DE2245560A1 - 5-Substd. 4-alkoxycarbonyl-2-thiazolines prepn. - useful as penicillin inters. - Google Patents
5-Substd. 4-alkoxycarbonyl-2-thiazolines prepn. - useful as penicillin inters.Info
- Publication number
- DE2245560A1 DE2245560A1 DE19722245560 DE2245560A DE2245560A1 DE 2245560 A1 DE2245560 A1 DE 2245560A1 DE 19722245560 DE19722245560 DE 19722245560 DE 2245560 A DE2245560 A DE 2245560A DE 2245560 A1 DE2245560 A1 DE 2245560A1
- Authority
- DE
- Germany
- Prior art keywords
- thiazoline
- alkoxycarbonyl
- thiazolines
- substd
- opt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229930182555 Penicillin Natural products 0.000 title abstract description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 title abstract description 3
- 229940049954 penicillin Drugs 0.000 title abstract description 3
- 150000002148 esters Chemical class 0.000 claims abstract description 16
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 13
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- -1 β-substituted Formylamino-acrylic acid Chemical class 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- XAVOIGGIQWDABI-UHFFFAOYSA-N CCOC(=O)C1N=CSC1(C)C Chemical compound CCOC(=O)C1N=CSC1(C)C XAVOIGGIQWDABI-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000003549 thiazolines Chemical class 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical class OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 description 1
- PENBDSUEMPXNAM-UHFFFAOYSA-N 2-isocyanoprop-2-enoic acid Chemical class [N+](#[C-])C(C(=O)O)=C PENBDSUEMPXNAM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- FFBSLEKOOXSDQB-UHFFFAOYSA-N ethyl 1-thia-3-azaspiro[4.5]dec-2-ene-4-carboxylate Chemical compound CCOC(=O)C1N=CSC11CCCCC1 FFBSLEKOOXSDQB-UHFFFAOYSA-N 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Verfahren zur Herstellung von 4-Alkoxyearbonyl-2-thiazolinen Es ist bekannt, daß Thiazolinderivate beispielsweise als Ausgangsverbindungen zur Synthese von Verbindungen mit Penicillinstruktur verwendet werden können. Geeignete in 2-Stellung unsubstituierte 4-Alkoxyearbonyl-2-thiazoline sind jedoch nach den bisher bekannten Verfahren nur schwierig und umständlich zu synthetisieren. So kann man 4-thoxycarbonyl-5,5-dimethyl-2-thiazolin durch einen Ringschluß des auch nur sehr schwer zugänglichen N-Formyl-penicillaminäthylesters mit Bortrifluoridätherat (M.R. Bell et al., J. Amer. Chem. Soc. 92, 2178 (1970)) oder durch eine Umsetzung mit Formo imidoäthylester (A.K. Bcse et al., J. Amer. Chem. Soc. 90, 4508 (1968)) erhalten.Process for the preparation of 4-alkoxyearbonyl-2-thiazolines It is known that thiazoline derivatives, for example, as starting compounds for synthesis of compounds with penicillin structure can be used. Suitable in 2-position However, unsubstituted 4-alkoxy carbonyl-2-thiazolines are according to the previously known Processes are difficult and cumbersome to synthesize. So you can use 4-thoxycarbonyl-5,5-dimethyl-2-thiazoline by ring closure of the N-formyl penicillamine ethyl ester, which is also very difficult to access with boron trifluoride etherate (M.R. Bell et al., J. Amer. Chem. Soc. 92, 2178 (1970)) or by a reaction with formo imidoethyl ester (A.K. Bcse et al., J. Amer. Chem. Soc. 90, 4508 (1968)).
Es wurde nun ein einfaches und leicht durchzurührendes Verfahren zur Herstellung von in 5-Stellung mono- oder disubstituierten 4-Alkoxycarbonyl-2-thiazolinen gefunden, bei dem man ß-substituierte -Isocy.anacrylsäureester in einem Lösungsmittel mit Schwefelwasserstoff umsetzt.It now became a simple and easy-to-perform process for Preparation of 4-alkoxycarbonyl-2-thiazolines mono- or disubstituted in the 5-position found, in which one ß-substituted -Isocy.anacryläureester in a solvent Reacts with hydrogen sulfide.
Das erfindungsgemäße Verfahren führt zu neuen 4-Alkoxycarbonyl-2-thiazolinen der Formel in der die Substituenten R1 und R2 Wasserstoff, einen gesättigte oder ungesättigten, geradkettigen, verzweigten oder cyclischen, gegebenenfalls substituierten Alkylrest mit 1 bis 18 Kohlenstoffatomen, einen gegebenenfalls substituierten aromatischen oder heteroaromatischen Rest, wobei R1 und R2 gleich oder verschieden sein können und nur einer der Substituenten Wasserstoff oder Methyl darstellt, oder R1 und R2 zusammen mit dem sie verbindenden Kohlenstoffatom einen cycloaliphatischen oder heterocyclischen Ring mit 3 bis 18 Ringgliedern und R3 einen gegebenenfalls substituierten niederen Alkylrest bedeuten.The process according to the invention leads to new 4-alkoxycarbonyl-2-thiazolines of the formula in which the substituents R1 and R2 are hydrogen, a saturated or unsaturated, straight-chain, branched or cyclic, optionally substituted alkyl radical having 1 to 18 carbon atoms, an optionally substituted aromatic or heteroaromatic radical, where R1 and R2 can be identical or different and only one of the Substituents represent hydrogen or methyl, or R1 and R2 together with the carbon atom connecting them represent a cycloaliphatic or heterocyclic ring with 3 to 18 ring members and R3 represent an optionally substituted lower alkyl radical.
Die -Isocyanacrylsäureester sind beispielsweise aus entsprechend ß-substituierten Formylamino-acrylsäureestern leicht zugängliche und in hohen Ausbeuten herstellbare Verbindungen, da die Formylamino-acrylester sich auf übliche Weise in die 6-Isocyanacrylsäureester überführen lassen, wobei man sich beispielsweise einer von Ugi und Mitarbeitern in der Angewandten Chemie 77, 492 (1965) beschriebenen oder anderen bekannten Methoden, wie die von R. Appel und Mitarbeitern, Angewandte Chemie 83, 143 (1965), bedienen kann.The isocyanacrylic acid esters are, for example, made from correspondingly β-substituted Formylamino-acrylic acid esters are easily accessible and can be prepared in high yields Compounds, since the formylamino-acrylic esters are converted in the usual way into the 6-isocyanacrylic acid esters get transferred, for example one of Ugi and coworkers in Angewandte Chemie 77, 492 (1965) described or other known methods, such as those of R. Appel and coworkers, Angewandte Chemie 83, 143 (1965), use can.
Die Formylaminoacrylsäureester wiederum kann man aus r-metallierten Isocyanessigsäureestern und den entsprechenden Carbonylverbindungen bequem und in hohen Ausbeuten erhalten. Für diese Umsetzung sei als Literaturstelle beispielsweise U. Schöllkopf und Mitarbeiter, Angewandte Chemie 81, 701 (1969), genannt.The formylaminoacrylic acid esters, in turn, can be obtained from r-metalated Isocyanoacetic acid esters and the corresponding carbonyl compounds conveniently and in obtained high yields. A reference for this implementation is, for example U. Schöllkopf and coworkers, Angewandte Chemie 81, 701 (1969), called.
Die als Ausgangsverbindungen verwendeten in ß-Stellung mono-oder disubstituierten o'-Isocyanacrylsäureester werden vorteilhaft in einem Lösungsmittel gelöst und mit Schwefelwasserstoff, der zweckmäßigerweise bei Temperaturen von 20 bis 400C eingeleitet wird, umgesetzt.The starting compounds used as mono- or disubstituted in the β-position o'-Isocyanacrylic acid esters are advantageously dissolved in a solvent and mixed with Hydrogen sulfide, which is expediently introduced at temperatures of 20 to 40 ° C will do.
Als Lösungsmittel können beispielsweise chlorierte Kohlenwasserstoffe, wie Chloroform, Tetrachlorkohlenstoff oder Methylenchlorid, Dialkyläther oder gesättigte cyclische Äther, wie Diäthyläther oder Tetrahydrofuran oder Dioxan oder Ester, wie Essigsäureäthylester, oder Alkohole, wie Methanol, Äthanol, Isopropanol oder Butanol, verwendet werden.Chlorinated hydrocarbons, such as chloroform, carbon tetrachloride or methylene chloride, Dialkyl ethers or saturated cyclic ethers such as diethyl ether or tetrahydrofuran or dioxane or esters, such as ethyl acetate, or alcohols, such as methanol, ethanol, isopropanol or butanol, can be used.
Die Umsetzung kann vorteilhaft in Gegenwart von Basen vorgenommen werden. Als zweckmäßige Basen können organische tertiäre Amine, insbesondere Triäthylamin, Tributylamin, N,N-Dimethylanilin oder Pyridin, Natriumalkoholat oder auch Alkalisulfide verwendet werden. Dabei werden die Basen etwa in Mengen von 1 bis 100, bevorzugt etwa 10 Molprozent, berechnet auf den -Isocyanacrylester, zugesetzt. Die Umsetzung der Tsocyanacrylester mit Schwefelwasserstoff kann aber auch ohne Zugabe einer Base ablaufen.The reaction can advantageously be carried out in the presence of bases will. Organic tertiary amines, in particular triethylamine, Tributylamine, N, N-dimethylaniline or pyridine, sodium alcoholate or alkali sulfides be used. The bases are preferred in amounts of from 1 to 100 about 10 mole percent, calculated on the isocyanacrylic ester, added. The implementation but the isocyanacrylic ester with hydrogen sulfide can also be used without adding a base expire.
In der Regel leitet man Schwefelwasserstoff bis zur Sättigung in die Lösung der Ausgangsverbindung ein. Die Umsetzung ist beendet, wenn von einer Probe des Reaktionsgemisches im IR-Spektrum kein Isonitril mehr nachweisbar ist.As a rule, hydrogen sulfide is fed into the until saturation Solution of the starting compound. The implementation is finished when from a sample of the reaction mixture in the IR spectrum isonitrile is no longer detectable.
Zur Aufarbeitung verdampft man in der Regel das Lösungsmittel und isoliert das 4-Alkoxycarbonyl-2-thiazolin beispielsweise durch eine Vakuumdestillation oder durch Umkristallisieren in einem geeigneten Lösungsmittel. Die erhaltenen 4-Alkoxycarbonyl-2-thiazoline sind charakterisiert durch NMR-Signale bei 1,8 bis 2,1 , J24 ca. 2,5 Hz für das C-2-Proton und durch eine IR-Absorption bei 1 560 com 1 (V NC) NC Ein besonderer Vorteil des erfindungsgemäßen Verfahrens ist die Verwendung von außerordentlich leicht zugänglichen Ausgangsmaterialien, wobei 4-Alkoxycarbonyl-2-thiazoline, die in verschiedenartigster Weise in 5-Stellung substituiert sein können, bequem und in guten Ausbeuten erhalten werden.For working up, the solvent is usually evaporated off and isolates the 4-alkoxycarbonyl-2-thiazoline, for example by vacuum distillation or by recrystallization in a suitable solvent. The 4-alkoxycarbonyl-2-thiazolines obtained are characterized by NMR signals at 1.8 to 2.1, J24 approx. 2.5 Hz for the C-2 proton and by an IR absorption at 1 560 com 1 (V NC) NC A special one The advantage of the method according to the invention is the use of extraordinary readily available starting materials, being 4-alkoxycarbonyl-2-thiazoline, the can be substituted in the 5-position in a wide variety of ways, conveniently and can be obtained in good yields.
Die in 5-Stellung mono- oder disubstituierten 4-Alkoxycarbonyl-2-thiazoline sind wertvolle Zwischenprodukte zur Synthese von Heilmitteln. Insbesondere eignen sie sich zur Synthese von Verbindungen der Penicillinreihe. Mit den bisher bekannten Verfahren konnten die Substituenten in 5-Stellung der Thiazolinverbindung nicht in der Breite variiert werden, wie es mit dem erfindungsgemäßen Verfahren möglich geworden ist.The 4-alkoxycarbonyl-2-thiazolines mono- or disubstituted in the 5-position are valuable intermediates for the synthesis of Remedies. In particular they are suitable for the synthesis of compounds of the penicillin series. With the so far known processes could use the substituents in the 5-position of the thiazoline compound cannot be varied in terms of breadth, as is the case with the method according to the invention has become possible.
Das neue Verfahren läßt sich durch das folgende Formelschema veranschaulichen: Der Schwefelwasserstoff wird an den xIsocyanacrylsäureester der Formel 1 angelagert. Als Zwischenprodukt kann man einen ß-Mercapto- s-isocyanpropionssiureester der Formel 2 formulieren, das anschließend zum Thiazolinderivat cyclisiert wird. Dieses als Vorstufe der C'vclisierung entstehende Zwischenprodukt kann bei der Umsetzung von ß-Phenyl-S-isocyanacrylsäureester mit Schwefelwasserstoff IR-spektroskopisch nachgewiesen werden (V NC 2160 cm v SH 2400 cm 1).The new procedure can be illustrated by the following equation: The hydrogen sulfide is attached to the xisocyanacrylic acid ester of formula 1. A β-mercaptos-isocyanpropionic acid ester of the formula 2 can be formulated as an intermediate product, which is then cyclized to the thiazoline derivative. This intermediate product, which occurs as a precursor of the cyclization, can be detected by IR spectroscopy during the reaction of β-phenyl-S-isocyanacrylic acid ester with hydrogen sulfide (V NC 2160 cm v SH 2400 cm 1).
Bei den verwendeten ß-substituierten ocrIsocyanacrylsäureestern der Formel 1 handelt es sich vorzugsweise um Ester von niederen Alkoholen mit 1 bis 7 Kohlenstoffatomen, wie Äthanol, Methanol, n-Propanol, Isopropanol, n-Butanol, Isobutanol, tert.-Butanol oder Benzylalkohol.In the ß-substituted ocrisocyanacrylic acid esters used Formula 1 are preferably esters of lower alcohols with 1 to 7 carbon atoms, such as ethanol, methanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol or benzyl alcohol.
Dementsprechend bedeutet in den Formeln 1 und 3 R3 bevorzugt einen niederen, gegebenenfalls durch Phenyl substituierten Alkylrest. Die bevorzugten ß-substituierten cC-Isocyanacrylester sind die Äthylester.Accordingly, in formulas 1 and 3, R3 preferably denotes one lower alkyl radical, optionally substituted by phenyl. The preferred ß-substituted cC-isocyanacrylic esters are the ethyl esters.
Die Substituenten R1 und R2 an dem <-Isocyanacrylester, die nach der Umsetzung am Thiazolring gemäß Formel 3 in 5-Stellung wiederzufinden sind, können die verschiedensten über ein Kohlenstoffatom gebundenen Reste bedeuten.The substituents R1 and R2 on the <-Isocyanacrylester, which after the reaction on the thiazole ring according to formula 3 can be found in the 5-position mean the most varied of radicals bonded via a carbon atom.
R1 und R2 können die verschiedensten organischen Reste bedeuten, sie können gleich oder verschieden sein und einer der Substituenten kann ein Wasserstoffatom bedeuten.R1 and R2 can mean a wide variety of organic radicals, they may be the same or different and one of the substituents may be a hydrogen atom mean.
Als Reste für R1 bzw. R2 haben sich gesättigte oder ungesättigte, geradkettige, verzweigte oder cyclische, gegebenenfalls substltuierte Alkylreste mit 1 bis 18 Kohlenstoffatomen, wie ethyl, Äthyl, tert-.-Butyl, Isopropyl, n-Hexyl, Hexadecyl oder Cyclohexyl bewährt.The residues for R1 and R2 have been saturated or unsaturated, straight-chain, branched or cyclic, optionally substituted alkyl radicals with 1 to 18 carbon atoms, such as ethyl, ethyl, tert-butyl, isopropyl, n-hexyl, Hexadecyl or cyclohexyl proven.
R1 und R2 können zusammen mit dem sie verbindenden KohlenslJoffatom einen cycloaliphatischen oder heterocyclischen Ring mit 3 bis 18, bevorzugt 3 bis 8 Gliedern im Ring bedeuten In diesem besonderen Fall werden 5-Spirocycloalkan-4-alkoxycarbonyl-2-thiazoline erhalten, wie die Spirocyclohexan-, Spirocyclopental-, Spirocyclopropan- oder Spiro-oxa- (bzw. -thia- oder -aza-) cycloalkanverbindung.R1 and R2 can together with the carbon dioxide atom connecting them a cycloaliphatic or heterocyclic ring with 3 to 18, preferably 3 to 8 members in the ring mean In this particular case are 5-spirocycloalkane-4-alkoxycarbonyl-2-thiazolines obtained, such as the Spirocyclohexan-, Spirocyclopental-, Spirocyclopropan- or Spiro-oxa- (or -thia- or -aza-) cycloalkane compound.
R1 bzw. R2 können-aromatische carbocyclische oder aromatische heterocyclische Ringe, wie Phenyl, Naphthyl, Furyl, Pyridyl oder Thienyl bedeuten.R1 and R2 can be aromatic carbocyclic or aromatic heterocyclic Rings such as phenyl, naphthyl, furyl, pyridyl or thienyl mean.
R1 bzw. R2 können auch ungesättigte Reste, wie den Styrilrest oder Allyl, Dimethylallyl, Cyclohexenyl bedeuten.R1 and R2 can also be unsaturated radicals, such as the styril radical or Mean allyl, dimethylallyl, cyclohexenyl.
Die für R1 und R2 genannten Reste können noch zusätzlich substituiert sein, beispielsweise durch Reste wie Phenyl, Halogen, insbesondere Fluor, Chlor, Brom, Alkoxy, Alkylthio, Dialkylamino, Alkoxycarbonyl oder Trialkylsilyl.The radicals mentioned for R1 and R2 can also be substituted be, for example by radicals such as phenyl, halogen, especially fluorine, chlorine, Bromine, alkoxy, alkylthio, dialkylamino, alkoxycarbonyl or trialkylsilyl.
Entsprechend den für die Substituenten R1, R2 und R3 genannten Bedeutungen lassen sich nach dem erfindungsgemäßen Verfahren neue in 5-Stellung mono- oder disubstituierte 4-Alkoxyearbonyl-2-thiazoline und bereits bekannte herstellen.Corresponding to the meanings given for the substituents R1, R2 and R3 new ones mono- or disubstituted in the 5-position can be obtained by the process according to the invention 4-Alkoxyearbonyl-2-thiazoline and already known produce.
Als Beispiele für als Ausgangsverbindungen verwendete A-Isocyanacrylsäureester seien genannt: ob o;-Isocyan-ß,ß-dimethylacrylsäureäthylester, CL- Isocyan-cyclohexylidenessigsäureäthylester, oL-Isocyan-ß-tert . -butylacrylsäureäthylester, 46-Isocyanzimtsäureäthylester, α-Isocyan-ß-furyl-acrylsäureäthylester, α-Isocyan-5-phenyl-pentadien-(2,4)-säureäthylester, c«-Isocyanß-methylacrylsäureäthylester, X -Isocyan-ß-methyl-ß-isopropylacrylsäureäthylester, oL-Isocyan-ß-methyl-ß-phenylacrylsäureäthylester.As examples of A-isocyanacrylic acid esters used as starting compounds may be mentioned: whether o; -isocyan-ß, ß-dimethylacrylic acid ethyl ester, CL-isocyano-cyclohexylideneacetic acid ethyl ester, oL-isocyan-ß-tert. -butyl acrylate, ethyl 46-isocyanate, α-isocyan-ß-furyl-acrylate, α-Isocyan-5-phenyl-pentadiene- (2,4)-acid ethyl ester, c «-isocyano-methyl acrylic acid ethyl ester, X -isocyan-ß-methyl-ß-isopropyl acrylic acid ethyl ester, oL-isocyan-ß-methyl-ß-phenyl acrylic acid ethyl ester.
Als Beispiele für die nach dem neuen Verfahren hergestellten 5-substituierten 4-Alkoxycarbonyl-2-thiazoline seien genannt: 4-Äthoxycarbonyl-5,5-dimethyl-2-thiazolin, 4-Äthoxycarbonyl-5-spirocyclohexan-2-thiazolin, 4-Äthoxycarbonyl-5-tert.-butyl-2-thiazolin, 4-Äthoxycarbonyl-5-phenyl-2-thiazolin, 4-Athoxycarbonyl-5-furyl(2)-2-thiazolin, 4-Äthoxycarbonyl-5-styril-2-thiazolin, 4-Äthoxyearbonyl-5-methyl-2-thiazolin, 4-Athoxycarbonyl-5-methyl-5-isopropyl-2-thiazolin, 4-Athoxyearbonyl-5-methyl-5-phenyl-2-thiazolin.As examples of the 5-substituted ones produced by the new process 4-alkoxycarbonyl-2-thiazolines may be mentioned: 4-ethoxycarbonyl-5,5-dimethyl-2-thiazoline, 4-ethoxycarbonyl-5-spirocyclohexane-2-thiazoline, 4-ethoxycarbonyl-5-tert.-butyl-2-thiazoline, 4-ethoxycarbonyl-5-phenyl-2-thiazoline, 4-ethoxycarbonyl-5-furyl (2) -2-thiazoline, 4-ethoxycarbonyl-5-styril-2-thiazoline, 4-ethoxy carbonyl-5-methyl-2-thiazoline, 4-ethoxycarbonyl-5-methyl-5-isopropyl-2-thiazoline, 4-ethoxy carbonyl-5-methyl-5-phenyl-2-thiazoline.
Beispiele 1. 4-Äthoxycarbonyl-5,5-dimethyl-2-thiazolin (R1=R2=CH3): In die Lösung von 6,8 g (44,4 mMol) a-Isocyan-ß,ß-dimethylacrylsäureäthylester und 1,0 g (10 mMol) Triäthylamin, in 10 ml Tetrahydrofuran, leitet man bis zur Sättigung, ca. 1 Stunde lang, Schwefelwasserstoff ein. Die Temperatur hält man unter 400C. Man zieht das Lösungsmittel unter vermindertem Druck ab und erhält bei der Destillation 6,6 g (80 %) 4-Athoxyearbonyl-5,5-dimethyl-2-thiazolin vom Sdp. 1 800. Examples 1. 4-ethoxycarbonyl-5,5-dimethyl-2-thiazoline (R1 = R2 = CH3): In the solution of 6.8 g (44.4 mmol) of α-isocyan-ß, ß-dimethylacrylate and ethyl ester 1.0 g (10 mmol) of triethylamine, in 10 ml of tetrahydrofuran, is passed to saturation, for about 1 hour, apply hydrogen sulfide. The temperature is kept below 400C. The solvent is drawn off under reduced pressure and obtained in the distillation 6.6 g (80%) 4-ethoxyearbonyl-5,5-dimethyl-2-thiazoline with a b.p. 1,800.
2. 4-Athoxyearbonyl-2-thiazolin-5-spirocyclohexan (R1=R2 =-(CH2)5-) In die Lösung von 3,8 g (20 mMol) s -Isocyan-cyclohexylidenessigsäureäthylester und 0,2 g (2 mMol) Pyridin in 10 ml Tetrahydrofuran wird bis zur Sättigung, ca. 1 Stunde lang, Schwefelwasserstoff eingeleitet. Nach der Aufarbeitung gemäß Beispiel 1 erhält man 3,5 g (78 %) 4-Äthoxycarbonyl-2-thiazolin-5-spirocyclohexan vom Sdp.0,1 100-102°.2. 4-Athoxyearbonyl-2-thiazoline-5-spirocyclohexane (R1 = R2 = - (CH2) 5-) Into the solution of 3.8 g (20 mmol) of ethyl isocyanate-cyclohexylideneacetate and 0.2 g (2 mmol) of pyridine in 10 ml of tetrahydrofuran is added to saturation, approx. Hydrogen sulfide was passed in for 1 hour. After working up according to the example 1 gives 3.5 g (78%) of 4-ethoxycarbonyl-2-thiazoline-5-spirocyclohexane with a boiling point of 0.1 100-102 °.
3. 4-Äthoxycarbonyl-5-tert.-butyl-2-thiazolin (R1=H, R2=tertO-Butyl): In die Lösung von 3,6 g (20 mMol) c-Isocyan-ß-tert.-butyl-acrylsäureäthylester und 0,2 g (2 mMol) Triäthylamin in 10 ml Chloroform leitet man 1 Stunde lang Sehwefelwasserstoff ein. Man erhält nach der Aufarbeitung 3,6 g (83 %) trans-und cis-4-Äthoxyearbonyl-5-tert.-butyl-2-thiazolin mit Sdp.0,3 95-98° (Isomerenverhältnis 4:1).3. 4-Ethoxycarbonyl-5-tert-butyl-2-thiazoline (R1 = H, R2 = tert-butyl): In the solution of 3.6 g (20 mmol) of c-isocyan-ß-tert-butyl-acrylic acid ethyl ester and 0.2 g (2 mmol) of triethylamine in 10 ml of chloroform is passed in for 1 hour a. After work-up, 3.6 g (83%) of trans- and cis-4-ethoxy carbonyl-5-tert-butyl-2-thiazoline are obtained with bp 0.3 95-98 ° (isomer ratio 4: 1).
4. 4-Äthoxycarbonyl-5-phenyl-2-thiazolin (R1=H, R2-C6H5): a): In die Lösung von 5,9 g (25 mMol) α-Isocyan-zimtsäureäthylester (trans-Isomeres) und 0,25 g (0,25 mMol) Triäthylamin in 15 ml Chloroform leitet man 45 Minuten lang Schwefelwasserstoff ein. Man zieh das Lösungsmittel unter vermindertem Druck ab, wobei 5,8 g Öl hinterbleiben, das zu 90 % aus trans- und cis-4-Äthoxycarbonyl-5-phenyl-2-thiäzolin (Mengenverhältnis 3:1) besteht. Ausbeute 90 %.4. 4-Ethoxycarbonyl-5-phenyl-2-thiazoline (R1 = H, R2-C6H5): a): In the Solution of 5.9 g (25 mmol) of ethyl α-isocyanate-cinnamate (trans isomer) and 0.25 g (0.25 mmol) of triethylamine in 15 ml of chloroform is passed for 45 minutes Hydrogen sulfide. The solvent is removed under reduced pressure, 5.8 g of oil remaining, 90% of which consists of trans- and cis-4-ethoxycarbonyl-5-phenyl-2-thiazoline (Quantity ratio 3: 1) exists. Yield 90%.
b): Ohne Basenzusatz: Zur Lösung von 0,8 g (4 mMol) -Isocyan-Zimtsäureäthylester in 5 ml Chloroform leitet man bei 200 2 Stunden lang Schwefelwasserstoff ein. Im IR-Spektrum läßt sich 3-Mercapto-2-isocyan-3-phenylpropionsäureäthylester nachweisen. Man fügt dann 0,03 g Triäthylamin zu, rührt 1 Stunde und erhält nach dem Abdampfen des Lösungsmittels und der Aufarbeitung 0,9 g 4-Äthoxycarbonyl-5-phenyl-2-thiazolln, Das nach Versuch a) dargestellte 1:3 cis/trans-Isomerengemisch rührt man zur Aquillibrierung (Epimerisierung) am C-4 1 Stunde mit 5 ml 0,2 n Natriumäthylat in Äthanol. Man zieht das Solvens unter vermindertem Druck ab, versetzt mit 30 ml Äther, filtriert das ausgefallene Natriumäthylat ab, engt ein und erhält 1,1 g 4-Äthoxycarbonyl-5-phenyl-2-thiazolin mit einem' cis/trans-Verhältnis 1:9. b): Without addition of base: For the solution of 0.8 g (4 mmol) ethyl isocyanate cinnamate hydrogen sulfide is passed in at 200 for 2 hours in 5 ml of chloroform. in the The IR spectrum shows ethyl 3-mercapto-2-isocyan-3-phenylpropionate. 0.03 g of triethylamine is then added, the mixture is stirred for 1 hour and obtained after evaporation of the solvent and the work-up 0.9 g of 4-ethoxycarbonyl-5-phenyl-2-thiazolln, The 1: 3 cis / trans isomer mixture shown according to experiment a) is stirred for equilibration (Epimerization) at C-4 for 1 hour with 5 ml of 0.2 N sodium ethylate in ethanol. One draws the solvent is removed under reduced pressure, 30 ml are added Ether, the precipitated sodium ethylate is filtered off, concentrated and 1.1 g of 4-ethoxycarbonyl-5-phenyl-2-thiazoline are obtained with a 'cis / trans ratio 1: 9.
5. 4-Äthoxycarbonyl-5-furyl-2-thiazolin (Rt=H, R2:Furyl-(2)): In die Lösung von 5,7 g (30 mMol) x -Isocyan-ß-furyl-acrylsäureäthylester und 0,3 g (3 mMol) Triäthylamin in 15 ml Chloroform leitet man 45 Min.,bis zur Sättigung> Schwefelwasserstoff ein. Man dampft das Lösungsmittel unter vermindertem Druck ab, wobei 6,8 g Öl hinterbleiben, das zu 50 % aus trans- und cis-4-Äthoxycarbonyl-5-furyl-(2)-2-thiazolin (Isomerengemisch 8:1) besteht. Die Destillation liefert 5,4 g (80 %) mit Sdp.0,1 115-120°.5. 4-Ethoxycarbonyl-5-furyl-2-thiazoline (Rt = H, R2: furyl- (2)): In the Solution of 5.7 g (30 mmol) x -isocyan-ß-furyl-acrylic acid ethyl ester and 0.3 g (3 mmol) triethylamine in 15 ml of chloroform is passed for 45 min., until saturation> Hydrogen sulfide. The solvent is evaporated off under reduced pressure, 6.8 g of oil remaining, 50% of which consists of trans- and cis-4-ethoxycarbonyl-5-furyl- (2) -2-thiazoline (Mixture of isomers 8: 1). The distillation gives 5.4 g (80%) with a boiling point of 0.1 115-120 °.
6. 4-Äthoxycarbonyl-5-styryl-2-thiazolin (R1=H, R²= Styryl): In die Lösung von 4,6 g (20 mMol) « -Isocyan-5-phenylpentadien(2,4)-säureäthylester und 0,2 g (2 mMol) Triäthylamin in 10 ml Chloroform wird 1 Stunde, bis zur Sättigung, Schwefelwasserstoff eingeleitet. Nach dem Verdampfen des Lösungsmittels hinterbleiben 5,2 g Öl, das zu 40 % aus trans-und cis-4-Äthoxyearbonyl-5-styryl-2-thiazolin besteht. (Isomerenverhältnis 5:1). Ausbeute ca. 40 7.6. 4-Ethoxycarbonyl-5-styryl-2-thiazoline (R1 = H, R² = styryl): In the Solution of 4.6 g (20 mmol) of -isocyan-5-phenylpentadiene (2,4) ethyl ester and 0.2 g (2 mmol) of triethylamine in 10 ml of chloroform is added for 1 hour until saturation Hydrogen sulfide initiated. Left behind after evaporation of the solvent 5.2 g of oil, which consists of 40% trans- and cis-4-ethoxy-carbonyl-5-styryl-2-thiazoline. (Isomer ratio 5: 1). Yield approx. 40 7.
Claims (2)
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| DE19722245560 DE2245560A1 (en) | 1972-09-16 | 1972-09-16 | 5-Substd. 4-alkoxycarbonyl-2-thiazolines prepn. - useful as penicillin inters. |
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| DE19722245560 DE2245560A1 (en) | 1972-09-16 | 1972-09-16 | 5-Substd. 4-alkoxycarbonyl-2-thiazolines prepn. - useful as penicillin inters. |
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| EP0033151B1 (en) * | 1980-01-29 | 1984-05-02 | Hoechst Aktiengesellschaft | Hydroxyphenyl-thiazole-thiazoline and -thiazolidine carboxylic acids, process for their preparation and these compounds for use in influencing the collagen metabolism |
| US6521652B1 (en) | 1998-08-31 | 2003-02-18 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
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- 1972-09-16 DE DE19722245560 patent/DE2245560A1/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4457936A (en) * | 1980-01-29 | 1984-07-03 | Hoechst Aktiengesellschaft | Use of hydroxyphenyl-thiazole-, -thiazoline- and -thiazolidine-carboxylic acids, for influencing the collagen metabolism |
| EP0033151B1 (en) * | 1980-01-29 | 1984-05-02 | Hoechst Aktiengesellschaft | Hydroxyphenyl-thiazole-thiazoline and -thiazolidine carboxylic acids, process for their preparation and these compounds for use in influencing the collagen metabolism |
| US8008502B2 (en) | 1998-08-31 | 2011-08-30 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
| US6521652B1 (en) | 1998-08-31 | 2003-02-18 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
| US6525080B1 (en) | 1998-08-31 | 2003-02-25 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
| US6559315B1 (en) | 1998-08-31 | 2003-05-06 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
| USRE39132E1 (en) | 1998-08-31 | 2006-06-13 | University Of Florida, Research Foundation, Inc. | Thiazoline acid derivatives |
| US7126004B2 (en) | 1998-08-31 | 2006-10-24 | University Of Florida Research Foundation, Inc. | Thiazoline acid derivatives |
| US6864270B2 (en) | 1998-09-21 | 2005-03-08 | University Of Florida Research Foundation, Inc. | Iron binding agents |
| US7144904B2 (en) | 1998-09-21 | 2006-12-05 | University Of Florida Research Foundation, Inc. | Iron binding agents |
| US7879886B2 (en) | 1998-09-21 | 2011-02-01 | University Of Florida Research Foundation, Inc. | Iron binding agents |
| US8604216B2 (en) | 2003-09-09 | 2013-12-10 | University Of Florida Research Foundation, Inc. | Desferrithiocin derivatives and methods of use thereof |
| US9567309B2 (en) | 2005-04-04 | 2017-02-14 | University Of Florida Research Foundation, Inc. | Desferrithiocin polyether analogues |
| US8278458B2 (en) | 2005-04-04 | 2012-10-02 | University Of Florida Research Foundation, Inc. | Desferrithiocin polyether analogues |
| US8722899B2 (en) | 2005-04-04 | 2014-05-13 | University Of Florida Research Foundation, Inc. | Desferrithiocin polyether analogues |
| US9096553B2 (en) | 2005-04-04 | 2015-08-04 | University Of Florida Research Foundation, Incorporated | Desferrithiocin polyether analogues |
| US9994535B2 (en) | 2005-04-04 | 2018-06-12 | University Of Florida Foundation, Inc. | Desferrithiocin polyether analogues |
| US8324397B2 (en) | 2007-03-15 | 2012-12-04 | University Of Florida Research Foundation, Inc. | Desferrithiocin polyether analogues |
| US9730917B2 (en) | 2007-03-15 | 2017-08-15 | University Of Florida Research Foundation, Incorporated | Desferrithiocin polyether analogues |
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| US11931346B2 (en) | 2011-12-16 | 2024-03-19 | University Of Florida Research Foundation, Incorporated | Uses of 4′-desferrithiocin analogs |
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| US10570104B2 (en) | 2015-04-27 | 2020-02-25 | University Of Florida Research Foundation, Incorporated | Metabolically programmed metal chelators and uses thereof |
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