DE2611965A1 - (1,3,4)-Thiadiazole-(5)-thiols prodn. - by solvolysis of corresp. S-(thio)acyl derivs. or their thione tautomers, useful as intermediates for pharmaceuticals - Google Patents
(1,3,4)-Thiadiazole-(5)-thiols prodn. - by solvolysis of corresp. S-(thio)acyl derivs. or their thione tautomers, useful as intermediates for pharmaceuticalsInfo
- Publication number
- DE2611965A1 DE2611965A1 DE19762611965 DE2611965A DE2611965A1 DE 2611965 A1 DE2611965 A1 DE 2611965A1 DE 19762611965 DE19762611965 DE 19762611965 DE 2611965 A DE2611965 A DE 2611965A DE 2611965 A1 DE2611965 A1 DE 2611965A1
- Authority
- DE
- Germany
- Prior art keywords
- thiadiazole
- methyl
- thiols
- thione
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003814 drug Substances 0.000 title abstract description 3
- 125000002252 acyl group Chemical group 0.000 title abstract 2
- 239000000543 intermediate Substances 0.000 title abstract 2
- 241001061127 Thione Species 0.000 title description 3
- 238000003797 solvolysis reaction Methods 0.000 title 1
- JLAMDELLBBZOOX-UHFFFAOYSA-N 3h-1,3,4-thiadiazole-2-thione Chemical class SC1=NN=CS1 JLAMDELLBBZOOX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- -1 2-Methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione Chemical compound 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 abstract description 2
- 229960001139 cefazolin Drugs 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HMPUHXCGUHDVBI-UHFFFAOYSA-N 5-methyl-1,3,4-thiadiazol-2-amine Chemical compound CC1=NN=C(N)S1 HMPUHXCGUHDVBI-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- ZLHNYIHIHQEHJQ-UHFFFAOYSA-N N,N'-Diacetylhydrazine Chemical compound CC(=O)NNC(C)=O ZLHNYIHIHQEHJQ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YNNGZCVDIREDDK-UHFFFAOYSA-N aminocarbamodithioic acid Chemical compound NNC(S)=S YNNGZCVDIREDDK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SDFNVWYUGIJOLH-UHFFFAOYSA-N 1-(2-sulfanylidene-1,3,4-thiadiazol-3-yl)ethanone Chemical compound C(C)(=O)N1N=CSC1=S SDFNVWYUGIJOLH-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- SSVHMUZCBKRAPS-UHFFFAOYSA-N 5-(2-methylpropyl)-3h-1,3,4-thiadiazole-2-thione Chemical compound CC(C)CC1=NNC(=S)S1 SSVHMUZCBKRAPS-UHFFFAOYSA-N 0.000 description 1
- KKZAOQAHLBXTLJ-UHFFFAOYSA-N 5-benzyl-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(=S)NN=C1CC1=CC=CC=C1 KKZAOQAHLBXTLJ-UHFFFAOYSA-N 0.000 description 1
- UFSCJPPXRHCNLK-UHFFFAOYSA-N 5-ethyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CCC1=NN=C(S)S1 UFSCJPPXRHCNLK-UHFFFAOYSA-N 0.000 description 1
- ZTLMHGOWADYAHM-UHFFFAOYSA-N 5-phenyl-3h-1,3,4-thiadiazole-2-thione Chemical compound S1C(S)=NN=C1C1=CC=CC=C1 ZTLMHGOWADYAHM-UHFFFAOYSA-N 0.000 description 1
- CJMUOXLDOLNLKB-UHFFFAOYSA-N 5-propan-2-yl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC(C)C1=NNC(=S)S1 CJMUOXLDOLNLKB-UHFFFAOYSA-N 0.000 description 1
- PYVUFGZVZNBZRY-UHFFFAOYSA-N 5-propyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CCCC1=NNC(=S)S1 PYVUFGZVZNBZRY-UHFFFAOYSA-N 0.000 description 1
- BZCMLWMNUAGHHQ-UHFFFAOYSA-N 5-tert-butyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC(C)(C)C1=NN=C(S)S1 BZCMLWMNUAGHHQ-UHFFFAOYSA-N 0.000 description 1
- RCVFWLRRRNQJDX-UHFFFAOYSA-N C(C)(=O)N1N=C(SC1=S)C1=CC=CC=C1 Chemical compound C(C)(=O)N1N=C(SC1=S)C1=CC=CC=C1 RCVFWLRRRNQJDX-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KZXIQMSWVSTGQX-UHFFFAOYSA-N SC1=CN=NS1 Chemical class SC1=CN=NS1 KZXIQMSWVSTGQX-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LTEGRAHWBCMCQX-UHFFFAOYSA-N s-(5-methyl-1,3,4-thiadiazol-2-yl) ethanethioate Chemical compound CC(=O)SC1=NN=C(C)S1 LTEGRAHWBCMCQX-UHFFFAOYSA-N 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Description
Verfahren zur Herstellung von 1,3,4- Process for the production of 1,3,4-
Thiadiazol-5-thiolen Die Erfindung betrifft ein Verfahren zur Herstellung von 1,3,4-Thiadiazol-5-thiolen der allgemeinen Formel I worin R1 Wasserstoff, Alkyl mit 1 - 4 C-Atomen, Aralkyl mit 7 - 8 C-Atomen oder Aryl mit 6 - 7 C-Atomen bedeutet.Thiadiazole-5-thiols The invention relates to a process for the preparation of 1,3,4-thiadiazole-5-thiols of the general formula I. where R1 is hydrogen, alkyl with 1-4 carbon atoms, aralkyl with 7-8 carbon atoms or aryl with 6-7 carbon atoms.
Die Herstellung dieser Verbindungen ist zum Teil an sich bekannt, z.B. aus den deutschen Offenlegungsschriften 21 62 324 und 23 43 825. Danach kann man in 2-Stellung substituierte 1,3,4-Thiadiazol-5-thiole erhalten, indem man ein Salz der Dithiocarbazinsäure (H2N-NH-CS-SH) mit einem entsprechenden Orthoester, Iminoäther, Thiosäureester oder Thioamid umsetzt oder indem man ein Salz einer Dithiocarbazinsäure der allgemeinen Formel R1-CO-NH-NH-CS-SH (III), in der R1 H oder niederes Alkyl bedeutet, mit einer Säure zur Umsetzung bringt.The production of these compounds is partly known per se, e.g. from German Offenlegungsschrift 21 62 324 and 23 43 825. Thereafter, 1,3,4-thiadiazole-5-thiols substituted in the 2-position are obtained by a Salt of dithiocarbazic acid (H2N-NH-CS-SH) with a corresponding orthoester, Imino ether, thioic acid ester or thioamide, or by adding a salt of a dithiocarbazic acid of the general formula R1-CO-NH-NH-CS-SH (III), in which R1 is H or lower alkyl means reacting with an acid.
Die bekannten Verfahren haben verschiedene Nachteile.The known methods have various disadvantages.
So lassen teilweise die Ausbeuten zu wünschen übrig, teilweise ist die Qualität der erhaltenen Produkte unbefriedigend.So in some cases the yields leave something to be desired, in some cases it is the quality of the products obtained is unsatisfactory.
Der Erfindung lag die Aufgabe zugrunde, eine neues Verfahren zur Herstellung der Verbindungen der Formel I aufzufinden, daß diese Nachteile nicht oder nur in geringerem Maße besitzt. Diese Aufgabe wurde durch die Bereitstellung des nachstehend beschriebenen Verfahrens gelöst.The invention was based on the object of a new method for production of the compounds of formula I to find that these disadvantages are not or only in to a lesser extent. This task was accomplished by providing the below described method solved.
Es wurde gefunden, daß 1,3,4,-Thiadiazol-5-thiole der Formel I leicht, in hohen Ausbeuten und hervorragender Reinheit erhalten werden können, indem man funktionelle Derivate derselben solvolysiert, insbesondere entsprechende S-Acyl- oder S-Thiæcylderivate sowie die N-Acyl- oder N-Thioacylderivate der tautomeren 2-R1 -4, 5-Dihydro-1 3,4-thiadiazol-5-thione. Bevorzugte funktionelle Derivate entsprechen der allgemeinen Formel II X 0 oder S und R2 H, Alkyl oder Alkoxy mit jeweils 1 - 4 C-Atomen oder Aryl oder Aryloxy mit jeweils 6 - 10 C-Atomen bedeutet und R1 die oben angegebene Bedeutung hat.It has been found that 1,3,4-thiadiazole-5-thiols of the formula I can be obtained easily, in high yields and in excellent purity, by solvolyzing functional derivatives thereof, in particular corresponding S-acyl or S-thiacyl derivatives as well the N-acyl or N-thioacyl derivatives of the tautomeric 2-R1 -4, 5-dihydro-1 3,4-thiadiazole-5-thiones. Preferred functional derivatives correspond to the general formula II X denotes 0 or S and R2 denotes H, alkyl or alkoxy each with 1-4 carbon atoms or aryl or aryloxy each with 6-10 carbon atoms and R1 has the meaning given above.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung der 1,3,4-Thiadiazol-5-thiole der Formel I, dadurch gekennzeichnet, daß man eine Verbindung der Formel II mit einem solvolysierenden Mittel behandelt.The invention relates to a process for the preparation of 1,3,4-thiadiazole-5-thiols of formula I, characterized in that a compound of formula II with treated with a solvolyzing agent.
In den Formeln I und II bedeutet der Rest R1 vorzugsweise eine Methylgruppe.In the formulas I and II, the radical R1 preferably denotes a methyl group.
Die Bedeutung des Restes R2 ist nicht kritisch, da er unter den Bedingungen der erfindungsgemäßen Umsetzung abgespalten wird. So kann dieser Rest beispielsweise bedeuten: Methyl, Äthyl, Propyl, Isopropyl, n-Butyl, Isobutyl, sek.-Butyl, tert.-Butyl, Methoxy, Äthoxy, Propyloxy, Isopropyloxy, n-Butoxy, Isobutoxy, sek.-Butoxy, tert.-Butoxy, Phenyl, o-, m- oder p-Tolyl, 1- oder 2-Naphtyloxy.The meaning of the residue R2 is not critical, since it is under the conditions the reaction according to the invention is split off. So this rest can for example mean: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Methoxy, ethoxy, propyloxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, Phenyl, o-, m- or p-tolyl, 1- or 2-naphtyloxy.
Die Aryl- und Aryloxygruppen können auch Substituenten enthalten, beispielsweise ein oder mehrere Halogenatome wie F, Cl, Br; Hydroxygruppen; Alkoxygruppen, z.B.The aryl and aryloxy groups can also contain substituents, for example one or more halogen atoms such as F, Cl, Br; Hydroxyl groups; Alkoxy groups, e.g.
Methoxygruppen. Aus Gründen der Wirtschaftlichkeit sind unter den Resten R2 die niederen unsubsituierten bevorzugt, z.B. Methyl, Äthyl, Methoxy, Äthoxy, Phenyl oder Phenoxy. Vor allen anderen Resten R2 ist Methyl bevorzugt.Methoxy groups. For reasons of economy are among the R2 radicals are the lower unsubstituted ones, e.g. methyl, ethyl, methoxy, ethoxy, Phenyl or phenoxy. Methyl is preferred over all other R2 radicals.
Die Ausgangsstoffe der Formel II sind neu. Sie sind nach an sich bekannten Verfahren erhältlich, beispielsweise durch Diazotierung der entsprechenden 2-R1-5-Amino-1,3,4-thiadiazole und anschließende Reaktion mit Salzen der Formel M-CX-R2 (worin M ein Aquivalent eines Metalles, vorzugsweise Kalium oder Natrium bedeutet). Die Ausgangsstoffe der Formel II können auch hergestellt werden durch Umsetzung von. Hydrazinderivaten der Formel R1-CO-NH-NH-CX-R2 (worin R , R2 und X die angegebene Bedeutung haben, vorzugsweise jedoch X = 0 und R2 = R1 ist) mit Schwefelkohlen- stoff. Bei diesen Synthesen entstehen in der Regel die beiden tautomeren Formen der Verbindungen II nebeneinander. In der Regel ist die N-substituierte Thionform die stabilere; das S-substituierte Thiolderivat läßt sich in der Regel durch Erwärmen in die Thionform umlagern.The starting materials of the formula II are new. They are known per se Processes obtainable, for example by diazotization of the corresponding 2-R1-5-amino-1,3,4-thiadiazoles and subsequent reaction with salts of the formula M-CX-R2 (where M is an equivalent of a metal, preferably potassium or sodium). The starting materials of the Formula II can also be prepared by reacting. Hydrazine derivatives of the formula R1-CO-NH-NH-CX-R2 (in which R, R2 and X have the meaning given, but preferably X = 0 and R2 = R1) with carbon disulfide material. These syntheses usually give rise to the two tautomeric forms of the compounds II side by side. As a rule, the N-substituted thione form is the more stable; the S-substituted thiol derivative can usually be converted into the thione form by heating rearrange.
Als solvolysieende Mittel eignen sich in erster Linie hydrolysierende Mittel, vorzugsweise starke Säuren wie Salzsäure oder Schwefelsäure oder starke Basen wie Natrium- oder Kaliumhydroxid.Hydrolyzing agents are primarily suitable as solvolyzing agents Medium, preferably strong acids such as hydrochloric acid or sulfuric acid or strong Bases such as sodium or potassium hydroxide.
Die erfindungsgemäße Umsetzung kann in Gegenwart oder Abwesenheit eines inerten Lösungsmittels durchgeführt werden. Als Lösungsmittel sind Wasser und Alkohole wie Methanol, Äthanol, Isopropanol bevorzugt. Beispiele für weitere verwendbare Lösungsmittel sind Glykole und Glykoläther wie Methylglykol, Diglyme; Amide wie Dimethylformamid; Sulfoxide wie Dimethylsulfoxid; Sulfolan; Äther wie Tetrahydrofuran oder Dioxan; auch Gemische der genannten Lösungsmittel untereinander, besonders die Gemische mit Wasser. Die Reaktionstemperatur ist nicht kritisch; vorzugsweise wird die Reaktion bei Temperaturen zwischen Oo und dem Siedepunkt des verwendeten Lösungsmittels, insbesondere zwischen etwa 10 und etwa 1000 vorgenommen.The reaction according to the invention can be carried out in the presence or absence an inert solvent can be carried out. The solvent is water and alcohols such as methanol, ethanol, isopropanol are preferred. Examples of more Usable solvents are glycols and glycol ethers such as methyl glycol, diglyme; Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Sulfolane; Ether like Tetrahydrofuran or dioxane; also mixtures of the solvents mentioned with one another, especially the mixtures with water. The reaction temperature is not critical; preferably the reaction is used at temperatures between Oo and the boiling point of the Solvent, in particular between about 10 and about 1000 made.
Die erhaltenen Verbindungen der Formel I, insbesondere das bevorzugte 2-Methyl-1,3,4-thiadiazol-5-thiol sind wertvolle Zwischenprodukte zur Herstellung von Arzneimitteln wie Cefazolin. Ihre Umsetzung zu solchen Antibiotica kann nach literaturbekannten Verfahren erfolgen.The compounds of formula I obtained, especially the preferred one 2-Methyl-1,3,4-thiadiazole-5-thiol are valuable intermediate products for the production of drugs such as cefazolin. Their implementation on such antibiotics can after methods known from the literature take place.
Beispiel 1 Man löst 1 g 2-Methyl-5-acetylmercapto-1,3,4-thiadiazol (F. 68 - 700) oder 2-Methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion (F. 43 - 450; beide Ausgangs stoffe sind nebeneinander erhältlich durch Diazotierung von 2-Methyl-5-amino-1,3,4-thiadiazol und Reaktion des erhaltenen Diazoniumsalzes mit Kalium-thioacetat oder durch Umsetzung von 1,2-Diacetylhydrazin mit CS2) in 10 ml Methanol, versetzt mit einer Lösung von 0,23 g KOH in 10 ml Methanol und läßt 16 Stunden bei 200 unter Stickstoff stehen. Die Lösung wird eingedampft und mit Wasser behandelt. Man filtriert das erhaltene 2-Methyl-1,3,4-thiadiazol-5-thiol ab, wäscht mit Wasser und trocknet unter vermindertem Druck bei 500. F. 182 - 1840.Example 1 1 g of 2-methyl-5-acetylmercapto-1,3,4-thiadiazole is dissolved (F. 68-700) or 2-methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione (F. 43 - 450; Both starting materials are available side by side by diazotization of 2-methyl-5-amino-1,3,4-thiadiazole and reaction of the diazonium salt obtained with Potassium thioacetate or by reacting 1,2-diacetylhydrazine with CS2) in 10 ml Methanol, mixed with a solution of 0.23 g of KOH in 10 ml of methanol and leaves 16 Stand under nitrogen at 200 hours. The solution is evaporated and made up with water treated. The 2-methyl-1,3,4-thiadiazole-5-thiol obtained is filtered off and washed with water and dry under reduced pressure at 500. F. 182 - 1840.
Änalog erhält man aus 5-Acetylmercapto-1,3,4-thiadiazol oder 4-Acetyl-4,5-dihydro-1 ,3,4-thiadiazol-5-thion 2-Äthyl-5-acetylmercapto-1 , 3, 4-thiadiazol oder 2-Athyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion 2-n-Propyl-5-acetylmercapto-1 , 3, 4-thiadiazol oder 2-n-Propyl-4-acetyl-4, 5-dihydro-1,3,4-thiadiazol-5-thior 2-Isopropyl-5-acetylmercapto-1 , 3, 4-thiadiazol oder 2-Isopropyl-4-acetyl-4,5-dihydro-1 ,3,4-thiadiazol-5-thion 2-Isobutyl-5-acetylmercapto-1 , 3,4-thiadiazol oder 2-Isobutyl-4-acetyl-4,5-dihydro-1 ,3,4-thiadiazol-5-thion 2-tert.-Butyl-5-acetylmercapto-1 , 3,4-thiadiazol oder 2-tert.-Butyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion 2-Phenyl-5-acetylmercapto-1 , 3, 4-thiadiazol oder 2-Phenyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5 -thion 2-Benzyl-5-acetylmercapto-1,3,4-thiadiazol oder 2-Benzyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion: 1,3,4-Thiadiazol-5-thiol, F. 1430 2-Äthyl-1,3,4-thiadiazol-5-thiol, F. 76° 2-n-Propyl-1,3,4-thiadiazol-5-thiol, F. 50 - 51° 2-Isopropyl-1,3,4-thiadiazol-5-thiol, F. 43 - 450 2-Isobutyl-1,3,4-thiadiazol-5-thiol, F. 58 - 600 2-tert.-Butyl-1,3,4-thiadiazol-5-thiol, F. 119 - 1200 2-Phenyl-1,3,4-thiadiazol-5-thiol, F. 210 - 2120 2-Benzyl-1,3,4-thiadiazol-5-thiol, F. 116 - 1170.In a similar way, one obtains from 5-acetylmercapto-1,3,4-thiadiazole or 4-acetyl-4,5-dihydro-1 , 3,4-thiadiazole-5-thione, 2-ethyl-5-acetylmercapto-1, 3, 4-thiadiazole or 2-ethyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5- thion 2-n-propyl-5-acetylmercapto-1,3,4-thiadiazole or 2-n-propyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thior 2-isopropyl-5-acetylmercapto-1, 3, 4-thiadiazole or 2-isopropyl-4-acetyl-4,5-dihydro-1 , 3,4-thiadiazole-5-thione, 2-isobutyl-5-acetylmercapto-1, 3,4-thiadiazole or 2-isobutyl-4-acetyl-4,5-dihydro-1 , 3,4-thiadiazole-5-thione, 2-tert-butyl-5-acetylmercapto-1, 3,4-thiadiazole or 2-tert-butyl-4-acetyl-4,5-dihydro-1,3, 4-thiadiazole-5-thione 2-phenyl-5-acetylmercapto-1 , 3, 4-thiadiazole or 2-phenyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione, 2-benzyl-5-acetylmercapto-1,3,4-thiadiazole or 2-benzyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione: 1,3,4-thiadiazole-5-thiol, F. 1430 2-ethyl-1,3,4-thiadiazole-5-thiol, M.p. 76 ° 2-n-propyl-1,3,4-thiadiazole-5-thiol, F. 50 - 51 ° 2-isopropyl-1,3,4-thiadiazole-5-thiol, mp 43-450 2-isobutyl-1,3,4-thiadiazole-5-thiol, F. 58 - 600 2-tert-butyl-1,3,4-thiadiazole-5-thiol, F. 119 - 1200 2-phenyl-1,3,4-thiadiazole-5-thiol, M.p. 210-2120 2-Benzyl-1,3,4-thiadiazole-5-thiol, M.p. 116-1170.
Beispiel 2 Eine Lösung von 1 g 2-Methyl-5-acetylmercaptol,3,4-thiadiazol (oder 1 g 2-Methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion) und 0,6 ml konzentrierter Salzsäure in 20 ml Methanol wird unter Stickstoff 24 Stunden bei 200 stehengelassen. Man arbeitet analog Beispiel 1 auf und erhält 2-Methyl-1,3,4-thiadiazol-5-thiol, F. 182 - 1840.Example 2 A solution of 1 g of 2-methyl-5-acetylmercaptol, 3,4-thiadiazole (or 1 g of 2-methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione) and 0.6 ml more concentrated Hydrochloric acid in 20 ml of methanol is left to stand at 200 for 24 hours under nitrogen. The procedure is analogous to Example 1 and 2-methyl-1,3,4-thiadiazole-5-thiol is obtained, F. 182 - 1840.
Beispiel 3 Man löst 5 g 2-Methyl-5-amino-1,3,4-thiadiazol in 30 ml konzentrierter Salzsäure, kühlt auf 00 und versetzt innerhalb 90 Minuten unter Rühren mit einer Lösung von 6,9 g Natriumnitrit in 30 ml Wasser bei 0 bis 50 Nach weiterem einstündigem Rühren wird die Suspension in eine 700 warme Lösung von 13,9 g Kalium-thioacetat und 11,6 g Natriumcarbonat in 70 ml Wasser gegossen und eine Stunde bei 700 weitergerührt. Die dabei entstehenden isomeren Acetylderivate, 2-Methyl-5-acetyl-mercapto-1 3, 4-thiadiazol und 2-Methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazol-5-thion, werden nicht isoliert. Man versetzt mit einer Lösung von 16 g NaOH in 80 ml Wasser und rührt eine weitere Stunde bei 700. Die Lösung wird abgekühlt, filtriert, das Filtrat angesäuert und mit Methylenchlorid extrahiert. Man wäscht den Extrakt, trocknet, dampft ein und erhält 2-Methyl-1,3,4-thiadiazol-5-thiol, F. 182 - 184°.Example 3 5 g of 2-methyl-5-amino-1,3,4-thiadiazole are dissolved in 30 ml concentrated hydrochloric acid, cool to 00 and added within 90 minutes with stirring with a solution of 6.9 g of sodium nitrite in 30 ml of water at 0 to 50 after further The suspension is stirred for one hour in a warm solution of 13.9 g of potassium thioacetate and poured 11.6 g of sodium carbonate into 70 ml of water and stirred at 700 for one hour. The resulting isomeric acetyl derivatives, 2-methyl-5-acetyl-mercapto-1 3, 4-thiadiazole and 2-methyl-4-acetyl-4,5-dihydro-1,3,4-thiadiazole-5-thione not isolated. A solution of 16 g of NaOH in 80 ml of water is added stir for a further hour at 700. The solution is cooled, filtered, the filtrate acidified and extracted with methylene chloride. The extract is washed, dried, evaporates and receives 2-methyl-1,3,4-thiadiazole-5-thiol, mp 182-184 °.
Beispiel 4 Man diazotiert 11,5 g 2-Methyl-5-amino-1,3,4-thiadiazol analog Beispiel 3 und gibt die erhaltene Suspension des Diazoniumsalzes vorsichtig unter Rühren in eine 700 warme Lösung von 16 g Kaliumxanthogenat und 11,6 g Natriumcarbonat in 70 ml Wasser. Dabei entsteht 2-Methyl-5-äthoxythiocarbonylmercapto-13,4-thiadiazol neben 2-Methyl-4-äthoxythiocarbonyl-4,5-dihydro-1,3,4-thiadiazol-5-thion; diese Substanzen werden nicht isoliert.Example 4 11.5 g of 2-methyl-5-amino-1,3,4-thiadiazole are diazotized analogously to Example 3 and carefully gives the suspension of the diazonium salt obtained with stirring in a 700 warm solution of 16 g of potassium xanthate and 11.6 g of sodium carbonate in 70 ml of water. This produces 2-methyl-5-ethoxythiocarbonylmercapto-13,4-thiadiazole besides 2-methyl-4-ethoxythiocarbonyl-4,5-dihydro-1,3,4-thiadiazole-5-thione; these Substances are not isolated.
Man rührt eine Stunde bei 700, trägt unter Stickstoff eine Lösung von 16 g NaOH in 80 ml Wasser ein und rührt noch eine Stunde bei 700. Die Lösung wird abgekühlt, filtriert und das Filtrat analog Beispiel 3 aufgearbeitet. Man erhält 2-Methyl-1,3,4-thiadiazol-5-thiol, F. 182 - 1840 Beispiel 5 Eine Lösung von 1 g 2-Methyl-5-phenoxythiocarbonylmercapto-1,3,4-thiadiazol (F. 98 - 990) oder 2-Methyl-4-phenoxy-thiocarbonyl-4,5-dihydro-1,3,4-thiadiazol-5-thion; (F. 79 - 800; beide Ausgangsstoffe sind nebeneinander erhältlich durch Diazotierung von 2-Methyl-5-amino-l ,3,4-thiadiazol und Reaktion des erhaltenen Diazoniumsalzes mit Kaliumdithiokohlensäure-O-phenylester) und 0,7 ml konzentrierter Salzsäure in 16 ml Methanol wird eine Stunde gekocht. Man kühlt ab, arbeitet analog Beispiel 1 auf und erhält 2-Methyl-1,3,4-thiadiazol-5-thiol, F. 182 - 1840.The mixture is stirred for one hour at 700, a solution is carried under nitrogen of 16 g of NaOH in 80 ml of water and stir for another hour at 700. The solution it is cooled and filtered, and the filtrate is worked up as in Example 3. You get 2-methyl-1,3,4-thiadiazole-5-thiol, m.p. 182-1840 Example 5 One Solution of 1 g of 2-methyl-5-phenoxythiocarbonylmercapto-1,3,4-thiadiazole (F. 98 - 990) or 2-methyl-4-phenoxy-thiocarbonyl-4,5-dihydro-1,3,4-thiadiazole-5-thione; (F. 79 - 800; both starting materials can be obtained side by side by diazotization of 2-methyl-5-amino-l, 3,4-thiadiazole and reaction of the diazonium salt obtained with potassium dithiocarbonic acid-O-phenyl ester) and 0.7 ml of concentrated hydrochloric acid in 16 ml of methanol is boiled for one hour. One cools down, works analogously to the example 1 and receives 2-methyl-1,3,4-thiadiazole-5-thiol, m.p. 182 - 1840.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762611965 DE2611965A1 (en) | 1976-03-20 | 1976-03-20 | (1,3,4)-Thiadiazole-(5)-thiols prodn. - by solvolysis of corresp. S-(thio)acyl derivs. or their thione tautomers, useful as intermediates for pharmaceuticals |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762611965 DE2611965A1 (en) | 1976-03-20 | 1976-03-20 | (1,3,4)-Thiadiazole-(5)-thiols prodn. - by solvolysis of corresp. S-(thio)acyl derivs. or their thione tautomers, useful as intermediates for pharmaceuticals |
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| DE2611965A1 true DE2611965A1 (en) | 1977-09-29 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5155122A (en) * | 1988-11-29 | 1992-10-13 | Warner-Lambert Company | 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxy-phenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents |
| US5376670A (en) * | 1988-11-29 | 1994-12-27 | Warner-Lambert Company | 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents |
| WO2010073011A2 (en) | 2008-12-23 | 2010-07-01 | Betagenon Ab | Compounds useful as medicaments |
-
1976
- 1976-03-20 DE DE19762611965 patent/DE2611965A1/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5155122A (en) * | 1988-11-29 | 1992-10-13 | Warner-Lambert Company | 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxy-phenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents |
| US5376670A (en) * | 1988-11-29 | 1994-12-27 | Warner-Lambert Company | 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxyphenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents |
| WO2010073011A2 (en) | 2008-12-23 | 2010-07-01 | Betagenon Ab | Compounds useful as medicaments |
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