as carboxylic, hydroxy, mercapto, amino or sulfo
- the process of the present invention allows the VP to be functionalized in position 3 directly in a single step with groups such as thiol, amino, hydroxy, mercapto, carboxyl or sulfo, by reaction of the anion of the carboxamide of the VP with different precursors cyclic of these functionalities.
- groups such as thiol, amino, hydroxy, mercapto, carboxyl or sulfo
- the nature and length of the spacer can be chosen between the VP group and the reactive functional group.
- a first aspect of the present invention refers to functionalized VP of general formula (I) or any of its salts (from now on compounds of the invention):
- A is a CR 1 R 2 group, a carbonyl group (CO) or a sulfone group
- R 1 and R 2 are the same or different and represent a hydrogen (H) or a methyl group (CH 3 );
- X is a radical selected from the group comprising a hydroxyl (OH), a thiol (SH), a sulfonyl (SO 3 H), an amine (NR 3 R 4 , NHR 3 or NH 2 ) or a carboxyl (CO 2 H );
- R, R 3 and R 4 are a non-functional moiety in the reaction, are the same or different and represent an aryl group (C 6 -Ci 8 ) or an alkyl group
- alkyl group refers, in the present invention, to aliphatic, linear or branched chains, having 1 to 10 carbon atoms, for example, this group can be methyl, ethyl, n-propyl, / -propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, etc.
- the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms.
- aryl refers in the present invention to an aromatic carbocyclic chain, having from 6 to 18 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings.
- a non-limiting example of aryl is a phenyl, naphthyl, indenyl, etc. group.
- the aryl group is a phenyl.
- X is a hydroxyl group, whereby the compound is selected from those of formula 3- (hydroxyalkyl) -1-vinyl-2-pyrrolidone when A is a CR 1 R 2 group , or 3- ( 1-oxo- ⁇ -hydroxyalkyl) -1-vinyl-2-pyrrolidone, when A a carbonyl group (CO).
- the compounds are, for example, but not limited to, 3- (2-hydroxyethyl) -1-vinyl-2-pyrrolidone, 3- (1-oxo-5- hydroxypentyl) -1-vinyl-2-pyrrolidone or 3- ( 1 -oxo-6-hydroxyhexyl) -1-vinyl-2-pyrrolidone.
- X is a thiol group, giving rise to compounds such as, but not limited to, formula 3- (2-mercaptoethyl) -1-vinyl- 2-pyrrolidone.
- X is a sulfonyl group, giving rise to compounds such as, but not limited to, formula 3- (3- sulfopropyl) -1-vinyl-2-pyrrolidone.
- A is a carbonyl group and X an aromatic amine (NHR 3 or NH2) giving rise to compounds of formula 3- (1-oxo- ⁇ -aminoaryl) -1-vinyl-2-pyrrolidone, 3- ( 1-oxo- ⁇ -alkylaminoaryl) -1-vinyl-2-pyrrolidone or 3- (1-oxo- ⁇ -arylaminoaryl) -1-vinyl-2-pyrrolidone, where the number ⁇ will depend on the aryl group.
- the aryl and alkyl groups refer respectively to the terms "aryl" and "alkyl” described above.
- the compounds are, for example, but not limited to, the compounds 3- (2- aminobenzoyl) -1-vinyl-2-pyrrolidone or 3- (N-methyl-2-aminobenzoyl) -1-vinyl-2-pyrrolidone.
- A is a carbonyl group and X is a non-aromatic amine (NHR 3 or NH 2 ), giving rise to compounds of formula 3- (1-oxo- ⁇ -aminoalkyl) -1-vinyl-2-pyrrolidone or 3- (1-Oxo- ⁇ -alkylaminoalkyl) -1-vinyl-2-pyrrolidone, where the number ⁇ will depend on the alkyl group and the alkyl group refers to the term described above.
- the compounds are, for example, but not limited to 3- (1-oxo-2-aminopropyl) -1-vinyl-2-pyrrolidone.
- A is a CR 1 R 2 group and X is an amine (NR 3 R 4 or NHR 3 or NH 2 ), giving rise to compounds of formula 3- ( ⁇ -aminoalkyl) -1-vinyl-2- pyrrolidone, 3- ( ⁇ -alkylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- ( ⁇ - arylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- ( ⁇ -dialkylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- ( ⁇ -diarylaminoalkyl) -1-vinyl-2-pyrrolidone, 3- ( ⁇ - alkylaminoalkyl) -1-vinyl-2-pyrrolidone, where the number ⁇ will depend on the alkyl group R.
- aryl and alkyl groups refer respectively to the terms "aryl” and “alkyl” described above.
- the compounds are 3 - (- 2-aminoethyl) -1-vinyl-2-pyrrolidone or 3- (2-Dimethylaminoethyl) -1-vinyl-2-pyrrolidone.
- A is a carbonyl group and X is a carboxyl (CO 2 H), giving rise to compounds of formula 3- (1-oxo- ⁇ -carboxyalkyl) -1-vinyl-2-pyrrolidone, where the number ⁇ It will depend on the alkyl group and the alkyl group refers to the term described above. As for example, but not limited, the compound is 3- (1-oxo-2-carboxyethyl) -1-vinyl-2-pyrrolidone.
- A is a sulfone group (-
- SO 2 -) and X is an amino group (NH 2 or NHR 3 ), giving rise to compounds of formula 3- ( ⁇ -aminoalkylsulfonyl) -1-vinyl-2-pyrrolidone or 3- ( ⁇ -alkylaminosulfonyl) -1- vinyl-2-pyrrolidone or 3- ( ⁇ -arylaminosulfonyl) -1-vinyl-2-pyrrolidone.
- the compound is 3- (2- aminoethylsulfonyl) -1-vinyl-2-pyrrolidone.
- a second aspect of the present invention refers to the process for obtaining the compounds of general formula (I) comprising the following steps: a. deprotonation in position 3 of 1-vinyl-2-pyrrolidone (VP) by the addition of a base; b. The reaction of a precursor ring of formula (II) with 1-vinyl-2-pyrrolidone obtained in step (a).
- VP 1-vinyl-2-pyrrolidone
- Scheme 1 represents the synthesis of the compounds of formula (I) described according to the process of the invention:
- A is the group susceptible to attack and R indicates the type and length of the spacer.
- X ' is a precursor of the reactive group (X), usually an X group that has been deprotonated or carboxylated and is selected from an N-carboxyanhydride, ether, thioether, cyclic amine, ester, amide or anhydride group.
- the compound of formula (2) can be selected from the list comprising a cyclic compound that contains as part of the cycle a group, such as, but not limited to, N-carboxyanhydride, ether, thioether, amine, amide, ester, sultone , sultama or anhydride.
- a group such as, but not limited to, N-carboxyanhydride, ether, thioether, amine, amide, ester, sultone , sultama or anhydride.
- Non-limiting examples of these X'-A groups, which form the above compounds, may be: CH 2 -O, CH 2 -S (for small rings of 3 or 4 links), OCO (lactone), OSO 2 (sultone) , OCN (lactam), SO 2 N (sultama) for rings of 4, 5, 6 or 7 links.
- the addiction to the reaction of an excess of the cyclic compound can give rise to an oligomerization process obtaining macromonomers.
- the cycle is a lactone and is added in excess, VP-oligo (lactone) could be obtained.
- a preferred embodiment of the process of the invention comprises bringing the reaction to a temperature between -10O 0 C and 5O 0 C, more preferably at a temperature between -85 0 C and -20 0 C.
- the first step of the synthetic route of the process of the invention consists in the formation of activated 1-vinyl-2-pyrrolidone, such as an enolate of carboxamide by the action of a base.
- the functionalization of VP is achieved by nucleophilic attack of the enolate and the corresponding ring opening to cycles susceptible to this attack as shown in scheme 1.
- the main driving force of the reaction is the high annular tension, while in the case of larger cycles such as lactones or sultones of 5 or 6 links - among others - the electrophilic susceptibility associated with the functional group It is the main responsible for the attack and the opening.
- the optimal temperature range lies between 85 0 C and -2O 0 C, more preferably at a temperature of about -78 0 C.
- ethylene oxide, ethylene sulfide or 1, 3-propane sultone in the cases that result products where vinylpyrrolidone contains or a unit of 2-hydroxyethylene or 2-mercaptoethylene respectively.
- vinylpyrrolidone contains or a unit of 2-hydroxyethylene or 2-mercaptoethylene respectively.
- a vinyl pyrrolidone with a single 3-sulfopropyl group is obtained.
- monomer units with functional groups are obtained that have a short spacer of two or three methylene groups between the functional group and the VP.
- This reaction can also be carried out with cyclic lactones as examples of larger cycles in which the annular tension is no longer the driving force of the reaction. In this case, longer spacers are obtained and the overall yields of the reactions are between 30 and 60%.
- the precursor ring of formula (II) may be of the lactam type, lactones of different sizes, cyclic ethers or thioethers of 3 or 4 carbon atoms, cyclic amines of 3 or 4 carbon atoms, cyclic alkylultones, alkyl sulfonamides cyclic or cyclic ammonium salts.
- precursor rings where R is different from a linear alkyl chain can be used, such as but not limited to propylene oxide [to give 3- (2-hydroxypropyl) -1-vinyl-2-pyrrolidone), or a aromatic ring in ortho.
- the monomers corresponding to the compounds of general formula (I), for example, but not limited to VP functionalized with amine, carboxyl, sulfo, hydroxy, or mercapto groups, can be homopolymerized or copolymerized with 1-vinyl-2-pyrrolidone to form polymers or copolymers whose main chain consists exclusively of vinyl pyrrolidone units, that is, to form functionalized polypyrrolidone.
- these functional groups can be used before or after homo- or copolymerization to covalently anchor active compounds such as drugs or nutraceuticals.
- a third aspect of the present invention refers to the use of the compounds of general formula (I) for obtaining polymers or copolymers.
- Another aspect of the present invention relates to polymers or copolymers comprising a compound of general formula (I) as a monomer.
- the compounds of general formula (I), when X is a thiol group, can be a very useful tool in polymerization because it is difunctional, since SH is a very reactive transfer agent and, therefore, can be used to obtain macromonomers, grafts or crosslinks.
- Fig. 1.- Represents a 1 H NMR spectrum of the 1: 1 copolymer of VP and VP- (CH 2 ) S -SO 3 Li (D 2 O, 300 MHz).
- This product was prepared with a 35% yield, from VP (5.0 ml_, 47 mmol, 1.08 equiv) and ethylene sulfide (2.8 g, 47 mmol, 1.0 equiv) following the methodology described for the compound (1).
- This product was obtained with a 28% yield, from VP (5.0 ml_, 47 mmol, 1.08 equiv) and ⁇ -valerolactone (4.0 ml_, 43.5 mmol, 1.0 equiv) as starting products.
- the route used was the one described for the product (3).
- reaction mass was maintained for 30 minutes at - 78 0 C. After this time, a solution of 11.7g of 1, 3- propanosultone (93 mmol, 2 equivalents) was dripped in 30 ml_ of THF anhydrous. During the addition the temperature should not exceed -76 0 C.
- EXAMPLE 2 Polymerization and copolymerization of vinyl pyrrolidone (VP) and VP derivatives.
- VP vinyl pyrrolidone
- VP derivatives a polymer formed from polystyrene (PS) and polystyrene (PS)
- monomers were dissolved in a total concentration of 1 M and initiator in a concentration of 1.5 x 10 ⁇ 2 M.
- the oxygen present in the solution was displaced by bubbling with N 2 for 30 minutes It was then allowed to polymerize for the appropriate time and temperature.
- the polymer or copolymer was isolated and purified by precipitation in a non-solvent. If it is soluble in water, it was purified by dialysis in 3000 cut-off membranes.
- Reaction example 55 mg of VP (previously distilled) and 196 mg of VP- (CH 2 ) 3 -S ⁇ 3 Li (1: 1 molar ratio) were dissolved in 1 ml_ distilled water. 2.5 mg of azobisisobutyro nitrile (AIBN) was added. N 2 (carefully) was bubbled in the solution for 30 minutes and then the vial was closed and left in a closed oven at 50 ° C for 48 hours. After this time, the reaction was slowly precipitated in a large excess of acetone. The solid precipitated product was filtered, washed with acetone, and dried in vacuo to constant temperature. The 1 H NMR spectrum of this copolymer (D 2 O, 300 MHz) is shown in Figure 1.
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Abstract
The invention relates to 1-vinyl-2-pyrrolidone compounds functionalized with hydroxyl, thiol, sulphonyl, amine or carboxyl groups. The invention also relates to the method for the functionalization of 1-vinyl-2-pyrrolidone at position 3, comprising the opening of cyclic precursors in a single-step reaction. The invention further relates to polymers or copolymers including said compounds and to the various uses thereof.
Description
FUNCIONALIZACION DE 1-VINIL-2-PIRROLIDONA EN POSICIÓN 3 MEDIANTE APERTURA DE PRECURSORES CÍCLICOS FUNCTIONALIZATION OF 1-VINYL-2-PIRROLIDONE IN POSITION 3 THROUGH OPENING OF CYCLIC PRECURSORS
La presente invención se refiere a un procedimiento para Ia funcionalización de 1 -vinil-2-pirrolidona en posición 3 mediante apertura de precursores cíclicos y en una reacción de un solo paso. Además, Ia presente invención se refiere a los compuestos VP funcionalizados y a polímeros o copolímeros que los incluyen, así como sus diferentes usos.The present invention relates to a process for the functionalization of 1-vinyl-2-pyrrolidone in position 3 by opening cyclic precursors and in a single step reaction. In addition, the present invention relates to functionalized VP compounds and polymers or copolymers that include them, as well as their different uses.
ESTADO DE LA TÉCNICASTATE OF THE TECHNIQUE
Poli-1 -vinil-2-pirrolidona, PVP, es un polímero no-iónico y soluble en agua que se emplea en muchas aplicaciones. Se usa por ejemplo en cosmética, artículos de higiene personal, pinturas, adhesivos, lentes de contacto así como en el área médica. PVP ha sido usado incluso como sustituto de plasma sanguíneo debido a su biocompatibilidad conocida. También se usa como aditivo nutricional, estabilizante (E1201 ), excipiente de compuestos farmacológicos o, en combinación con yodo, para Ia preparación de betadine®.Poly-1-vinyl-2-pyrrolidone, PVP, is a non-ionic and water soluble polymer that is used in many applications. It is used for example in cosmetics, personal hygiene items, paints, adhesives, contact lenses as well as in the medical area. PVP has even been used as a blood plasma substitute due to its known biocompatibility. It is also used as a nutritional additive, stabilizer (E1201), excipient of pharmacological compounds or, in combination with iodine, for the preparation of betadine®.
PVPPVP
Debido a su relevancia existe obviamente un gran interés en Ia funcionalización de PVP, es decir, incorporar químicamente grupos que puedan alterar algunas de sus propiedades y/o permitan incorporar diferentes moléculas.Due to its relevance there is obviously a great interest in the functionalization of PVP, that is, chemically incorporating groups that can alter some of its properties and / or allow the incorporation of different molecules.
También en el campo biomédico de los conjugados, el PVP es, debido a
su solubilidad en agua y biocompatibilidad, un polímero muy interesante. Puede servir como portador de compuestos bioactivos o farmacológicos o para preparar compuestos poliméricos solubles en agua y farmacológicamente activos.Also in the biomedical field of conjugates, the PVP is, due to its water solubility and biocompatibility, a very interesting polymer. It can serve as a carrier of bioactive or pharmacological compounds or to prepare water soluble and pharmacologically active polymeric compounds.
Estos sistemas pueden ser empleados como alternativa a materiales de soporte ya existentes.These systems can be used as an alternative to existing support materials.
En el caso de una modificación de Ia cadena lateral, un grupo determinado de unidades monoméricas lleva el grupo funcional en Ia cadena lateral. En comparación con modificaciones en el grupo terminal de las cadenas poliméricas las modificaciones en Ia cadena lateral son multifuncionales y permiten el control de Ia cantidad de grupos funcionales ya que está controlada por el grado de modificación de las unidades monoméricas.In the case of a modification of the side chain, a certain group of monomer units carries the functional group in the side chain. In comparison with modifications in the terminal group of the polymer chains, the modifications in the side chain are multifunctional and allow the control of the number of functional groups since it is controlled by the degree of modification of the monomer units.
Con el fin de obtener PVP funcionalizado en Ia cadena lateral se pueden distinguir tres estrategias: funcionalización del homopolímero PVP por reacciones de modificación química (B1 ), funcionalización del monómero VP y posterior homo - o copolimerización con VP puro (B2) y copolimerización de VP puro con diferentes tipos de monómeros que llevan un grupo funcional o un compuesto bioactivo (B3).In order to obtain functionalized PVP in the side chain, three strategies can be distinguished: functionalization of the PVP homopolymer by chemical modification reactions (B1), functionalization of the VP monomer and subsequent homo- or copolymerization with pure VP (B2) and VP copolymerization pure with different types of monomers that carry a functional group or a bioactive compound (B3).
En el caso B3 Ia funcionalización no se lleva a cabo en las unidades del VP sino en comonómeros reactivos como anhídrido maléico (MA) y sus derivados, ácido acrílico (AA), aminoalquilacrilamidas (US5206322),
aminoalquil e hidroxialquilolefinas (US3563968) u otros. Estas copolimerizaciones con otros componentes que no sean vinilpirrolidona no deberían considerarse funcionalizaciones auténticas de PVP porque conducen a cadenas macromoleculares que no solo contienen unidades de VP. Este tipo de procesos de copolimerización tiene Ia desventaja asociada a las reactividades diferenciales de los comonómeros que en algunos casos pueden resultar muy relevantes (Sánchez-Chaves, M, Martínez, G, Madruga, EL, et al., J Polvm Sci PoI Chem, 2002, 40 (8): 1192-1199) y pueden conducir a una heterogeneidad composicional extrema del polímero resultante.In case B3 the functionalization is not carried out in the VP units but in reactive comonomers such as maleic anhydride (MA) and its derivatives, acrylic acid (AA), aminoalkylacrylamides (US5206322), aminoalkyl and hydroxyalkyllefins (US3563968) or others. These copolymerizations with components other than vinyl pyrrolidone should not be considered authentic PVP functionalizations because they lead to macromolecular chains that not only contain VP units. This type of copolymerization process has the disadvantage associated with the differential reactivities of the comonomers that in some cases can be very relevant (Sánchez-Chaves, M, Martínez, G, Madruga, EL, et al., J Polvm Sci PoI Chem, 2002, 40 (8): 1192-1199) and can lead to extreme compositional heterogeneity of the resulting polymer.
Otros grupos de investigación siguiendo Ia estrategia B1 han intentado funcionalizar el PVP por modificación del polímero. PVP es un polímero que contiene grupos de amidas cíclicas que se pueden abrir, por ejemplo, por hidrólisis con Io que se obtiene copolímeros multifuncionales de cadena lateral en las que, sin embargo, no se mantiene Ia integridad de los anillos. Se ha descrito también Ia bromación del PVP a altas temperaturas Io que conduce a un polímero con una modificación bastante poco específica.Other research groups following strategy B1 have tried to functionalize the PVP by polymer modification. PVP is a polymer that contains cyclic amide groups that can be opened, for example, by hydrolysis with which multifunctional side chain copolymers are obtained in which, however, the integrity of the rings is not maintained. The bromination of PVP at high temperatures has also been described, which leads to a polymer with a rather little specific modification.
La desventaja general de Ia modificación de polímeros es Ia imposibilidad de purificar los productos obtenidos. De hecho resulta imposible eliminar unidades que no hayan reaccionado o aquellos que hayan conducido a reacciones secundarias no deseadas ya que todos ellos están anclados covalentemente a las cadenas macromoleculares.The general disadvantage of the modification of polymers is the impossibility of purifying the products obtained. In fact it is impossible to eliminate units that have not reacted or those that have led to unwanted side reactions since all of them are covalently anchored to macromolecular chains.
Por esta razón, Ia mejor alternativa para Ia preparación de derivados de PVP multifuncionales de cadena lateral con un control versátil del número de grupos funcionales y de Ia composición y que además tengan una distribución al azar de grupos funcionales es Ia modificación del monómero de Ia VP seguida por homo- o copolimerización con VP no modificado
(estrategia B2). De este modo se puede obtener cadenas principales hechas de PVP puro manteniendo además Ia integridad de los anillos de Ia pirrolidona. Además las reactividades del VP original y VP modificada van a ser muy similares y se puede evitar así las inconveniencias en copolimerización provocadas por reactividades diferenciales mencionadas anteriormente.For this reason, the best alternative for the preparation of multifunctional side chain PVP derivatives with a versatile control of the number of functional groups and of the composition and which also have a random distribution of functional groups is the modification of the VP monomer followed by homo- or copolymerization with unmodified VP (strategy B2). In this way, main chains made of pure PVP can be obtained while maintaining the integrity of the pyrrolidone rings. In addition the reactivities of the original VP and modified VP will be very similar and thus the inconveniences in copolymerization caused by differential reactivities mentioned above can be avoided.
Como amida cíclica Ia VP contiene un enlace carbono-hidrógeno fuertemente polarizado en posición α del grupo carbonilo. Con bases fuertes se puede abstraer este hidrógeno, formando el anión del enolato de Ia carboxamida. Se puede emplear este compuesto intermedio para atacar haluros de alquilo de una manera nucleófila.As a cyclic amide, the VP contains a strongly polarized carbon-hydrogen bond in the α position of the carbonyl group. With strong bases this hydrogen can be abstracted, forming the anion of the enolato of the carboxamide. This intermediate compound can be used to attack alkyl halides in a nucleophilic manner.
Se puede usar esta reacción para conectar a Ia VP grupos consistentes de hidrocarburos puros y se ha empleado para alquilar el monómero o para sintetizar entrecruzantes alquílicos portadores de dos unidades de VP (Engstrom JUA, Helgee B. Macromol. Chem. Phvs. 2006, 207: 536-544; White, LA, Jonson, S, Hoyle, CE, et al., Polvmer, 1999, 40 (23): 6597-6605 o incluso para conectar una biomolécula como el colesterol (Cho, I, Jeong, Sw., Macromol Chem Phvsic. 1995, 196 (3): 869-875) que solo contiene átomos de hidrógeno y carbono. Sin embargo, Ia inestabilidad del anión del enolato no permite llevar a cabo Ia reacción con haluros de alquilo que además contienen otros grupos como carboxílico, hidroxi, mercapto, amino o sulfo. VP con grupos hidroxi se ha intentado sintetizar en el pasado por reacción del anión del enolato de Ia VP con un haluro de alquilo alifático que contenía un grupo hidroxi protegido por un grupo íerc-butil-dimetil silano (Engstrom JUA, Helgee B. Macromol. Chem. Phvs. 2006, 207: 536- 54) y posterior desprotección. Sin embargo, solo fue posible obtener mezclas entre compuestos hidroxilados mono- y di-sustituidos y el rendimiento general de Ia reacción resultó muy bajo
DESCRIPCIÓN DE LA INVENCIÓNThis reaction can be used to connect groups consisting of pure hydrocarbons to the VP and it has been used to rent the monomer or to synthesize alkyl crosslinkers carrying two VP units (Engstrom JUA, Helgee B. Macromol. Chem. Phvs. 2006, 207 : 536-544; White, LA, Jonson, S, Hoyle, CE, et al., Polvmer, 1999, 40 (23): 6597-6605 or even to connect a biomolecule such as cholesterol (Cho, I, Jeong, Sw ., Macromol Chem Phvsic. 1995, 196 (3): 869-875) that only contains hydrogen and carbon atoms, however, the instability of the anion of the enolato does not allow to carry out the reaction with alkyl halides that also contain others groups such as carboxylic, hydroxy, mercapto, amino or sulfo.VP with hydroxy groups has been attempted to synthesize in the past by reaction of the enolate anion of the VP with an aliphatic alkyl halide containing a hydroxy group protected by an íerc-butyl group -dimethyl silane (Engstrom JUA, Helgee B. Macromol. Ch em. Phvs. 2006, 207: 536-54) and subsequent deprotection. However, it was only possible to obtain mixtures between mono- and di-substituted hydroxylated compounds and the overall yield of the reaction was very low DESCRIPTION OF THE INVENTION
La presente invención proporciona un procedimiento para sintentizar VP que contiene grupos funcionales, como carboxílico, hidroxi, mercapto, amino o sulfo, en su cadena lateral. Este procedimiento da lugar a grupos funcionales en una reacción de un solo paso por apertura de anillos de compuestos cíclicos apropiados. Estos compuestos funcionalizados pueden, en una segunda etapa, reaccionar bajo condiciones suaves con un compuesto activo para obtener conjugados de diferente naturaleza.The present invention provides a method for synthesizing VP containing functional groups, such as carboxylic, hydroxy, mercapto, amino or sulfo, in its side chain. This procedure gives rise to functional groups in a one-step reaction by opening rings of appropriate cyclic compounds. These functionalized compounds can, in a second stage, react under mild conditions with an active compound to obtain conjugates of different nature.
Más concretamente, el procedimiento de Ia presente invención permite funcionalizar en posición 3 Ia VP directamente en un solo paso con grupos tales como tiol, amino, hidroxi, mercapto, carboxilo o sulfo, por reacción del anión de Ia carboxamida de Ia VP con diferentes precursores cíclicos de estas funcionalidades. En función de Ia naturaleza del electrófilo se puede elegir Ia naturaleza y Ia longitud del espaciador entre el grupo VP y el grupo funcional reactivo.More specifically, the process of the present invention allows the VP to be functionalized in position 3 directly in a single step with groups such as thiol, amino, hydroxy, mercapto, carboxyl or sulfo, by reaction of the anion of the carboxamide of the VP with different precursors cyclic of these functionalities. Depending on the nature of the electrophile, the nature and length of the spacer can be chosen between the VP group and the reactive functional group.
Por todo ello, un primer aspecto de Ia presente invención se refiere a VP funcionalizadas de fórmula general (I) o cualquiera de sus sales (a partir de ahora compuestos de Ia invención):Therefore, a first aspect of the present invention refers to functionalized VP of general formula (I) or any of its salts (from now on compounds of the invention):
(i) donde: A es un grupo CR1R2, un grupo carbonilo (CO) o un grupo sulfona(i) where: A is a CR 1 R 2 group, a carbonyl group (CO) or a sulfone group
(-SO2-); donde(-SO 2 -); where
R1 y R2 son iguales o diferentes y representan a un hidrógeno (H) o un grupo metilo (CH3);
X es un radical seleccionado del grupo que comprende un hidroxilo (OH), un tiol (SH), un sulfonilo (SO3H), una amina (NR3R4, NHR3 o NH2) o un carboxilo (CO2H);R 1 and R 2 are the same or different and represent a hydrogen (H) or a methyl group (CH 3 ); X is a radical selected from the group comprising a hydroxyl (OH), a thiol (SH), a sulfonyl (SO 3 H), an amine (NR 3 R 4 , NHR 3 or NH 2 ) or a carboxyl (CO 2 H );
R, R3 y R4 son un resto no funcional en Ia reacción, son iguales o diferentes y representan a un grupo arilo (C6-Ci8) o un grupo alquilo
R, R 3 and R 4 are a non-functional moiety in the reaction, are the same or different and represent an aryl group (C 6 -Ci 8 ) or an alkyl group
El grupo "alquilo" se refiere, en Ia presente invención, a cadenas alifáticas, lineales o ramificadas, que tiene de 1 a 10 átomos de carbonos, por ejemplo, este grupo puede ser metilo, etilo, n-propilo, /-propilo, n-butilo, tere-butilo, sec-butilo, n-pentilo, etc. Preferiblemente el grupo alquilo tiene 1 , 2, 3, 4, 5 ó 6 átomos de carbono.The "alkyl" group refers, in the present invention, to aliphatic, linear or branched chains, having 1 to 10 carbon atoms, for example, this group can be methyl, ethyl, n-propyl, / -propyl, n-butyl, tere-butyl, sec-butyl, n-pentyl, etc. Preferably the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms.
El término "arilo" se refiere en Ia presente invención a una cadena carbocíclica aromática, que tiene de 6 a 18 átomos de carbono, pudiendo ser de anillo único ó múltiple, en este último caso con anillos separados y/o condensados. Un ejemplo, no limitante, de arilo es un grupo fenilo, naftilo, indenilo, etc.. Preferiblemente el grupo arilo es un fenilo. Y en el caso deThe term "aryl" refers in the present invention to an aromatic carbocyclic chain, having from 6 to 18 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings. A non-limiting example of aryl is a phenyl, naphthyl, indenyl, etc. group. Preferably the aryl group is a phenyl. And in the case of
R, en Ia fórmula anterior (I), el anillo aromático preferiblemente estaría en posición orto.R, in the above formula (I), the aromatic ring would preferably be in ortho position.
En una realización preferida, X es un grupo hidroxilo, por Io que el compuesto se selecciona de entre los de fórmula 3-(hidroxialquil)-1 -vinil-2- pirrolidona cuando A es un grupo CR1R2, o 3-(1-oxo-ω-hidroxialquil)-1-vinil- 2-pirrolidona, cuando A un grupo carbonilo (CO). Los compuestos son, por ejemplo, pero sin limitarse, 3-(2-hidroxietil)-1-vinil-2-pirrolidona, 3-(1-oxo-5- hidroxipentil)-1 -vinil-2-pirrolidona ó 3-(1 -oxo-6-hidroxihexil)-1 -vinil-2- pirrolidona.In a preferred embodiment, X is a hydroxyl group, whereby the compound is selected from those of formula 3- (hydroxyalkyl) -1-vinyl-2-pyrrolidone when A is a CR 1 R 2 group , or 3- ( 1-oxo-ω-hydroxyalkyl) -1-vinyl-2-pyrrolidone, when A a carbonyl group (CO). The compounds are, for example, but not limited to, 3- (2-hydroxyethyl) -1-vinyl-2-pyrrolidone, 3- (1-oxo-5- hydroxypentyl) -1-vinyl-2-pyrrolidone or 3- ( 1 -oxo-6-hydroxyhexyl) -1-vinyl-2-pyrrolidone.
En una realización preferida, X es un grupo tiol, dando lugar a compuestos como por ejemplo, pero sin limitarse, de fórmula 3-(2-mercaptoetil)-1-vinil-
2-pirrolidona.In a preferred embodiment, X is a thiol group, giving rise to compounds such as, but not limited to, formula 3- (2-mercaptoethyl) -1-vinyl- 2-pyrrolidone.
Otra realización preferida es aquella en que X es un grupo sulfonilo, dando lugar a compuestos como por ejemplo, pero sin limitarse, de fórmula 3-(3- sulfopropil)-1 -vinil-2-pirrolidona.Another preferred embodiment is that in which X is a sulfonyl group, giving rise to compounds such as, but not limited to, formula 3- (3- sulfopropyl) -1-vinyl-2-pyrrolidone.
En otra realización preferida, A es un grupo carbonilo y X una amina aromática (NHR3 ó NH2) dando lugar a compuestos de fórmula 3-(1-oxo-ω- aminoaril)-1 -vinil-2-pirrolidona, 3-(1 -oxo-ω-alquilaminoaril)-1 -vinil-2- pirrolidona o 3-(1-oxo-ω-arilaminoaril)-1-vinil-2-pirrolidona, donde el número ω dependerá del grupo aril. Los grupos aril y alquil se refieren respectivamente a los términos "arilo" y "alquilo" descritos anteriormente. Los compuestos son, por ejemplo, pero sin limitarse, los compuestos 3-(2- aminobenzoil)-1 -vinil-2-pirrolidona ó 3-(N-metil-2-aminobenzoil)-1 -vinil-2- pirrolidona.In another preferred embodiment, A is a carbonyl group and X an aromatic amine (NHR 3 or NH2) giving rise to compounds of formula 3- (1-oxo-ω-aminoaryl) -1-vinyl-2-pyrrolidone, 3- ( 1-oxo-ω-alkylaminoaryl) -1-vinyl-2-pyrrolidone or 3- (1-oxo-ω-arylaminoaryl) -1-vinyl-2-pyrrolidone, where the number ω will depend on the aryl group. The aryl and alkyl groups refer respectively to the terms "aryl" and "alkyl" described above. The compounds are, for example, but not limited to, the compounds 3- (2- aminobenzoyl) -1-vinyl-2-pyrrolidone or 3- (N-methyl-2-aminobenzoyl) -1-vinyl-2-pyrrolidone.
En otra realización preferida, A es un grupo carbonilo y X una amina no aromática (NHR3 ó NH2), dando lugar a compuestos de fórmula 3-(1-oxo- ω-aminoalquil)-1 -vinil-2-pirrolidona o 3-(1 -oxo-ω-alquilaminoalquil)-1 -vinil-2- pirrolidona, donde el número ω dependerá del grupo alquil y el grupo alquil se refiere al término descrito anteriormente. Los compuestos son, por ejemplo, pero sin limitarse, 3-(1-oxo-2-aminopropil)-1-vinil-2-pirrolidona.In another preferred embodiment, A is a carbonyl group and X is a non-aromatic amine (NHR 3 or NH 2 ), giving rise to compounds of formula 3- (1-oxo- ω-aminoalkyl) -1-vinyl-2-pyrrolidone or 3- (1-Oxo-ω-alkylaminoalkyl) -1-vinyl-2-pyrrolidone, where the number ω will depend on the alkyl group and the alkyl group refers to the term described above. The compounds are, for example, but not limited to 3- (1-oxo-2-aminopropyl) -1-vinyl-2-pyrrolidone.
En otra realización preferida, A es un grupo CR1R2 y X una amina (NR3R4 ó NHR3 ó NH2), dando lugar a compuestos de fórmula 3-(ω-aminoalquil)-1- vinil-2-pirrolidona, 3-(ω-alquilaminoalquil)-1 -vinil-2-pirrolidona, 3-(ω- arilaminoalquil)-1 -vinil-2-pirrolidona, 3-(ω-dialquilaminoalquil)-1 -vinil-2- pirrolidona, 3-(ω-diarilaminoalquil)-1-vinil-2-pirrolidona, 3-(ω- alquilarilaminoalquil)-1-vinil-2-pirrolidona, donde el número ω dependerá del grupo alquil R. Los grupos aril y alquil se refieren respectivamente a los
términos "arilo" y "alquilo" descritos anteriormente. Como por ejemplo, pero sin limitarse, los compuestos son 3-(-2-aminoetil)-1-vinil-2-pirrolidona o 3- (2-Dimetilaminoetil)-1-vinil-2-pirrolidona.In another preferred embodiment, A is a CR 1 R 2 group and X is an amine (NR 3 R 4 or NHR 3 or NH 2 ), giving rise to compounds of formula 3- (ω-aminoalkyl) -1-vinyl-2- pyrrolidone, 3- (ω-alkylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- (ω- arylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- (ω-dialkylaminoalkyl) -1 -vinyl-2-pyrrolidone, 3- (ω-diarylaminoalkyl) -1-vinyl-2-pyrrolidone, 3- (ω- alkylaminoalkyl) -1-vinyl-2-pyrrolidone, where the number ω will depend on the alkyl group R. The aryl and alkyl groups refer respectively to the terms "aryl" and "alkyl" described above. As for example, but not limited to, the compounds are 3 - (- 2-aminoethyl) -1-vinyl-2-pyrrolidone or 3- (2-Dimethylaminoethyl) -1-vinyl-2-pyrrolidone.
En otra realización preferida, A es un grupo carbonilo y X un carboxilo (CO2H), dando lugar a compuestos de fórmula 3-(1-oxo-ω-carboxialquil)-1- vinil-2-pirrolidona, donde el número ω dependerá del grupo alquil y el grupo alquil se refiere al término descrito anteriormente. Como por ejemplo, pero sin limitarse, el compuesto es 3-(1-oxo-2-carboxietil)-1-vinil- 2-pirrolidona.In another preferred embodiment, A is a carbonyl group and X is a carboxyl (CO 2 H), giving rise to compounds of formula 3- (1-oxo-ω-carboxyalkyl) -1-vinyl-2-pyrrolidone, where the number ω It will depend on the alkyl group and the alkyl group refers to the term described above. As for example, but not limited, the compound is 3- (1-oxo-2-carboxyethyl) -1-vinyl-2-pyrrolidone.
Otra realización preferida es aquella en que A es un grupo sulfona (-Another preferred embodiment is that in which A is a sulfone group (-
SO2-) y X es un grupo amino (NH2 o NHR3), dando lugar a compuestos de fórmula 3-(ω-aminoalquilsulfonil)-1-vinil-2-pirrolidona o 3-(ω- alquilaminosulfonil)-1-vinil-2-pirrolidona o 3-(ω-arilaminosulfonil)-1-vinil-2- pirrolidona. Como por ejemplo, pero sin limitarse, el compuesto es 3-(2- aminoetilsulfonil)-1-vinil-2-pirrolidona.SO 2 -) and X is an amino group (NH 2 or NHR 3 ), giving rise to compounds of formula 3- (ω-aminoalkylsulfonyl) -1-vinyl-2-pyrrolidone or 3- (ω-alkylaminosulfonyl) -1- vinyl-2-pyrrolidone or 3- (ω-arylaminosulfonyl) -1-vinyl-2-pyrrolidone. As for example, but not limited, the compound is 3- (2- aminoethylsulfonyl) -1-vinyl-2-pyrrolidone.
Un segundo aspecto de Ia presente invención se refiere al procedimiento para Ia obtención de los compuestos de fórmula general (I) que comprende los siguientes pasos: a. deprotonación en Ia posición 3 de 1 -vinil-2-pirrolidona (VP) mediante Ia adición de una base; b. Ia reacción de un anillo precursor de fórmula (II) con 1 -vinil-2- pirrolidona obtenida en el paso (a).A second aspect of the present invention refers to the process for obtaining the compounds of general formula (I) comprising the following steps: a. deprotonation in position 3 of 1-vinyl-2-pyrrolidone (VP) by the addition of a base; b. The reaction of a precursor ring of formula (II) with 1-vinyl-2-pyrrolidone obtained in step (a).
El esquema 1 representa Ia síntesis de los compuestos de fórmula (I) descrita según el procedimiento de Ia invención:
Scheme 1 represents the synthesis of the compounds of formula (I) described according to the process of the invention:
(H) (i) donde: A, X y R están descritos anteriormente y X' es un grupo precursor del grupo X.(H) (i) where: A, X and R are described above and X 'is a precursor group of group X.
A es el grupo susceptible de ataque y R indica el tipo y longitud del espaciador. X' es un precursor del grupo reactivo (X), normalmente un grupo X que ha sido desprotonado o carboxilado y que se selecciona de entre un grupo N-carboxianhídrido, éter, tioéter, amina cíclica, éster, amida o anhídrido.A is the group susceptible to attack and R indicates the type and length of the spacer. X 'is a precursor of the reactive group (X), usually an X group that has been deprotonated or carboxylated and is selected from an N-carboxyanhydride, ether, thioether, cyclic amine, ester, amide or anhydride group.
El compuesto de fórmula (2) se puede seleccionar de Ia lista que comprende un compuesto cíclico que contiene como parte del ciclo un grupo, como por ejemplo, pero sin limitarse, N-carboxianhídrido, éter, tioéter, amina, amida, éster, sultona, sultama o anhídrido. Ejemplos no limitantes de estos grupos X'-A, que forman los compuestos anteriores, pueden ser: CH2-O, CH2-S (para anillos pequeños de 3 o 4 eslabones), OCO (lactona), OSO2 (sultona), OCN (lactama), SO2N (sultama) para anillos de 4, 5, 6 o 7 eslabones.The compound of formula (2) can be selected from the list comprising a cyclic compound that contains as part of the cycle a group, such as, but not limited to, N-carboxyanhydride, ether, thioether, amine, amide, ester, sultone , sultama or anhydride. Non-limiting examples of these X'-A groups, which form the above compounds, may be: CH 2 -O, CH 2 -S (for small rings of 3 or 4 links), OCO (lactone), OSO 2 (sultone) , OCN (lactam), SO 2 N (sultama) for rings of 4, 5, 6 or 7 links.
En algunas ocasiones, Ia adicción a Ia reacción de un exceso del compuesto cíclico puede dar lugar a un proceso de oligomerización obteniéndose macromonómeros. Como por ejemplo, si el ciclo es una lactona y se añade en exceso, se podría obtener VP-oligo(lactona).In some occasions, the addiction to the reaction of an excess of the cyclic compound can give rise to an oligomerization process obtaining macromonomers. As for example, if the cycle is a lactone and is added in excess, VP-oligo (lactone) could be obtained.
Una realización preferida del procedimiento de Ia invención comprende llevar Ia reacción a una temperatura de entre -10O0C y 5O0C, más preferiblemente a una temperatura de entre -850C y -20 0C.
El primer paso de Ia ruta sintética del procedimiento de Ia invención consiste en Ia formación de Ia 1 -vinil-2-pirrolidona activada, como por ejemplo un enolato de Ia carboxamida por Ia acción de una base.A preferred embodiment of the process of the invention comprises bringing the reaction to a temperature between -10O 0 C and 5O 0 C, more preferably at a temperature between -85 0 C and -20 0 C. The first step of the synthetic route of the process of the invention consists in the formation of activated 1-vinyl-2-pyrrolidone, such as an enolate of carboxamide by the action of a base.
Como base se refieren, en Ia presente invención, aquellas bases Io suficientemente básicas como para desprotonar el grupo carboxamido en posición 3, como por ejemplo, pero sin limitarse, n-butil litio, sec-butil litio, bis(trimetilsilil)amiduro de litio (LHMDS). Más preferiblemente diisopropilamiduro de litio (LDA).Reference is made in the present invention to those bases which are basic enough to deprotonate the carboxamide group in position 3, for example, but not limited to, n-butyl lithium, sec-butyl lithium, bis (trimethylsilyl) lithium amide. (LHMDS). More preferably lithium diisopropylamide (LDA).
En un segundo paso, Ia funcionalización de VP se consigue mediante ataque nucleofílico del enolato y Ia correspondiente apertura de anillo a ciclos susceptibles de este ataque como se muestra en el esquema 1. En el caso de heterociclos de 3 y 4 eslabones como óxido de etileno, sulfuro de etileno, u otros, Ia fuerza conductora principal de Ia reacción es Ia alta tensión anular, mientras que en el caso de ciclos más grandes como lactonas o sultonas de 5 o 6 eslabones -entre otros- Ia susceptibilidad electrofílica asociada al grupo funcional es Ia responsable principal del ataque y de Ia apertura.In a second step, the functionalization of VP is achieved by nucleophilic attack of the enolate and the corresponding ring opening to cycles susceptible to this attack as shown in scheme 1. In the case of 3 and 4 link heterocycles such as ethylene oxide , ethylene sulfide, or others, the main driving force of the reaction is the high annular tension, while in the case of larger cycles such as lactones or sultones of 5 or 6 links - among others - the electrophilic susceptibility associated with the functional group It is the main responsible for the attack and the opening.
Por todo ello, son de gran utilidad aquellos grupos susceptibles hacia un ataque nucleófilo por parte del anión de Ia carboxamida de Ia VP a muy bajas temperaturas. El rango de temperaturas óptimo se sitúa entre 850C y -2O0C, Más preferiblemente a una temperatura de aproximadamente -780C. Por ejemplo, pero sin limitarse, óxido de etileno, sulfuro de etileno o 1 ,3-propanosultona, en los casos que resultan productos donde Ia vinilpirrolidona contiene o una unidad de 2- hidroxietileno o de 2-mercaptoetileno respectivamente. También en el caso de Ia modificación con propanosultona se obtiene una vinilpirrolidona con un solo grupo 3-sulfopropilo. Como resultado se obtienen unidades monoméricas con grupos funcionales que tienen un espaciador corto de
dos o tres grupos metilénicos entre el grupo funcional y Ia VP.Therefore, those groups susceptible to a nucleophilic attack by the anion of the carboxamide of the VP at very low temperatures are very useful. The optimal temperature range lies between 85 0 C and -2O 0 C, more preferably at a temperature of about -78 0 C. For example, without limitation, ethylene oxide, ethylene sulfide or 1, 3-propane sultone, in the cases that result products where vinylpyrrolidone contains or a unit of 2-hydroxyethylene or 2-mercaptoethylene respectively. Also in the case of the modification with propanosultone a vinyl pyrrolidone with a single 3-sulfopropyl group is obtained. As a result, monomer units with functional groups are obtained that have a short spacer of two or three methylene groups between the functional group and the VP.
Esta reacción se puede llevar también a cabo con lactonas cíclicas como ejemplos de ciclos más grandes en los que Ia tensión anular ya no es Ia fuerza conductora de Ia reacción. En este caso, se obtienen espaciadores más largos y los rendimientos generales de las reacciones están entre el 30 y 60%.This reaction can also be carried out with cyclic lactones as examples of larger cycles in which the annular tension is no longer the driving force of the reaction. In this case, longer spacers are obtained and the overall yields of the reactions are between 30 and 60%.
Por todo Io anterior, el anillo precursor de fórmula (II) puede ser de tipo lactama, lactonas de diferente tamaño, éteres o tioéteres cíclicos de 3 o 4 átomos de carbono, aminas cíclicas de 3 o 4 átomos de carbono, alquilsultonas cíclicas, alquilsulfonamidas cíclicas o sales de amonio cíclicas.Throughout the foregoing, the precursor ring of formula (II) may be of the lactam type, lactones of different sizes, cyclic ethers or thioethers of 3 or 4 carbon atoms, cyclic amines of 3 or 4 carbon atoms, cyclic alkylultones, alkyl sulfonamides cyclic or cyclic ammonium salts.
Por otro lado, se pueden utilizar anillos precursores donde R es diferente de una cadena alquílica lineal, como por ejemplo pero sin limitarse óxido de propileno [para dar 3-(2-hidroxipropil)-1-vinil-2-pirrolidona), o un anillo aromático en orto.On the other hand, precursor rings where R is different from a linear alkyl chain can be used, such as but not limited to propylene oxide [to give 3- (2-hydroxypropyl) -1-vinyl-2-pyrrolidone), or a aromatic ring in ortho.
Los monómeros correspondientes a los compuestos de fórmula general (I), como por ejemplo, pero sin limitarse VP funcionalizados con grupos amina, carboxilo, sulfo, hidroxi, o mercapto, pueden ser homopolimerizados o copolimerizados con 1 -vinil-2-pirrolidona para formar polímeros o copolímeros cuya cadena principal consiste exclusivamente en unidades de vinilpirrolidona, es decir, para formar poli-vinilpirrolidona funcionalizada. Además, estos grupos funcionales pueden ser empleados antes o después de Ia homo- o copolimerización para anclar covalentemente compuestos activos como fármacos o nutracéuticos.The monomers corresponding to the compounds of general formula (I), for example, but not limited to VP functionalized with amine, carboxyl, sulfo, hydroxy, or mercapto groups, can be homopolymerized or copolymerized with 1-vinyl-2-pyrrolidone to form polymers or copolymers whose main chain consists exclusively of vinyl pyrrolidone units, that is, to form functionalized polypyrrolidone. In addition, these functional groups can be used before or after homo- or copolymerization to covalently anchor active compounds such as drugs or nutraceuticals.
Además, estos derivados de VP se pueden copolimerizar con otros comonómeros vinílicos diferentes de Ia propia VP.
Por tanto, un tercer aspecto de Ia presente invención se refiere al uso de los compuestos de fórmula general (I) para Ia obtención de polímeros o copolímeros.In addition, these VP derivatives can be copolymerized with other vinyl comonomers other than the VP itself. Therefore, a third aspect of the present invention refers to the use of the compounds of general formula (I) for obtaining polymers or copolymers.
Otro aspecto de Ia presente invención se refiere a polímeros o copolímeros que comprenden un compuesto de fórmula general (I) como monómero.Another aspect of the present invention relates to polymers or copolymers comprising a compound of general formula (I) as a monomer.
Por otro lado, los compuestos de fórmula general (I), cuando X es un grupo tiol, pueden ser una herramienta muy útil en polimerización pues es difuncional, puesto que SH es un agente de transferencia muy reactivo y, por tanto, puede ser usado para obtener macromonómeros, injertos o entrecruzamientos.On the other hand, the compounds of general formula (I), when X is a thiol group, can be a very useful tool in polymerization because it is difunctional, since SH is a very reactive transfer agent and, therefore, can be used to obtain macromonomers, grafts or crosslinks.
A Io largo de Ia descripción y las reivindicaciones Ia palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en Ia materia, otros objetos, ventajas y características de Ia invención se desprenderán en parte de Ia descripción y en parte de Ia práctica de Ia invención. Los siguientes ejemplos y figuras se proporcionan a modo de ilustración, y no se pretende que sean limitativos de Ia presente invención.Throughout the description and the claims, the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
BREVE DESCRIPCIÓN DE LA FIGURABRIEF DESCRIPTION OF THE FIGURE
Fig. 1.- Representa un espectro de 1H RMN del copolímero 1 :1 de VP y VP-(CH2)S-SO3Li (D2O, 300 MHz).Fig. 1.- Represents a 1 H NMR spectrum of the 1: 1 copolymer of VP and VP- (CH 2 ) S -SO 3 Li (D 2 O, 300 MHz).
EJEMPLOS DE PREPARACIÓN DE LA INVENCIÓNEXAMPLES OF PREPARATION OF THE INVENTION
A continuación se ilustrará Ia invención mediante unos ensayos realizados por los inventores, que pone de manifiesto Ia efectividad del procedimiento de Ia invención para Ia obtención de los compuestos de fórmula general (I).
EJEMPLO 1.- Preparación de compuestos de fórmula general (I)Next, the invention will be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the process of the invention for obtaining the compounds of the general formula (I). EXAMPLE 1.- Preparation of compounds of general formula (I)
Preparación del compuesto (3-(2-hidroxietil)-1-vinil-2-pirrolidona (1)Preparation of the compound (3- (2-hydroxyethyl) -1-vinyl-2-pyrrolidone (1)
Sobre una disolución de diisopropilamida de litio (2.0 M, en THF, hexano y etilbenceno, 84.2 ml_, 1.8 equivalentes) en 280 ml_ de THF anhidro, se adicionó lentamente (gota a gota) una disolución de VP recién destilada (10.0 ml_, 94 mmol, 1.08 equivalentes) en THF anhidro (30 ml_) a una temperatura de -780C y bajo una atmósfera inerte.On a solution of lithium diisopropylamide (2.0 M, in THF, hexane and ethylbenzene, 84.2 ml_, 1.8 equivalents) in 280 ml_ of anhydrous THF, a solution of freshly distilled VP (10.0 ml_, 94 was slowly added dropwise) mmol, 1.08 equiv) in anhydrous THF (30 ml_) at -78 0 C and under an inert atmosphere.
Completada Ia adición, Ia masa de reacción se mantuvo a esa temperatura durante 30 minutos. Al cabo de este tiempo, 4.3 ml_ (80.7 mmol, 1.0 equivalentes) de una disolución de óxido de etileno se adicionó lentamente sobre Ia disolución anterior.Upon completion of the addition, the reaction mass was maintained at that temperature for 30 minutes. After this time, 4.3 ml_ (80.7 mmol, 1.0 equivalents) of an ethylene oxide solution was added slowly over the previous solution.
La disolución resultante se mantuvo agitándose durante 1h a una temperatura de -780C, después se aumenta Ia temperatura hasta situarla a -3O0C durante 2h. Transcurrido este tiempo, Ia masa de reacción se hidrolizó con CH2CI2:H2O (2:1 ; 300 ml_). La fracción acuosa se extrajo con CH2CI2 (2x200 mL) y el combinado de las fases orgánicas se secaron con sulfato sódico anhidro (Na2SO4) y tras eliminar el sólido inorgánico por filtración, el disolvente se eliminó a presión reducida.The resulting solution was stirred for 1 h at kept at -78 0 C, then the temperature is increased until it reached to -3 ° droop 0 C for 2h. After this time, the reaction mass was hydrolyzed with CH 2 CI 2 : H 2 O (2: 1; 300 ml_). The aqueous fraction was extracted with CH 2 CI 2 ( 2 x 200 mL) and the combined organic phases were dried with anhydrous sodium sulfate (Na 2 SO 4 ) and after removing the inorganic solid by filtration, the solvent was removed under reduced pressure.
El residuo seco se purificó por cromatografía en gel de sílice, usando CH2CI2THF (10:1 ) como eluyente. Rendimiento: 45%.
1H RMN (CDCI3, 300 MHz) δ: 7.01 (dd, 1 H, N-CH=, J=16.0 y 9.0 Hz), 4.45 (d, 1 H, cis N-CH=CHH J=9.0 Hz), 4.40 (d, 1 H, trans N-CH=CHH, J=16.0 Hz), 3.92 (br, 1 H, OH), 3.78-3.74 y 3.71-3.66 (ambos m, 1 H cada m, CH2- OH), 3.54-3.49 y 3.41-3.36 (ambos m, 1 H cada m, N-CH2), 2.72-2.65 (m, 1 H, CH-CO), 2.36-2.22 (m, 1 H, CHH-CH2-OH), 1.99-1.92 (m, 1 H, N-CH2- CHH), 1.82-1.74 (m, 1 H, CHH-CH2-OH), 1.71-1.65 (m, 1 H, N-CH2-CHH). 13C RMN (CDCI3, 75.4 MHz) δ: 176.13 (CO), 129.45 (N-CH=), 95.42 (N- CH=CH2), 61.48 (CH2-OH), 43.50 (CH2-N), 41.83 (CH-CO), 34.39 (CH2- CH2-OH), 25.38 (CH2-CH-CO).The dried residue was purified by silica gel chromatography, using CH 2 CI 2 THF (10: 1) as eluent. Yield: 45%. 1 H NMR (CDCI 3 , 300 MHz) δ: 7.01 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 4.45 (d, 1 H, cis N-CH = CHH J = 9.0 Hz) , 4.40 (d, 1 H, trans N-CH = CHH, J = 16.0 Hz), 3.92 (br, 1 H, OH), 3.78-3.74 and 3.71-3.66 (both m, 1 H every m, CH 2 - OH), 3.54-3.49 and 3.41-3.36 (both m, 1 H every m, N-CH 2 ), 2.72-2.65 (m, 1 H, CH-CO), 2.36-2.22 (m, 1 H, CHH- CH 2 -OH), 1.99-1.92 (m, 1 H, N-CH 2 - CHH), 1.82-1.74 (m, 1 H, CHH-CH 2 -OH), 1.71-1.65 (m, 1 H, N -CH 2 -CHH). 13 C NMR (CDCI 3 , 75.4 MHz) δ: 176.13 (CO), 129.45 (N-CH =), 95.42 (N- CH = CH 2 ), 61.48 (CH 2 -OH), 43.50 (CH 2 -N) , 41.83 (CH-CO), 34.39 (CH 2 - CH 2 -OH), 25.38 (CH 2 -CH-CO).
Preparación del compuesto 3-(2-mercaptoetil)-1-vinil-2-pirrolidona(2)Preparation of compound 3- (2-mercaptoethyl) -1-vinyl-2-pyrrolidone (2)
Este producto se preparó con un 35% de rendimiento, a partir de VP (5.0 ml_, 47 mmol, 1.08 equiv) y sulfuro de etileno (2.8 g, 47 mmol, 1.0 equiv) siguiendo Ia metodología descrita para el compuesto (1).This product was prepared with a 35% yield, from VP (5.0 ml_, 47 mmol, 1.08 equiv) and ethylene sulfide (2.8 g, 47 mmol, 1.0 equiv) following the methodology described for the compound (1).
1H RMN (CDCI3, 300 MHz) δ: 7.02 (dd, 1 H, N-CH=, J=16.0 and 9.0 Hz), 4.44 (d, 1 H, cis N-CH=CHH J= 9.0 Hz), 4.40 (d, 1 H, trans N-CH=CHH, 1 H NMR (CDCI 3 , 300 MHz) δ: 7.02 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 4.44 (d, 1 H, cis N-CH = CHH J = 9.0 Hz) , 4.40 (d, 1 H, trans N-CH = CHH,
J=16.0 Hz), 3.53-3.48 (m, 1 H, CHH-N), 3.42-3.35 (m, 1 H, CHH-N), 2.76-J = 16.0 Hz), 3.53-3.48 (m, 1 H, CHH-N), 3.42-3.35 (m, 1 H, CHH-N), 2.76-
2.62 (m, 3H, CH2-SH, CH-CO), 2.36-2.27 (m, 1 H, CHH-CH2-N), 2.18-2.102.62 (m, 3H, CH 2 -SH, CH-CO), 2.36-2.27 (m, 1 H, CHH-CH 2 -N), 2.18-2.10
(m, 1 H, CHH-CH2-SH), 1.78-1.62 (m, 2H, CHH-CH2-N, CHH-CH2-SH ),(m, 1 H, CHH-CH 2 -SH), 1.78-1.62 (m, 2H, CHH-CH 2 -N, CHH-CH 2 -SH),
1.37 (t, 1 H, SH, J=7.8 Hz). 13C RMN (CDCI3, 75.4 MHz) δ: 174.64 (CO), 129.08 (N-CH=), 96.10 (N-1.37 (t, 1 H, SH, J = 7.8 Hz). 1 3 C NMR (CDCI 3 , 75.4 MHz) δ: 174.64 (CO), 129.08 (N-CH =), 96.10 (N-
CH=CH2), 43.17 (CH2-N), 41.42 (CH-CO), 34.50 (CH2-CH2-SH), 26.15CH = CH 2 ), 43.17 (CH 2 -N), 41.42 (CH-CO), 34.50 (CH 2 -CH 2 -SH), 26.15
(CH2-CH2-N), 21.55 (CH2-SH).
Preparación del compuesto 3-(1-oxo-6-hidroxihexil)-1-vinil-2- pirrolidona (3)(CH 2 -CH 2 -N), 21.55 (CH 2 -SH). Preparation of compound 3- (1-oxo-6-hydroxyhexyl) -1-vinyl-2-pyrrolidone (3)
Sobre una disolución de diisopropilamiduro de litio (2.0 M, en THF, hexano y etilbenceno, 84.2 ml_, 1.8 equivalentes) en 280 ml_ de THF anhidro, se adiciona lentamente (gota a gota) una disolución de VP recién destilada (10.0 ml_, 94 mmol, 1.08 equivalentes) en THF anhidro (30 ml_) a una temperatura de -780C y bajo una atmósfera inerte.On a solution of lithium diisopropylamide (2.0 M, in THF, hexane and ethylbenzene, 84.2 ml_, 1.8 equivalents) in 280 ml_ of anhydrous THF, a solution of freshly distilled VP (10.0 ml_, 94 is slowly added dropwise) mmol, 1.08 equiv) in anhydrous THF (30 ml_) at -78 0 C and under an inert atmosphere.
Finalizada Ia adición, Ia disolución se mantuvo a esta temperatura durante 2h, tras ese periodo 9.9 ml_ de ε-caprolactona (87.3 mmol, 1.0 equiv) se adicionaron lentamente. La disolución resultante se agitó a -78 0C durante una hora y posteriormente se permitió recuperar, lentamente, temperatura ambiente. A esta temperatura, los alcoholatos metálicos precipitaron y fue necesario introducir el matraz en un baño de ultrasonidos. Al final de Ia reacción, monitorizada con TLC, Ia disolución se hidrolizó con CH2CI2-H2O (2:1 , 300 mL). La fase acuosa se extrajo con CH2CI2 (2x100 mL) y el combinado de fases orgánicas se secaron sobre sulfato sódico anhidro (Na2SO4) y se evaporó a presión reducida. Finalmente el producto se obtuvo tras una purificación sobre gel de sílice, usando CH2CI2:THF (10:1 ) como eluyente. Rendimiento: 55%.After the addition, the solution was maintained at this temperature for 2 hours, after that period 9.9 ml_ of ε-caprolactone (87.3 mmol, 1.0 equiv) was added slowly. The resulting solution was stirred at -78 0 C for one hour and then allowed to slowly recover room temperature. At this temperature, the metal alcoholates precipitated and it was necessary to introduce the flask into an ultrasonic bath. At the end of the reaction, monitored with TLC, the solution was hydrolyzed with CH 2 CI 2 -H 2 O (2: 1, 300 mL). The aqueous phase was extracted with CH2CI2 (2x100 mL) and the combined organic phases were dried over anhydrous sodium sulfate (Na 2 SO 4 ) and evaporated under reduced pressure. Finally the product was obtained after purification on silica gel, using CH 2 CI 2 : THF (10: 1) as eluent. Yield: 55%.
1H RMN (CDCI3, 300 MHz) δ: 7.02 (dd, 1 H, N-CH=, J=16.0 y 9.0 Hz), 4.52 (d, 1 H, cis N-CH=CHH J=9.0 Hz), 4.48 (d, 1 H, trans N-CH=CHH, J=16.0 Hz), 3.67-3.48 (m, 4H, CH2-N-, CH2-OH), 3.10-2.98 (m, 1 H, CH-CO), 2.68- 2.52 (m, 2H, OC-CH2), 2.19-2.05 (m, 1 H, CHH-CH2-N), 1.72-1.48 (m, 5H,
CH2-CH2-CH2-CH2-OH, CHH-CH2-N), 1.45-1.31 (m, 2H, CH2-CH2-CH2- OH). 1 H NMR (CDCI 3 , 300 MHz) δ: 7.02 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 4.52 (d, 1 H, cis N-CH = CHH J = 9.0 Hz) , 4.48 (d, 1 H, trans N-CH = CHH, J = 16.0 Hz), 3.67-3.48 (m, 4H, CH 2 -N-, CH 2 -OH), 3.10-2.98 (m, 1 H, CH-CO), 2.68-252 (m, 2H, OC-CH 2 ), 2.19-2.05 (m, 1 H, CHH-CH 2 -N), 1.72-1.48 (m, 5H, CH 2 -CH 2 -CH 2 -CH 2 -OH, CHH-CH 2 -N), 1.45-1.31 (m, 2H, CH 2 -CH 2 -CH 2 -OH).
13C RMN (CDCI3, 75.4 MHz) δ: 206.19 (OC-CH2), 173.99 (OC-N), 125.90 (N-CH=), 96.27 (N-CH=CH2), 63.24 (CH2-OH), 54.30 (OC-CH-CO), 42.97 (CH2-N), 41.97 (OC-CH2), 32.77 (CH2-CH2-OH), 25.49 (CH2-CH2-CH2-OH), 24.30 (CO-CH2-CH2), 23.21 (CH2-CH2-N). 13 C NMR (CDCI 3 , 75.4 MHz) δ: 206.19 (OC-CH 2 ), 173.99 (OC-N), 125.90 (N-CH =), 96.27 (N-CH = CH 2 ), 63.24 (CH 2 - OH), 54.30 (OC-CH-CO), 42.97 (CH 2 -N), 41.97 (OC-CH 2 ), 32.77 (CH 2 -CH 2 -OH), 25.49 (CH 2 -CH 2 -CH 2 - OH), 24.30 (CO-CH 2 -CH 2 ), 23.21 (CH 2 -CH 2 -N).
Preparación del compuesto 3-(1-oxo-5-hidroxipentil)-1-vinil-2- pirrolidona (4)Preparation of compound 3- (1-oxo-5-hydroxypentyl) -1-vinyl-2-pyrrolidone (4)
Este producto se obtuvo con un 28% de rendimiento, a partir de VP (5.0 ml_, 47 mmol, 1.08 equiv) y δ-valerolactona (4.0 ml_, 43.5 mmol, 1.0 equiv) como productos de partida. La vía que se empleó fue Ia descrita para el producto (3).This product was obtained with a 28% yield, from VP (5.0 ml_, 47 mmol, 1.08 equiv) and δ-valerolactone (4.0 ml_, 43.5 mmol, 1.0 equiv) as starting products. The route used was the one described for the product (3).
1H NMR (CDCI3, 300 MHz) δ: 7.02 (dd, 1 H, N-CH=, J=16.0 y 9.0 Hz), 4.52 1 H NMR (CDCI 3 , 300 MHz) δ: 7.02 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 4.52
(d, 1 H, cis N-CH=CHH, J=16.0 Hz), 4.48 (d, 1 H, trans N-CH=CHH, J=9.0 Hz), 3.67-3.49 (m, 4H, CH2-N, CH2-OH), 3.09-2.98 (m, 1 H, CH-CO), 2.69-(d, 1 H, cis N-CH = CHH, J = 16.0 Hz), 4.48 (d, 1 H, trans N-CH = CHH, J = 9.0 Hz), 3.67-3.49 (m, 4H, CH 2 - N, CH 2 -OH), 3.09-2.98 (m, 1 H, CH-CO), 2.69-
2.51 (m, 2H, OC-CH2), 2.20-2.05 (m, 1 H, CHH-CH2-N), 1.72-1.49 (m, 5H,2.51 (m, 2H, OC-CH 2 ), 2.20-2.05 (m, 1 H, CHH-CH 2 -N), 1.72-1.49 (m, 5H,
CH2-CH2-CH2-OH, CHH-CH2-N).CH 2 -CH 2 -CH 2 -OH, CHH-CH 2 -N).
13C NMR (CDCI3, 75.4 MHz) δ: 206.21 (OC-CH2), 171.60 (OC-N), 125.31 13 C NMR (CDCI 3 , 75.4 MHz) δ: 206.21 (OC-CH 2 ), 171.60 (OC-N), 125.31
(N-CH=), 96.95 (N-CH=CH2), 63.44 (CH2-OH), 55.21 (OC-CH-CO), 43.02 (CH2-N), 41.85 (OC-CH2), 31.65 (CH2-CH2-OH), 24.72 (OC-CH2-CH2),(N-CH =), 96.95 (N-CH = CH 2 ), 63.44 (CH 2 -OH), 55.21 (OC-CH-CO), 43.02 (CH 2 -N), 41.85 (OC-CH 2 ), 31.65 (CH 2 -CH 2 -OH), 24.72 (OC-CH 2 -CH 2 ),
22.95 (CH2-CH2-N).
Preparación del compuesto 3-(3- sulfopropil)-1-vinil-2-pirrolidona (5)22.95 (CH 2 -CH 2 -N). Preparation of compound 3- (3- sulfopropyl) -1-vinyl-2-pyrrolidone (5)
Sobre una disolución de diisopropilamida de litio (2.0 M, en THF, hexano y etilbenceno, 42.0 ml_, 1.8 equivalentes) en 140 ml_ de THF anhidro, se adicionó lentamente (gota a gota) una disolución de VP recién destilada (5.0 ml_, 46 mmol, 1.0 equivalente) en THF anhidro (10 ml_) a una temperatura de -780C y bajo una atmósfera inerte.On a solution of lithium diisopropylamide (2.0 M, in THF, hexane and ethylbenzene, 42.0 ml_, 1.8 equivalents) in 140 ml_ of anhydrous THF, a solution of freshly distilled VP (5.0 ml_, 46) was added slowly (drop by drop) mmol, 1.0 eq) in anhydrous THF (10 ml_) at -78 0 C and under an inert atmosphere.
Tras esa adición, Ia masa de reacción se mantuvo durante 30 minutos a - 780C. Al cabo de este tiempo, se goteaba una disolución de 11.7g de 1 ,3- propanosultona (93 mmol, 2 equivalentes) en 30 ml_ de THF anhidro. Durante Ia adición Ia temperatura no debe exceder los -760C.After that addition, the reaction mass was maintained for 30 minutes at - 78 0 C. After this time, a solution of 11.7g of 1, 3- propanosultone (93 mmol, 2 equivalents) was dripped in 30 ml_ of THF anhydrous. During the addition the temperature should not exceed -76 0 C.
La disolución resultante se mantuvo agitándose durante 3h a una temperatura de -780C, transcurrido este tiempo, se permite que Ia temperatura del reactor vaya subiendo hasta temperatura ambiente. Y se dejó reaccionando durante 12h. Finalmente Ia masa de reacción se hidrolizó con CH2CI2:H2O (2:1 ; 300 ml_). La fracción acuosa se extrajo con CH2CI2 (2x200 mL). La fase acuosa se llevó a sequedad a presión reducida y el residuo sólido se purificó cromatográficamente sobre gel de sílice, empleando como eluyente CH2CI2:Me0H (4:1 ). Rendimiento: 60%.The resulting solution was stirred for 3h at kept at -78 0 C, after which time the temperature is allowed to go up the reactor to room temperature. And it was left reacting for 12h. Finally, the reaction mass was hydrolyzed with CH 2 CI 2 : H 2 O (2: 1; 300 ml_). The aqueous fraction was extracted with CH 2 CI 2 ( 2 x 200 mL). The aqueous phase was dried under reduced pressure and the solid residue was chromatographically purified on silica gel, using CH 2 CI 2 : Me0H (4: 1) as eluent. Yield: 60%.
1H RMN (D2O, 300 MHz) δ: 6.79 (dd, 1 H, N-CH=, J=15.9 y 9.1 Hz), 4.52 (d, 1 H, cis N-CH=CHH J=15.9 Hz), 4.48 (d, 1 H, trans N-CH=CHH, J=9.1 Hz), 3.48-3.44 (m, 1 H, CHH-N), 3.38-3.34 (m, 1 H, CHH-N), 2.85-2.70 (m, 2H, CH2-SO3 "), 2.59-2.51 (m, 1 H, CH-CO), 2.23-2.14 (m, 1 H, CHH-CH2-N),
1.80-1.59 (m, 4H, CHH-CH2-N, CHH-CH2-CH2-SO3 "), 1.41-1.33 (m, 1 H, CHH-CH2-CH2-SO3 "). 1 H NMR (D 2 O, 300 MHz) δ: 6.79 (dd, 1 H, N-CH =, J = 15.9 and 9.1 Hz), 4.52 (d, 1 H, cis N-CH = CHH J = 15.9 Hz ), 4.48 (d, 1 H, trans N-CH = CHH, J = 9.1 Hz), 3.48-3.44 (m, 1 H, CHH-N), 3.38-3.34 (m, 1 H, CHH-N), 2.85-2.70 (m, 2H, CH 2 -SO 3 " ), 2.59-2.51 (m, 1 H, CH-CO), 2.23-2.14 (m, 1 H, CHH-CH 2 -N), 1.80-1.59 (m, 4H, CHH-CH 2 -N, CHH-CH 2 -CH 2 -SO 3 " ), 1.41-1.33 (m, 1 H, CHH-CH 2 -CH 2 -SO 3 " ).
13C RMN (D2O, 75.4 MHz) δ: 178.16 (OC-N), 128.56 (N-CH=), 97.76 (N- CH=CH2), 50.85 (CH2-SO3 "), 43.90 (CH2-N), 42.36 (OC-CH), 29.33 (CH2- CH2-CH2-SO3 "), 23.40 (CH2-CH2-N), 21.75 (CH2-CH2-SO3 "). 13 C NMR (D 2 O, 75.4 MHz) δ: 178.16 (OC-N), 128.56 (N-CH =), 97.76 (N- CH = CH 2 ), 50.85 (CH 2 -SO 3 " ), 43.90 ( CH 2 -N), 42.36 (OC-CH), 29.33 (CH 2 - CH 2 -CH 2 -SO 3 " ), 23.40 (CH 2 -CH 2 -N), 21.75 (CH 2 -CH 2 -SO 3 " ).
Preparación del compuesto 3-(2-aminobenzoil)-1-vinil-2-pirrolidona (6)Preparation of compound 3- (2-aminobenzoyl) -1-vinyl-2-pyrrolidone (6)
Sobre una disolución de diisopropilamida de litio (1.8 M, en THF, hexano y etilbenceno, 7.49 ml_, 2.2 equivalentes) en 10 ml_ de THF anhidro, se adicionó lentamente (gota a gota) una disolución de VP recién destilada (0.65 ml_, 6.13 mmol, 1.0 equivalente) en THF anhidro (5 ml_) a una temperatura de -780C y bajo una atmósfera inerte.On a solution of lithium diisopropylamide (1.8 M, in THF, hexane and ethylbenzene, 7.49 ml_, 2.2 equivalents) in 10 ml_ of anhydrous THF, a solution of freshly distilled VP (0.65 ml_, 6.13) was slowly added (dropwise) mmol, 1.0 eq) in anhydrous THF (5 ml_) at a temperature of -78 0 C and under an inert atmosphere.
Tras esa adición, Ia masa de reacción se mantuvo durante 30 minutos a - 780C. Al cabo de este tiempo, se goteaba una disolución de 1g de anhídrido isatoico (6.13 mmol, 1.0 equivalentes) en 35 ml_ de THF anhidro.After this addition, the mass reaction was kept for 30 minutes at - 78 0 C. After this time, a solution of 1 g of isatoic anhydride (6.13 mmol, 1.0 equiv) in 35 ml_ of anhydrous THF is dripped.
La disolución resultante se mantuvo agitándose durante 3h a una temperatura de -780C, transcurrido este tiempo, se permite que Ia temperatura del reactor vaya subiendo hasta temperatura ambiente. Y se dejó reaccionando durante 12h. Finalmente Ia masa de reacción se hidrolizó con CH2CI2:H2O (2:1 ; 300 ml_). La fase acuosa se extrajo con CH2CI2 (2x100 mL) y el combinado de fases orgánicas se secaron sobre
sulfato sódico anhidro (Na2SO4) y se evaporó a presión reducida. Finalmente el residuo sólido se purificó cromatográficamente sobre gel de sílice, empleando como eluyente CH2CI2:Et2O (50:1 ). Rendimiento: 40%.The resulting solution was stirred for 3h at kept at -78 0 C, after which time the temperature is allowed to go up the reactor to room temperature. And it was left reacting for 12h. Finally, the reaction mass was hydrolyzed with CH 2 CI 2 : H 2 O (2: 1; 300 ml_). The aqueous phase was extracted with CH 2 CI 2 ( 2 x 100 mL) and the combined organic phases were dried over anhydrous sodium sulfate (Na 2 SO 4 ) and evaporated under reduced pressure. Finally, the solid residue was chromatographically purified on silica gel, using CH 2 CI 2 : Et 2 O (50: 1) as eluent. Yield: 40%.
1H RMN (CDCI3, 400 MHz) δ: 7.93 (d, 2H, CH, J=4.0Hz), 7.28 (t, 2H, CH, J=4.0Hz), 7.07 (dd, 1 H, N-CH=, J=16.0 y 9.0 Hz), 6.70 (t, 2H, CH J=4.0Hz), 6.65 (d, 2H, CH, J=4.0Hz), 6.30 (br, 2H, NH2), 4.58 (dd, 1 H, CO- CH-CO, J=5.2 y J= 9.6Hz), 4.45 (d,1 H, cis N-CH=CHH, J=9.0Hz), 4.40 (d, 1 H, trans N-CH-CHH, J=16.0Hz), 3.68 (m, 1 H, N-CHH), 3.55 (td, N-CHH, J=4.4 y J=9.2Hz), 2.63 (m, 1 H, N-CH2-CHH), 2.32 (m,1 H, N-CH2-CHH). 1 H NMR (CDCI 3 , 400 MHz) δ: 7.93 (d, 2H, CH, J = 4.0Hz), 7.28 (t, 2H, CH, J = 4.0Hz), 7.07 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 6.70 (t, 2H, CH J = 4.0Hz), 6.65 (d, 2H, CH, J = 4.0Hz), 6.30 (br, 2H, NH 2 ), 4.58 (dd , 1 H, CO-CH-CO, J = 5.2 and J = 9.6Hz), 4.45 (d, 1 H, cis N-CH = CHH, J = 9.0Hz), 4.40 (d, 1 H, trans N- CH-CHH, J = 16.0Hz), 3.68 (m, 1 H, N-CHH), 3.55 (td, N-CHH, J = 4.4 and J = 9.2Hz), 2.63 (m, 1 H, N-CH 2 -CHH), 2.32 (m, 1 H, N-CH 2 -CHH).
13C RMN (CDCI3, 100 MHz) δ: 196.91 (CO), 169.40 (CO-N), 151.25 (C- NH2), 134.98 (CH-CH-C-NH2), 132.72 (N-CH=), 129.35 (CH-C-CO)1117.17 (CH-CH-C-CO), 117.01 (C-CO), 115.98 (CH-C-NH2), 95.32 (CH2=CH-N), 51.05 (CO-CH-CO), 43.61 (CH2-N), 22.15 (CH2-CH2-N). 13 C NMR (CDCI 3 , 100 MHz) δ: 196.91 (CO), 169.40 (CO-N), 151.25 (C-NH 2 ), 134.98 (CH-CH-C-NH 2 ), 132.72 (N-CH = ), 129.35 (CH-C-CO) 1 117.17 (CH-CH-C-CO), 117.01 (C-CO), 115.98 (CH-C-NH 2 ), 95.32 (CH 2 = CH-N), 51.05 (CO-CH-CO), 43.61 (CH 2 -N), 22.15 (CH 2 -CH 2 -N).
Preparación del compuesto 3-(2-metilaminobenzoil)-1-vinil-2- pirrolidona (7)Preparation of compound 3- (2-methylaminobenzoyl) -1-vinyl-2-pyrrolidone (7)
Sobre una disolución de diisopropilamida de litio (1.8 M, en THF, hexano y etilbenceno, 5.08 ml_, 1.8 equivalentes) en 10 ml_ de THF anhidro, se adicionó lentamente (gota a gota) una disolución de VP recién destilada (0.53 ml_, 5.64 mmol, 1.0 equivalente) en THF anhidro (5 ml_) a una temperatura de -780C y bajo una atmósfera inerte.
Tras esa adición, Ia masa de reacción se mantuvo durante 30 minutos a - 780C. Al cabo de este tiempo, se goteaba una disolución de 1g de anhídrido N-metilisatoico (5.64 mmol, 1.0 equivalentes) en 35 ml_ de THF anhidro.On a solution of lithium diisopropylamide (1.8 M, in THF, hexane and ethylbenzene, 5.08 ml_, 1.8 equivalents) in 10 ml_ of anhydrous THF, a solution of freshly distilled VP (0.53 ml_, 5.64 was slowly added dropwise) mmol, 1.0 eq) in anhydrous THF (5 ml_) at a temperature of -78 0 C and under an inert atmosphere. After this addition, the mass reaction was kept for 30 minutes at - 78 0 C. After this time, a solution of 1 g of N-methylisatoic anhydride (5.64 mmol, 1.0 equiv) in 35 ml_ of anhydrous THF was dripped.
La disolución resultante se mantuvo agitándose durante 3h a una temperatura de -780C, transcurrido este tiempo, se permite que Ia temperatura del reactor se recupere hasta temperatura ambiente. Y se dejó reaccionando durante 12h. Finalmente Ia masa de reacción se hidrolizó con CH2CI2:H2O (2:1 ; 300 ml_). La fase acuosa se extrajo con CH2CI2 (2x100 mL) y el combinado de fases orgánicas se secaron sobre sulfato sódico anhidro (Na2SO4) y se evaporó a presión reducida. Finalmente el residuo sólido se purificó cromatográficamente sobre gel de sílice, empleando como eluyente Hexano:Acetato de etilo (5:1 ). Rendimiento: 45%.The resulting solution was stirred for 3h at kept at -78 0 C, after which time it allows the temperature of the reactor is recovered to room temperature. And it was left reacting for 12h. Finally, the reaction mass was hydrolyzed with CH 2 CI 2 : H 2 O (2: 1; 300 ml_). The aqueous phase was extracted with CH 2 CI 2 ( 2 x 100 mL) and the combined organic phases were dried over anhydrous sodium sulfate (Na 2 SO 4 ) and evaporated under reduced pressure. Finally, the solid residue was chromatographically purified on silica gel, using as eluent Hexane: Ethyl acetate (5: 1). Yield: 45%.
1H RMN (CDCI3, 400 MHz) δ: 8.80 (br, 1 H, NHMe), 7.94 (d, 2H, CH, J=4.0Hz), 7.40 (t, 2H, CH, J=4.0Hz), 7.07 (dd, 1 H, N-CH=, J=16.0 y 9.0 Hz), 6.70-6.62 (m, 2H, 2=CH), 4.59 (dd, 1 H, CO-CH-CO, J=4.8 y J= 9.3Hz), 4.50 (d,1 H, cis N-CH=CHH, J=9.0Hz), 4.45 (d, 1 H, trans N-CH- CHH, J=16.0Hz), 3.68 (m, 1 H, N-CHH), 3.55 (m, N-CHH), 2.90 (d, 3H, N- CH3, J=5.1 Hz), 2.60 (m, 1 H, N-CH2-CHH), 2.35 (m,1 H, N-CH2-CHH). 1 H NMR (CDCI 3 , 400 MHz) δ: 8.80 (br, 1 H, NHMe), 7.94 (d, 2H, CH, J = 4.0Hz), 7.40 (t, 2H, CH, J = 4.0Hz), 7.07 (dd, 1 H, N-CH =, J = 16.0 and 9.0 Hz), 6.70-6.62 (m, 2H, 2 = CH), 4.59 (dd, 1 H, CO-CH-CO, J = 4.8 and J = 9.3Hz), 4.50 (d, 1 H, cis N-CH = CHH, J = 9.0Hz), 4.45 (d, 1 H, trans N-CH-CHH, J = 16.0Hz), 3.68 (m, 1 H, N-CHH), 3.55 (m, N-CHH), 2.90 (d, 3H, N-CH 3 , J = 5.1 Hz), 2.60 (m, 1 H, N-CH 2 -CHH), 2.35 (m, 1 H, N-CH 2 -CHH).
13C RMN (CDCI3, 100 MHz) δ: 197.26 (CO), 169.90 (CO-N), 153.06 (C- NH2), 135.94 (CH-CH-C-NH2), 133.62 (N-CH=), 129.64 (CH-C-CO)1116.60 (CH-CH-C-CO), 114.72 (C-CO), 111.55 (CH-C-NH2), 95.46 (CH2=CH-N), 51.15 (CO-CH-CO), 43.89 (CH2-N), 29.55 (CH3-N), 22.68 (CH2-CH2-N). 13 C NMR (CDCI 3 , 100 MHz) δ: 197.26 (CO), 169.90 (CO-N), 153.06 (C-NH 2 ), 135.94 (CH-CH-C-NH 2 ), 133.62 (N-CH = ), 129.64 (CH-C-CO) 1 116.60 (CH-CH-C-CO), 114.72 (C-CO), 111.55 (CH-C-NH 2 ), 95.46 (CH 2 = CH-N), 51.15 (CO-CH-CO), 43.89 (CH 2 -N), 29.55 (CH 3 -N), 22.68 (CH 2 -CH 2 -N).
EJEMPLO 2.- Polimerización y copolimerización de vinil pirrolidona (VP) y derivados de VP.
En un vial se añadió Ia cantidad apropiada de disolvente, y se disolvieron monómeros en una concentración total de 1 M e iniciador en una concentración de 1.5 x 10~2 M. Se desplazó el oxígeno presente en Ia disolución por borboteo con N2 durante 30 minutos. A continuación se dejó polimerizar durante el tiempo y a Ia temperatura, apropiadas. Tras Ia polimerización el polímero o copolímero se aisló y purificó por precipitación en un no-solvente. Si es soluble en agua se purificó mediante diálisis en membranas de cut-off de 3000.EXAMPLE 2.- Polymerization and copolymerization of vinyl pyrrolidone (VP) and VP derivatives. In a vial the appropriate amount of solvent was added, and monomers were dissolved in a total concentration of 1 M and initiator in a concentration of 1.5 x 10 ~ 2 M. The oxygen present in the solution was displaced by bubbling with N 2 for 30 minutes It was then allowed to polymerize for the appropriate time and temperature. After polymerization, the polymer or copolymer was isolated and purified by precipitation in a non-solvent. If it is soluble in water, it was purified by dialysis in 3000 cut-off membranes.
Ejemplo de reacción: 55 mg de VP (destilada previamente) y 196 mg de VP-(CH2)3-Sθ3Li (relación molar 1 :1 ) se disolvieron en 1 ml_ agua destilada. Se añadió 2.5 mg de azobisisobutiro nitrilo (AIBN). Se borboteó N2 (con cuidado) en Ia disolución durante 30 minutos y a continuación se cerró el vial y se dejó en una estufa cerrada a 50° C durante 48 horas. Tras este tiempo, Ia reacción se precipitó lentamente en un gran exceso de acetona. El producto precipitado sólido se filtró, se lavó con acetona, y se secó a vacío hasta temperatura constante. El espectro de 1H RMN de este copolímero (D2O, 300 MHz) se muestra en Ia Figura 1.
Reaction example: 55 mg of VP (previously distilled) and 196 mg of VP- (CH 2 ) 3 -Sθ 3 Li (1: 1 molar ratio) were dissolved in 1 ml_ distilled water. 2.5 mg of azobisisobutyro nitrile (AIBN) was added. N 2 (carefully) was bubbled in the solution for 30 minutes and then the vial was closed and left in a closed oven at 50 ° C for 48 hours. After this time, the reaction was slowly precipitated in a large excess of acetone. The solid precipitated product was filtered, washed with acetone, and dried in vacuo to constant temperature. The 1 H NMR spectrum of this copolymer (D 2 O, 300 MHz) is shown in Figure 1.
Claims
1. Compuesto de fórmula general (I) o cualquiera de sus sales:1. Compound of general formula (I) or any of its salts:
R1 y R2 son iguales o diferentes y representan un hidrógeno o un metilo; X es un radical seleccionado del grupo que comprende un hidroxiloR 1 and R 2 are the same or different and represent a hydrogen or a methyl; X is a radical selected from the group comprising a hydroxyl
(OH), un tiol (SH), un sulfonilo (SO3H), una amina (NR3R4, NHR3 o NH2) o un carboxilo (CO2H);(OH), a thiol (SH), a sulfonyl (SO 3 H), an amine (NR 3 R 4 , NHR 3 or NH 2 ) or a carboxyl (CO 2 H);
R, R3 y R4, son iguales o diferentes y representa a un grupo arilo (C6-Ciβ) o un grupo alquilo (C1-C10).R, R 3 and R 4 are the same or different and represent an aryl group (C6-Ciβ) or an alkyl group (C1-C10).
2. Compuesto según Ia reivindicación 1 , donde R, R3 ó R4 son un grupo alquilo (CrC6).2. Compound according to claim 1, wherein R, R 3 or R 4 are an alkyl group (CrC 6 ).
3. Compuesto según cualquiera de las reivindicaciones 1 ó 2, donde A es un grupo carbonilo.3. Compound according to any one of claims 1 or 2, wherein A is a carbonyl group.
4. Compuesto según cualquiera de las reivindicaciones 1 a 3, donde X es un grupo hidroxilo.4. Compound according to any one of claims 1 to 3, wherein X is a hydroxyl group.
5. Compuesto según Ia reivindicación 4, seleccionado de Ia lista que comprende: 3-(2-hidroxietil)-1-vinil-2-pirrolidona, 3-(1-oxo-5- hidroxipentil)-1-vinil-2-pirrolidona ó 3-(1-oxo-6-hidroxihexil)-1-vinil-2- pirrolidona. 5. Compound according to claim 4, selected from the list comprising: 3- (2-hydroxyethyl) -1-vinyl-2-pyrrolidone, 3- (1-oxo-5- hydroxypentyl) -1-vinyl-2-pyrrolidone or 3- (1-oxo-6-hydroxyhexyl) -1-vinyl-2-pyrrolidone.
6. Compuesto según cualquiera de las reivindicaciones 1 ó 2, donde X es un grupo tiol.6. Compound according to any of claims 1 or 2, wherein X is a thiol group.
7. Compuesto según Ia reivindicación 6, de fórmula 3-(2-mercaptoetil)-1- vinil-2-pirrolidona.7. Compound according to claim 6, of formula 3- (2-mercaptoethyl) -1-vinyl-2-pyrrolidone.
8. Compuesto según cualquiera de las reivindicaciones 1 ó 2, donde X es un grupo sulfonilo.8. A compound according to any one of claims 1 or 2, wherein X is a sulfonyl group.
9. Compuesto según Ia reivindicación 8, de fórmula 3-(3-sulfopropil)-1- vinil-2-pirrolidona.9. Compound according to claim 8, of formula 3- (3-sulfopropyl) -1-vinyl-2-pyrrolidone.
10. Compuesto según cualquiera de las reivindicaciones 1 a 3, donde X es un grupo amina.10. Compound according to any of claims 1 to 3, wherein X is an amine group.
11.Compuesto según Ia reivindicación 10, donde R es un grupo fenilo.11. Compound according to claim 10, wherein R is a phenyl group.
12. Compuesto según Ia reivindicación 11 , de fórmula 3-(2-aminobenzoil)-12. Compound according to claim 11, of formula 3- (2-aminobenzoyl) -
1 -vinil-2-pirrolidona o 3-(2-metilaminobenzoil)-1 -vinil-2-pirrolidona.1-vinyl-2-pyrrolidone or 3- (2-methylaminobenzoyl) -1-vinyl-2-pyrrolidone.
13. Compuesto según de Ia reivindicación 10, donde R es un grupo alquilo (Ci-C6).13. Compound according to claim 10, wherein R is an alkyl group (Ci-C 6 ).
14. Compuesto según Ia reivindicación 13, de fórmula 3-(1-oxo-2- aminopropil)-1-vinil-2-pirrolidona, 3-(2-aminoetil)-1-vinil-2-pirrolidona, 3-14. Compound according to claim 13, of formula 3- (1-oxo-2- aminopropyl) -1-vinyl-2-pyrrolidone, 3- (2-aminoethyl) -1-vinyl-2-pyrrolidone, 3-
(2-dimetilaminoetil)-1 -vinil-2-pirrolidona ó 3-(2-aminoetilsulfonil)-1 -vinil- 2-pirrolidona.(2-dimethylaminoethyl) -1-vinyl-2-pyrrolidone or 3- (2-aminoethylsulfonyl) -1-vinyl-2-pyrrolidone.
15. Compuesto según cualquiera de las reivindicaciones 1 a 3, donde X es un grupo carboxilo. 15. Compound according to any one of claims 1 to 3, wherein X is a carboxyl group.
16. Compuesto según Ia reivindicación 15, de fórmula 3-(1-oxo-2- carboxiletil)-1-vinil-2-pirrolidona.16. Compound according to claim 15, of formula 3- (1-oxo-2- carboxylethyl) -1-vinyl-2-pyrrolidone.
17. Procedimiento para Ia obtención del compuesto de fórmula general (I) que comprenden los siguientes pasos:17. Procedure for obtaining the compound of general formula (I) comprising the following steps:
a. desprotonación de Ia unidad monomérica 1 -vinil-2-pirrolidona en Ia posición 3 de 1 -vinil-2-pirrolidona, mediante Ia adición de una base; b. Ia reacción de un anillo precursor de fórmula (II) con 1 -vinil-2- pirrolidona obtenida en el paso (a).to. deprotonation of the 1-vinyl-2-pyrrolidone monomer unit in position 3 of 1-vinyl-2-pyrrolidone, by adding a base; b. The reaction of a precursor ring of formula (II) with 1-vinyl-2-pyrrolidone obtained in step (a).
(H)(H)
donde: A y R están descritos en Ia reivindicación 1 , y X' es un grupo precursor del grupo X, también descrito en Ia reivindicación 1.wherein: A and R are described in claim 1, and X 'is a precursor group of group X, also described in claim 1.
18. Procedimiento según Ia reivindicación 17, donde los anillos precursores de fórmula (II) se seleccionan de Ia lista que comprende, lactama, alquilsultona, lactona o un anillo que contiene un grupo N- carboxianhídrido, amina, sultama, éter, tioéter o anhídrido.18. Method according to claim 17, wherein the precursor rings of formula (II) are selected from the list comprising, lactam, alkylsultone, lactone or a ring containing an N-carboxyanhydride, amine, sultama, ether, thioether or anhydride group .
19. Procedimiento según cualquiera de las reivindicaciones 17 ó 18, donde Ia base del paso (a) es diisopropilamiduro de litio (LDA).19. Method according to any of claims 17 or 18, wherein the basis of step (a) is lithium diisopropylamide (LDA).
20. Procedimiento según cualquiera de las reivindicaciones 17 a 19, donde Ia temperatura de reacción es de entre -1000C y 5O0C 20. Method according to any of claims 17 to 19, wherein the reaction temperature is between -100 0 C and 5O 0 C
21. Procedimiento según Ia reivindicación 20, donde Ia temperatura de reacción es de entre -850C y -2O0C.21. Method according to claim 20, wherein the reaction temperature is between -85 0 C and -2O 0 C.
22. Uso del compuesto según cualquiera de las reivindicaciones 6 ó 7, para Ia obtención de macromonómeros, injertos o entrecruzamientos, en procesos de polimerización.22. Use of the compound according to any of claims 6 or 7, for obtaining macromonomers, grafts or crosslinks, in polymerization processes.
23. Uso del compuesto de fórmula general (I) para Ia obtención de polímeros o copolímeros.23. Use of the compound of general formula (I) to obtain polymers or copolymers.
24. Polímeros o copolímeros que comprenden un compuesto de fórmula general (I) como monómero. 24. Polymers or copolymers comprising a compound of general formula (I) as a monomer.
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| ESP200803380 | 2008-11-27 | ||
| ES200803380A ES2340130B1 (en) | 2008-11-27 | 2008-11-27 | FUNCTIONALIZATION OF 1-VINYL-2 PIRROLIDONE IN POSITION 3 THROUGH OPENING OF CYCLE PRECURSORS. |
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| CN109134404A (en) * | 2018-09-27 | 2019-01-04 | 湖南恒泰化工有限公司 | The preparation method of 3- N-morpholinyl |
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| EP1184372A1 (en) * | 2000-08-31 | 2002-03-06 | Pfizer Limited | Phenoxyphenylheterocycle derivatives as selective serotonin reuptake inhibitors (SSRIs) |
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| EP1184372A1 (en) * | 2000-08-31 | 2002-03-06 | Pfizer Limited | Phenoxyphenylheterocycle derivatives as selective serotonin reuptake inhibitors (SSRIs) |
Non-Patent Citations (4)
| Title |
|---|
| BABUDRI, F. ET AL.: "Organometallic induced self-condensation of carboxamides", TETRAHEDRON, vol. 38, no. 4, 1982, pages 557 - 561 * |
| ENGSTROM, J.U.A. ET AL.: "Hydrophilic Polymer Supports for Solid-Phase Synthesis: Hydroxy-Functional Beads of Poly(vinylpyrrolidone)", JOURNAL OF COMBINATORIAL CHEMISTRY, vol. 8, 2006, pages 355 - 360 * |
| NENAJDENKO, V.G. ET AL.: "Synthesis and the keto-enol equilibrium of 2-acyl lactams", RUSSIAN CHEMICAL BULLETIN, INTERNATIONAL EDITION, vol. 52, no. 11, 2003, pages 2473 - 2482 * |
| PEREZ PERRINO, M. ET AL.: "''''One-pot'' Synthesis of 1-Vinyl-2-pyrrolidone with Protic Functional Groups in 3-Position''.", MACROMOLECULAR CHEMISTRY AND PHYSICS, vol. 210, 2009, pages 1973 - 1978 * |
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| CN109134404A (en) * | 2018-09-27 | 2019-01-04 | 湖南恒泰化工有限公司 | The preparation method of 3- N-morpholinyl |
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