NO122432B - - Google Patents
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- Publication number
- NO122432B NO122432B NO271568A NO271568A NO122432B NO 122432 B NO122432 B NO 122432B NO 271568 A NO271568 A NO 271568A NO 271568 A NO271568 A NO 271568A NO 122432 B NO122432 B NO 122432B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- atoms
- methylthiophene
- acid
- hydrochloride
- Prior art date
Links
- -1 thiophene isonitriles Chemical class 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- DKGYESBFCGKOJC-UHFFFAOYSA-N thiophen-3-amine Chemical class NC=1C=CSC=1 DKGYESBFCGKOJC-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000009835 boiling Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000006114 decarboxylation reaction Methods 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- CQSJDKGNONPQOQ-UHFFFAOYSA-N 3-aminothiophene-2-carboxylic acid Chemical class NC=1C=CSC=1C(O)=O CQSJDKGNONPQOQ-UHFFFAOYSA-N 0.000 description 5
- HFOFPDGUBCVRIQ-UHFFFAOYSA-N 4-methylthiophen-3-amine Chemical compound CC1=CSC=C1N HFOFPDGUBCVRIQ-UHFFFAOYSA-N 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- GLQWRXYOTXRDNH-UHFFFAOYSA-N thiophen-2-amine Chemical class NC1=CC=CS1 GLQWRXYOTXRDNH-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VFNUTUQTELVMGI-UHFFFAOYSA-N N-[3-(diethylamino)-4-methylthiophen-2-yl]acetamide Chemical compound C(C)N(C1=C(SC=C1C)NC(C)=O)CC VFNUTUQTELVMGI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000003589 local anesthetic agent Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229960004194 lidocaine Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- RTZFKQORWVHODG-UHFFFAOYSA-N 2-[butyl(phenylmethoxycarbonyl)amino]acetic acid Chemical compound CCCCN(CC(O)=O)C(=O)OCC1=CC=CC=C1 RTZFKQORWVHODG-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N 7-chloro-3',4,6-trimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Chemical compound COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- POHGVLJVCVHDRH-UHFFFAOYSA-N N-[3-(butylamino)-4-methylthiophen-2-yl]acetamide Chemical compound C(CCC)NC1=C(SC=C1C)NC(C)=O POHGVLJVCVHDRH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- YICRPERKKBDRSP-UHFFFAOYSA-N methyl 3-amino-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(C)C=1N YICRPERKKBDRSP-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- BNRUONNHGBBDEG-UHFFFAOYSA-N (E)-N-(4-methylthiophen-3-yl)but-2-enamide Chemical compound C(C=CC)(=O)NC1=CSC=C1C BNRUONNHGBBDEG-UHFFFAOYSA-N 0.000 description 1
- RJUIDDKTATZJFE-NSCUHMNNSA-N (e)-but-2-enoyl chloride Chemical compound C\C=C\C(Cl)=O RJUIDDKTATZJFE-NSCUHMNNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DOPROHTZKDRGFX-UHFFFAOYSA-N 2,3-dihydrothiophen-2-amine Chemical class NC1CC=CS1 DOPROHTZKDRGFX-UHFFFAOYSA-N 0.000 description 1
- NKYZMZNNAWWQCF-UHFFFAOYSA-N 2,4-dimethylthiophen-3-amine Chemical compound CC1=CSC(C)=C1N NKYZMZNNAWWQCF-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- RRWZZMHRVSMLCT-UHFFFAOYSA-N 2-(butylazaniumyl)acetate Chemical compound CCCCNCC(O)=O RRWZZMHRVSMLCT-UHFFFAOYSA-N 0.000 description 1
- OQMYZVWIXPPDDE-UHFFFAOYSA-N 2-(cyclohexylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCCC1 OQMYZVWIXPPDDE-UHFFFAOYSA-N 0.000 description 1
- BITBVQPNBZYTBL-UHFFFAOYSA-N 2-(diethylamino)acetyl chloride;hydrochloride Chemical compound Cl.CCN(CC)CC(Cl)=O BITBVQPNBZYTBL-UHFFFAOYSA-N 0.000 description 1
- PRSWALMQXKFZFA-UHFFFAOYSA-N 2-(piperidin-1-ylamino)acetic acid Chemical compound OC(=O)CNN1CCCCC1 PRSWALMQXKFZFA-UHFFFAOYSA-N 0.000 description 1
- BHUGZIJOVAVBOQ-UHFFFAOYSA-N 2-(propylazaniumyl)acetate Chemical compound CCCNCC(O)=O BHUGZIJOVAVBOQ-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ARJAWSKDSA-M 2-Methyl-2-butenoic acid Natural products C\C=C(\C)C([O-])=O UIERETOOQGIECD-ARJAWSKDSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical class CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- FIMCOWPZXBVBIB-UHFFFAOYSA-N 2-chloro-N-(4-methylthiophen-3-yl)acetamide Chemical compound ClCC(=O)NC1=CSC=C1C FIMCOWPZXBVBIB-UHFFFAOYSA-N 0.000 description 1
- XBLYPENZTYSJMR-UHFFFAOYSA-N 2-chloro-n-(2,4-dimethylthiophen-3-yl)acetamide Chemical compound CC1=CSC(C)=C1NC(=O)CCl XBLYPENZTYSJMR-UHFFFAOYSA-N 0.000 description 1
- YWUMLYIEKOMXCF-UHFFFAOYSA-N 2-chloro-n-thiophen-3-ylacetamide Chemical compound ClCC(=O)NC=1C=CSC=1 YWUMLYIEKOMXCF-UHFFFAOYSA-N 0.000 description 1
- KXCUFSHZVJKKQN-UHFFFAOYSA-N 3-[[2-(butylamino)acetyl]amino]-4-methylthiophene-2-carboxylic acid Chemical compound C(CCC)NCC(=O)NC1=C(SC=C1C)C(=O)O KXCUFSHZVJKKQN-UHFFFAOYSA-N 0.000 description 1
- AKXYKVHNZQCHMF-UHFFFAOYSA-N 3-amino-4-methylthiophene-2-carboxylic acid Chemical compound CC1=CSC(C(O)=O)=C1N AKXYKVHNZQCHMF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CNDKEPQJHLNOTH-UHFFFAOYSA-N C(CCC)NC1=C(SC=C1)NC(C)=O Chemical compound C(CCC)NC1=C(SC=C1)NC(C)=O CNDKEPQJHLNOTH-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical class NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 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
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 108010061951 Methemoglobin Proteins 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
- YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000158147 Sator Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical class CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RTHZEWLREYQGED-UHFFFAOYSA-N ethyl 3-[(2-chloroacetyl)amino]-4-methylthiophene-2-carboxylate Chemical compound ClCC(=O)NC1=C(SC=C1C)C(=O)OCC RTHZEWLREYQGED-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- LDHQCZJRKDOVOX-IHWYPQMZSA-N isocrotonic acid Chemical group C\C=C/C(O)=O LDHQCZJRKDOVOX-IHWYPQMZSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- YUVKYHLYLVTJEN-UHFFFAOYSA-N methyl 3-[(2-chloroacetyl)amino]-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(C)C=1NC(=O)CCl YUVKYHLYLVTJEN-UHFFFAOYSA-N 0.000 description 1
- PWSUQEJRFKOGJV-UHFFFAOYSA-N methyl 3-formamido-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC=C(C)C=1NC=O PWSUQEJRFKOGJV-UHFFFAOYSA-N 0.000 description 1
- FFBGJTDOWCDBAY-UHFFFAOYSA-N methyl 3-isocyano-4-methylthiophene-2-carboxylate Chemical compound [N+](#[C-])C1=C(SC=C1C)C(=O)OC FFBGJTDOWCDBAY-UHFFFAOYSA-N 0.000 description 1
- XLFOHJYHWRZPSJ-UHFFFAOYSA-N methyl 4-[(2-chloroacetyl)amino]-3,5-dimethylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C)=C(NC(=O)CCl)C=1C XLFOHJYHWRZPSJ-UHFFFAOYSA-N 0.000 description 1
- XGRGVSLMGRDGLN-UHFFFAOYSA-N methyl 4-[(2-chloroacetyl)amino]-5-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(C)=C1NC(=O)CCl XGRGVSLMGRDGLN-UHFFFAOYSA-N 0.000 description 1
- KUUQEVITZAPQJB-UHFFFAOYSA-N methyl 4-[[2-(diethylamino)acetyl]amino]-3-methyl-2,3-dihydrothiophene-5-carboxylate Chemical compound CCN(CC)CC(=O)NC1=C(C(=O)OC)SCC1C KUUQEVITZAPQJB-UHFFFAOYSA-N 0.000 description 1
- GWIZXJHXFRMSQV-UHFFFAOYSA-N methyl 4-amino-3,5-dimethylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C)=C(N)C=1C GWIZXJHXFRMSQV-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003497 sciatic nerve Anatomy 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical class OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000000051 wattle Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Analogifremgangsmåte til fremstilling av terapeutisk virksomme, substituerte 3-aminoacylamino-tiofener. Analogous process for the preparation of therapeutically active, substituted 3-aminoacylamino-thiophenes.
Oppfinnelsens gjenstand er analogifremgangsmåter til fremstilling av substituerte 3-aminoacylamino-tiofener med den generelle formel The object of the invention is analogous methods for the preparation of substituted 3-aminoacylamino-thiophenes with the general formula
og syreaddisjonssalter derav, and acid addition salts thereof,
hvori R1 betyr hydrogen, en rettlinjet eller forgrenet alkylrest med 1-6 C-atomer, en cykloalkylrest med 5-6 C-atomer og en alkenylrest med 2-4 C-atomer, wherein R1 means hydrogen, a straight or branched alkyl radical of 1-6 C atoms, a cycloalkyl radical of 5-6 C atoms and an alkenyl radical of 2-4 C atoms,
Kfr. kl. 12p-l/01, 12p-2 Cf. at 12p-l/01, 12p-2
R2 betyr en rettlinjet eller forgrenet alkylrest med 1-6 C-atomer, R2 means a linear or branched alkyl residue with 1-6 C atoms,
en cykloalkylrest med 5~6 C-atomer eller en alkenylrest med 2-4 C-atomer, a cycloalkyl radical with 5~6 C atoms or an alkenyl radical with 2-4 C atoms,
eller R-^ og R ? danner sammen med N-atomet en piperidin- eller pyrrolidinrest, or R-^ and R ? forms together with the N atom a piperidine or pyrrolidine residue,
R-j, Rjj og R^ betyr hver hydrogen, en alkylrest med 1-4 C-atomer eller en karbalkoksygruppe, der alkoksygruppen inneholder l-4 C-atomer, R-j, Rjj and R^ each mean hydrogen, an alkyl radical with 1-4 C atoms or a carbolicoxy group, where the alkoxy group contains 1-4 C atoms,
A betyr en rettlinjet eller forgrenet alkylengruppe med 1-4 karbon-at omer. A means a linear or branched alkylene group with 1-4 carbon atoms.
Fremgangsmåten er karakterisert ved at man enten The procedure is characterized by either
a) omsetter 3-acylaminotiofener med formel a) reacts 3-acylaminothiophenes with formula
hvori X betyr halogen, f.eks. klor, brom eller jod, eller en alkoksy-, wherein X means halogen, e.g. chlorine, bromine or iodine, or an alkoxy-,
aralkoksy- resp. aryloksygruppe, med en forbindelse med formel aralkyl resp. aryloxy group, with a compound of formula
eller or
b) omsetter 3-aminotiofener med den generelle formel b) reacts 3-aminothiophenes with the general formula
resp. deres salter eller Grignardforbindelser med en karboksylsyre respectively their salts or Grignard compounds with a carboxylic acid
med formel with formula
hvori Rg betyr resten R1 eller en estergruppe, resp. et reaksjonsdyktig derivat herav, og deretter forsåper en eventuelt i sluttproduktet tilstedeværende estergruppe Rg, eller c) dehydrogenerer 3-amino-4,5- resp. -2,5-dihydrotiofener med formel in which Rg means the residue R1 or an ester group, resp. a reactive derivative thereof, and then saponifies an ester group Rg possibly present in the final product, or c) dehydrogenates 3-amino-4,5-resp. -2,5-dihydrothiophenes of formula
eller or
d) i 3-aminoacylaminotiofener med formel d) in 3-aminoacylaminothiophenes of formula
Innfører alkyl-, alkenyl- eller cykloalkylgruppen(e) R2Introduces the alkyl, alkenyl or cycloalkyl group(s) R2
og eventuelt eller and possibly or
e) til umettede acylaminotiofener med formel e) to unsaturated acylaminothiophenes of formula
hvori A' betyr en rettlinjet eller forgrenet alkenylrest med 2-4 in which A' means a straight or branched alkenyl radical with 2-4
karbonatomerj tilleirer forbindelser med formel carbon atom adds compounds with formula
eller or
f) omsetter tiofen-isonitriler med formel f) reacts thiophene isonitriles with formula
med forbindelser med formel og mettede, alifatiske aldehyder med 1-4 karbonatomer, hvoretter man eventuelt i ^3"» R4- og/eller R^-stilling forsåper tilstedeværende karbalkoksygrupper og dekarboksylerer og/eller eventuelt overfører de dannede forbindelser med syrer i farmasøytisk tålbare salter, idet i formlene II-IX R^-R^ og A har samme betydning som i formel I. a) De ved fremgangsmåten ifølge variant a) anvendte 3-halogenacylaminotiofener med formel II inneholder fortrinnsvis klor with compounds of the formula and saturated, aliphatic aldehydes with 1-4 carbon atoms, after which, optionally, in the ^3"» R4 and/or R^ position, carbolic oxy groups present are saponified and decarboxylated and/or optionally transferred with acids into pharmaceutically acceptable salts, in that in formulas II-IX R^-R^ and A have the same meaning as in formula I. a) The 3-halogenacylaminothiophenes of formula II used in the method according to variant a) preferably contain chlorine
eller brom i acylresten. Por omsetningen med 3-halogenacylaminotiofenene kommer det f.eks. på tale følgende forbindelser med formel III: alkylaminer, som metylamin, etylamin, n-propylamin, isopropylamin, n-butylamin, isobutylamin, sek.-butylamin, tert.-butylamin, alkenylaminer som allylamin, cykloalkylaminer som cyklo-heksylamin, og dialkylaminer som dietylamin og di-n- or bromine in the acyl residue. Through the reaction with the 3-halogenacylaminothiophenes, e.g. in question the following compounds of formula III: alkylamines, such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, alkenylamines such as allylamine, cycloalkylamines such as cyclohexylamine, and dialkylamines such as diethylamine and di-n-
butylamin, videre piperidin og pyrrolidin. Omset- butylamine, further piperidine and pyrrolidine. Turnover-
ningen av halogenacylaminotiofenene med aminene kan såvel gjennom-føres i nærvær som i fravær av oppløsningsmidler. Som oppløsnings-midler kommer det i betraktning: etere, dioksan, alkoholer som f.eks. metanol, etanol, propanol, mettede cykliske hydrokarboner som cykloheksan og metylcykloheksan, aromatiske hydrokarboner som benzen, toluen, xylen og klorerte hydrokarboner som klorbenzen, kloroform og tetraklormetan, eller karbontetraklorid. Reaksjonstemperaturene ligger mellom værelsetemperatur og det angjeldende oppløsningsmiddels kokepunkt. Ved omsetningen kan det eventuelt også anvendes trykk. For å nøytralisere den ved omsetningen dannede syre, arbeider man fortrinnsvis i et overskudd av det anvendte amin og anvender minst to deler amin på en del 3-halogenacylaminotiofen. Reaksjonsvarigheten The reaction of the haloacylaminothiophenes with the amines can be carried out both in the presence and in the absence of solvents. As solvents, the following come into consideration: ethers, dioxane, alcohols such as e.g. methanol, ethanol, propanol, saturated cyclic hydrocarbons such as cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene and chlorinated hydrocarbons such as chlorobenzene, chloroform and tetrachloromethane, or carbon tetrachloride. The reaction temperatures lie between room temperature and the boiling point of the solvent in question. Pressure may also be used during turnover. In order to neutralize the acid formed during the reaction, one preferably works in an excess of the amine used and uses at least two parts of amine to one part of 3-halogenacylaminothiophene. The reaction duration
utgjør, alt etter reaksjonstemperaturen, ca. 4-12 timer. For rensing utløses det som biprodukt dannede aminhydrohalogenid med vann, opp-løsningsmidlet og overskutende amin avdestilleres og det gjenblivende fremgangsmåteprodukt destilleres eller renses ved oppløsning i mineralsyre og utfelling med fortynnet natronlut. amounts, depending on the reaction temperature, to approx. 4-12 hours. For purification, the amine hydrohalide formed as a by-product is precipitated with water, the solvent and excess amine are distilled off and the remaining process product is distilled or purified by dissolution in mineral acid and precipitation with dilute caustic soda.
For fremstilling av de som utgangsstoffer anvendte halogenacylaminotiofener går man frem på i og for seg kjent måte. Eksempelvis omsetter man aminotiofener resp. aminotiofenkarbonsyreestere med halogenacylhalogenider og forsåper eventuelt de dannede produkter. Aminotiofenene og aminotiofenkarbonsyreestrene får man likeledes på i og for seg kjent måte, førstnevnte ved forsåpning og dekarboksylering av aminotiofenkarbonsyreestere, sistnevnte eksempelvis ved fremgangsmåten med omsetning av a,3-dihalogennitriler eller 2-acylamino-l,3_diketoner med tioglykolsyreestere i nærvær av alkaliske kondensasjonsmidler. Anvender man som utgangsstoffer amino-tiof en som i 4-stilling har en karbalkoksyrest, så kan man få disse tilsvarende metoden av Cheney og Piening "Journal of the American Chemical Society", bind 67, side 729, 731 (1945), fra de tilsvarende For the preparation of the halogenoacylaminothiophenes used as starting materials, one proceeds in a manner known per se. For example, aminothiophenes are converted resp. aminothiophene carboxylic acid esters with halogen acyl halides and optionally saponify the products formed. The aminothiophenes and the aminothiophene carboxylic acid esters are likewise obtained in a manner known per se, the former by saponification and decarboxylation of aminothiophene carboxylic acid esters, the latter for example by the process involving the reaction of α,3-dihalogenitriles or 2-acylamino-1,3-diketones with thioglycolic acid esters in the presence of alkaline condensing agents. If one uses as starting materials amino-thiophene which in the 4-position has a carbaloxy residue, one can obtain these corresponding methods by Cheney and Piening "Journal of the American Chemical Society", volume 67, pages 729, 731 (1945), from the equivalent
tiophanon-(3)-karbonsyreestere og hydroksylarain. thiophanone-(3)-carboxylic acid esters and hydroxylarain.
Istedenfor halogenacylaminotiofener kan man også gå ut fra alkoksy-, aralkoksy- eller aryloksyacylaminotiofener. Eksempelvis anvender man metoksy-, etoksy-, benzyloksy- eller fenoksy-substituerte acylaminotiofener. Man får dem f.eks. ved omsetning av aminotiofener resp. aminotiofenkarboksylsyreestere med alkoksy-, aralkoksy- eller aryloksy-karboksylsyrer og klormaursyreestere etter metoden for blandede anhydrider. Instead of haloacylaminothiophenes, one can also start from alkoxy, aralkyl or aryloxyacylaminothiophenes. For example, methoxy-, ethoxy-, benzyloxy- or phenoxy-substituted acylaminothiophenes are used. You get them e.g. by conversion of aminothiophenes resp. aminothiophene carboxylic acid esters with alkoxy, aralkyl or aryloxy carboxylic acids and chloroformic acid esters by the method of mixed anhydrides.
b) Man får fremgangsmåteproduktene også ifølge variant b) idet man omsetter 3-aminotiofenet med formel IV med en karboksylsyre b) The process products are also obtained according to variant b) by reacting the 3-aminothiophene of formula IV with a carboxylic acid
med formel V, eller fortrinnsvis et reaksjonsdyktig derivat av en slik syre. Som karboksylsyrer skal det eksempelvis nevnes: metylamino-eddiksyre, etylaminoeddiksyre, n-propylaminoeddiksyre, sek. butylaminoeddiksyre, cykloheksylaminoeddiksyre, dietylaminoeddiksyre og piperidylaminoeddiksyre. Istedenfor de nevnte aminoeddiksyrer lar det seg også anvende de tilsvarende substituerte a- og g-amino-propionsyrer, de forskjellige isomere aminosmørsyrer og aminovalerian-syrer. Som reaksjonsdyktige derivater av aminokarboksylsyrer kommer det f.eks. i betraktning syreklorider, syreestere, syreamider, syre-azider og syreanhydrider. Istedenfor 3-aminotiofener kan man også anvende deres salter, f.eks. alkali- eller jordalkalisalter eller Grignard-forbindelser (halogen-magnesiumforbindelser). Omsetningen gjennomføres hensiktsmessig i inerte oppløsningsmidler, eksempelvis i eter, benzen, toluen eller xylen. of formula V, or preferably a reactive derivative of such an acid. Examples of carboxylic acids include: methylaminoacetic acid, ethylaminoacetic acid, n-propylaminoacetic acid, sec. butylaminoacetic acid, cyclohexylaminoacetic acid, diethylaminoacetic acid and piperidylaminoacetic acid. Instead of the mentioned aminoacetic acids, it is also possible to use the correspondingly substituted α- and g-aminopropionic acids, the various isomeric aminobutyric acids and aminovaleric acids. As reactive derivatives of aminocarboxylic acids, there are e.g. considering acid chlorides, acid esters, acid amides, acid azides and acid anhydrides. Instead of 3-aminothiophenes, one can also use their salts, e.g. alkali or alkaline earth salts or Grignard compounds (halogen-magnesium compounds). The reaction is conveniently carried out in inert solvents, for example in ether, benzene, toluene or xylene.
I forbindelsene med formel VIII betyr Rg en esterrest slik den anvendes i peptid-kjemien generelt til beskyttelse av amino-grupper. Som eksempler skal nevnes: karbobenzoksy-, merkaptokarbonyl-, tosyl-, trifluoracetyl-, tert.butyloksykarbonyl-, og o-nitrofenyl-sulfenylresten. Avspaltningen foregår likeledes etter de i peptid-kjemien vanlige metoder, eksempelvis med natrium i flytende ammoniakk eller med bromhydrogen i iseddik. I mange tilfeller foregår spalt-ningen allerede med fortynnet saltsyre ved henstand. På denne måte fåes forbindelser hvori R1 betyr hydrogen. In the compounds of formula VIII, Rg means an ester residue as it is used in peptide chemistry in general to protect amino groups. Examples include: carbobenzoxy, mercaptocarbonyl, tosyl, trifluoroacetyl, tert.butyloxycarbonyl, and o-nitrophenyl-sulfenyl. The cleavage also takes place according to the usual methods in peptide chemistry, for example with sodium in liquid ammonia or with hydrogen bromide in glacial acetic acid. In many cases, the cleavage already takes place with diluted hydrochloric acid when allowed to stand. In this way, compounds are obtained in which R1 means hydrogen.
c) Dehydrogeneringen av utgangsstoffene med formlene Via og VIb gjennomføres på i og for seg kjent måte med vanlige de-hydreringsmidler. Som spesielt godt egnet dehydreringsmiddel har det vist seg kloranil. Derved anvendes som oppløsningsmiddel et aromatisk hydrokarbon som f.eks. toluen, xylen eller mesitylen, og oppvarmes fortrinnsvis 5-15 timer til kokning. Ved anvendelse av brom som dehydrogeneringsmiddel arbeider man hensiktsmessig under avkjøling, fortrinnsvis ved -10 til +10°C. Som oppløsningsmiddel anvender man da fortrinnsvis halogenerte hydrokarboner som f.eks. metylenklorid, kloroform, tetraklormetan. En katalyse av halogen-hydrogenspaltningen med basiske stoffer er ikke nødvendig. De som utgangsstoffer anvendte 3-(subst.amino)-acylamino-2,5- resp. -4,5-dihydrotiofener får man analogt de tilsvarende tiofener (sammenlign variant a)) under anvendelse av tilsvarende substituerte aminodi-hydrotiofener. Sistnevnte lar seg fremstille av tilsvarende substituerte tiofanoner ved innføring av ammoniakkgass eller ved oppvarmning med ammoniumacetat. c) The dehydrogenation of the starting materials with the formulas Via and VIb is carried out in a manner known per se, using common dehydrating agents. Chloranil has proven to be a particularly suitable dehydrating agent. An aromatic hydrocarbon such as e.g. toluene, xylene or mesitylene, and is preferably heated for 5-15 hours until boiling. When using bromine as a dehydrogenating agent, it is appropriate to work under cooling, preferably at -10 to +10°C. Halogenated hydrocarbons such as e.g. methylene chloride, chloroform, tetrachloromethane. A catalysis of the halogen-hydrogen splitting with basic substances is not necessary. They used 3-(subst.amino)-acylamino-2,5- or -4,5-dihydrothiophenes are obtained analogously to the corresponding thiophenes (compare variant a)) using correspondingly substituted aminodihydrothiophenes. The latter can be prepared from correspondingly substituted thiophanones by introducing ammonia gas or by heating with ammonium acetate.
d) Alkyleringen av utgangsstoffene med formel VII foregår etter kjente metoder f.eks. med aldehyder eller ketoner i nærvær av d) The alkylation of the starting materials with formula VII takes place according to known methods, e.g. with aldehydes or ketones in the presence of
reduksjonsmidler, som f.eks. maursyre. Som alkyleringsmidler lar det seg også anvende mineralsyreestere som f.eks. alkylhalogenider, svovel-syre- eller -fosforsyreestere. Arylsulfonsyreestere egner seg likeledes. Utgangsstoffene med formel VII er tilgjengelige ved hjelp av den under a) omtalte generelle fremgangsmåte til fremstilling av aminoacylaminotiofener. reducing agents, such as e.g. formic acid. As alkylating agents, it is also possible to use mineral acid esters such as e.g. alkyl halides, sulfuric acid or phosphoric acid esters. Aryl sulfonic acid esters are also suitable. The starting substances with formula VII are available by means of the general method for the preparation of aminoacylaminothiophenes mentioned under a).
e) Man kan gjennomføre fremgangsmåten også således at man omsetter acylaminotiofener resp. acylaminotiofenkarbonsyreestere som e) The method can also be carried out in such a way that acylaminothiophenes are converted resp. acylaminothiophene carboxylic acid esters which
i acylkjeden inneholder en dobbeltbinding med et tilsvarende substi-tuert primært eller sekundært amin. Som acylrester som inneholder dobbeltbindinger, kommer det f.eks. på tale: akrylsyre-, metakrylsyre-, tiglinsyre- og isokrotonsyrerester. in the acyl chain contains a double bond with a correspondingly substituted primary or secondary amine. As acyl residues containing double bonds, there are e.g. in question: acrylic acid, methacrylic acid, tiglic acid and isocrotonic acid residues.
Omsetningen med aminene kan såvel foregå ved værelsetemperatur som også ved høyere temperatur, med eller uten anvendelse av trykk og/eller oppløsningsmidler. Derved arbeides det for det meste med et aminoverskudd, fortrinnsvis anvender man ca. 3 mol pr. mol acylderivat. Fremstillingen av utgangsstoffene med formel IX foregår eksempelvis ved omsetning av de umettede syreklorider med aminotiofen resp. aminotiofenkarboksylsyreestere. Ved fremgangsmåten ifølge variant e) får man imidlertid ingen a-aminoacylaminotiofener. f) Fremstillingen av tiofen-isonitriler med formel X foregår etter i og for seg kjente metoder (Neuere Methoden der Pråp. org. Chemie, Bd. IV, side 43 og følgende) ved omsetning av de tilsvarende formylaminotiofener med vannavspaltende midler. Omsetningen med aldehyd og amin til fremgangsmåteproduktene gjennomføres ved værelsetemperatur i vandig/organisk mediumj ved tilsetning av syre innstilles pH-verdien på ca. 5-8. Reaksjonstiden ligger mellom få minutter og 100 timer. Ved anvendelse av primære aminer arbeides hensiktsmessig med et overskudd. The reaction with the amines can take place at room temperature as well as at a higher temperature, with or without the use of pressure and/or solvents. Thereby, work is mostly done with an excess of amine, preferably approx. 3 moles per moles of acyl derivative. The production of the starting substances with formula IX takes place, for example, by reacting the unsaturated acid chlorides with the aminothiophene or aminothiofencarboxylic acid esters. In the method according to variant e), however, no α-aminoacylaminothiophenes are obtained. f) The production of thiophene isonitriles of formula X takes place according to methods known per se (Neuere Methoden der Pråp. org. Chemie, Vol. IV, page 43 et seq.) by reacting the corresponding formylaminothiophenes with water-splitting agents. The reaction with aldehyde and amine to the process products is carried out at room temperature in an aqueous/organic medium, and by adding acid the pH value is set to approx. 5-8. The reaction time is between a few minutes and 100 hours. When using primary amines, it is appropriate to work with an excess.
Inneholder de etter metodene a) - d) fremstilte frem-gangsmåt eprodukter dessuten karbalkoksygrupper i Rj-j Ri|- og/eller Rj--stilling, så kan man fjerne disse hvis ønsket ved forsåpning og dekarboksylering. Porsåpningen gjennomføres på i og for seg kjent måte med alkali- eller jordalkali-hydroksyder. Derved kan det såvel arbeides ved værelsetemperatur som også ved forhøyet temperatur. Dekarboksyleringen foregår f.eks. ved oppvarmning med egnede organiske baser, eksempelvis chinolin eller dietylanilin i nærvær av kobberpulver, fortrinnsvis like under den organiske bases kokepunkt. If the products produced according to the methods a) - d) also contain carbolic oxy groups in the Rj-j Ri|- and/or Rj- position, then these can be removed if desired by saponification and decarboxylation. The pore opening is carried out in a manner known per se with alkali or alkaline earth hydroxides. This means that work can be carried out both at room temperature and at elevated temperatures. The decarboxylation takes place e.g. by heating with suitable organic bases, for example quinoline or diethylaniline in the presence of copper powder, preferably just below the boiling point of the organic base.
De ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelser er godt vannoppløselige i form av deres salter. For salt-dannelse kommer det på tale organiske og uorganiske syrer, eksempelvis eddiksyre, melkesyre, maleinsyre, sitronsyre, vinsyre, acetursyre, amidosulfonsyre, oksyetansulfonsyre, fosforsyre, klorhydrogen- og bromhydrogensyre. The compounds produced by the method according to the invention are highly water-soluble in the form of their salts. Salt formation includes organic and inorganic acids, for example acetic acid, lactic acid, maleic acid, citric acid, tartaric acid, aceturic acid, amidosulphonic acid, oxyethanesulphonic acid, phosphoric acid, hydrochloric acid and hydrobromic acid.
Saltene krystalliserer godt og er meget bestandige. Deres vandige oppløsninger er godt holdbare, kan uten videre steri-liseres og frembringer ingen vevirritasjon. Forbindelsene er såvel i fri form som i form av deres salter verdifulle terapeutika med interessante farmakologiske egenskaper. På grunn av deres virknings-styrke og deres lille toksisitet er de fremfor alt egnet som lokalanestetika. The salts crystallize well and are very stable. Their aqueous solutions are stable, can be easily sterilized and do not cause tissue irritation. The compounds, both in free form and in the form of their salts, are valuable therapeutics with interesting pharmacological properties. Because of their potency and their low toxicity, they are above all suitable as local anaesthetics.
Toksisiteten av forbindelsene fremstilt ifølge oppfinnelsen ligger i størrelsesorden som de tidligere kjente og generelt som infiltrasjons- og ledelsesanestetika benyttede forbindelser. De frembringer på grunn av deres kjemiske konstitusjon imidlertid i mindre grad fare for en allergisering enn de tidligere anvendte benzo-syre- eller anilinderivater. Faren for en gruppesensibilisering overfor sulfonamider og andre tilsvarende konstituerte forbindelser er således vesentlig mindre. The toxicity of the compounds produced according to the invention is in the same order of magnitude as the compounds previously known and generally used as infiltration and management anesthetics. Due to their chemical constitution, however, they pose a lesser risk of allergy than the previously used benzoic acid or aniline derivatives. The risk of group sensitization to sulfonamides and other similarly constituted compounds is thus significantly less.
Den lokale tålbarhet av forbindelsene av formel I tilsvarer denne for procain, det tidligere 'lokalt mest tålbare lokal-anestetikum. Dette ble bekreftet såvel ved undersøkelse av overflate-anestesi på kaninøye ifølge Regnier som også etter intrakutan injeksjon på kaninøre og i intrakutan kvaddelforsøk på mennesker (underarm) i selvforsøk. Derved ble det også prøvet å fastslå kompatibiliteten med vasokonstringenter og andre nødvendige tilsetninger som stabili- The local tolerability of the compounds of formula I is similar to that of procaine, previously the most tolerable local anesthetic. This was confirmed both by examination of surface anesthesia on a rabbit's eye according to Regnier and also after intracutaneous injection on a rabbit's ear and in an intracutaneous quill test on humans (forearm) in a self-experiment. In doing so, an attempt was also made to determine the compatibility with vasoconstrictors and other necessary additives such as stabilizers.
satorer. sators.
Varigheten av den infiltrasjonsanestetiske virkning av produktene fremstilt ifølge oppfinnelsen ble prøvet på marsvinkvaddel, modifisert ifølge E. Biilbring og J. Wajda (J. Pharmacol., London 85, 78 (1945)). Derved viste de nye stoffer seg likeverdige eller over-legne overfor de vanlige handelsprodukter. The duration of the infiltration anesthetic action of the products prepared according to the invention was tested on guinea pig's wattle, modified according to E. Biilbring and J. Wajda (J. Pharmacol., London 85, 78 (1945)). Thereby, the new substances proved to be equivalent or superior to the usual commercial products.
Undersøkelsen av den ledningsanestetiske virkning fore-gikk på frilagt Nervus ischiaticus på frosk ifølge Ther (NAUNYN-SCHMIEDERBERG's Arch., Exper. Path und Pharmakol. 220, 300 (1953)). Mens det ved 2-klor-6-metyl-N-butylaminoacetanilid-hydroklorid ved tilsvarende konsentrasjon (0,25^-ig) viser 80-100$ og ved forbindelsene av formel. I likeledes 80-100$ av frosker-ischiaticusnerven etter 1 minutt en fullstendig ledningsanestesi, er dette ved lidocain (0,25$-ig) f.eks. bare tilfelle ved kO- 60%. Følgende tabell viser videre at stoffene av formel I er virksomme lengere enn handels-produktet 2-klor-6-metyl-N-butylaminoacetanilidhydroklorid som har en virkningstid = 1. The examination of the conduction anesthetic effect took place on exposed Nervus ischiaticus in frog according to Ther (NAUNYN-SCHMIEDERBERG's Arch., Exper. Path und Pharmakol. 220, 300 (1953)). While with 2-chloro-6-methyl-N-butylaminoacetanilide hydrochloride at a corresponding concentration (0.25 µg) it shows 80-100$ and with the compounds of formula. In the same way 80-100$ of the frog sciatic nerve after 1 minute a complete cord anaesthesia, this is with lidocaine (0.25$-ig) e.g. only the case at kO- 60%. The following table also shows that the substances of formula I are effective longer than the commercial product 2-chloro-6-methyl-N-butylaminoacetanilide hydrochloride, which has a duration of action = 1.
Tabell. Table.
(3-n-propylamino-a-propionylamino-2-karbometoksy-4-metyltiofen) = 1,2 (3_n-butylamino-acetylamino-4-metyl-tiofen) = 1,2 (3-dietylamino-g-propionylamino-2-karbometoksy-4-metyl-tiofen) = 1,6 (3-n-propylamino-a-propionylamino-2-carbomethoxy-4-methylthiophene) = 1.2 (3_n-butylamino-acetylamino-4-methyl-thiophene) = 1.2 (3-diethylamino-g-propionylamino-2 -carbomethoxy-4-methyl-thiophene) = 1.6
Toksisiteten ved intravenøs permanent infusjon av forbindelsene (infusjonshastighet 1 ml/min.) ble undersøkt ved forskjellige konsentrasjoner pr. kg på kaniner for å fastslå utskillelses-hastigheten (eliminasjon). Mens lidocain bare tåles inntil en konsentrasjon på 0,5 mg/kg pr. minutt over 2 timers infusjon, er dette ved forbindelsene av formel I tilfelle inntil 2 mg/kg pr. minutt. Forbindelsene av formel I har altså en bedre av-giftningsevne enn lidocain. The toxicity by permanent intravenous infusion of the compounds (infusion rate 1 ml/min.) was investigated at different concentrations per kg on rabbits to determine the excretion rate (elimination). While lidocaine is only tolerated up to a concentration of 0.5 mg/kg per minute over a 2 hour infusion, this is for the compounds of formula In the case of up to 2 mg/kg per minute. The compounds of formula I thus have a better detoxification capacity than lidocaine.
Endelig viser de nye lokalanestetika på katt ingen methemoglobindannelse. Finally, the new local anesthetics on cats show no methemoglobin formation.
Stoffene fremstilt ifølge oppfinnelsen er egnet til fremstilling av farmasøytiske tilberedninger med lokalanestetisk virkning. Hensiktsmessig anvender man stoffene da i form av iso-toniske oppløsninger. Slike oppløsninger er, uten at det inntrer spaltning, steriliserbare etter de vanlige metoder og er egnet til injeksjon resp. infiltrasjon. Oppløsningene kan inneholde vasokon-striktoriske tilsetninger, som f.eks. adrenalin eller noradrenalin. Oppløsningenes konsentrasjon med hensyn til de lokalanestetisk virksomme stoffer av formel I kan utgjøre mellom 0,1 og 5%-Eksempel 1. The substances produced according to the invention are suitable for the production of pharmaceutical preparations with local anesthetic effect. Appropriately, the substances are then used in the form of isotonic solutions. Such solutions are, without cleavage occurring, sterilizable using the usual methods and are suitable for injection or infiltration. The solutions may contain vasocon-strictor additives, such as e.g. adrenaline or norepinephrine. The concentration of the solutions with regard to the local anesthetic active substances of formula I can amount to between 0.1 and 5%-Example 1.
3- n- butylamino- acetylamino- 2- karbometoksy- 4- metyltiofen. 3- n- butylamino- acetylamino- 2- carbomethoxy- 4- methylthiophene.
24,7 g 3-kloracetylamino-2-karbometoksy-4-metyltiofen (fremstilt av 3-amino-2-karbometoksy-4-metyltiofen (smp. 84-85°C) og kloracetylklorid, smp. ll8°C (fra metanol)), oppløses i 200 ml toluen. Deretter tilsetter man 22 g n-butylamin og oppvarmer til kokning i 6-7 timer. Etter avkjøling utvaskes med vann det dannede butylaminhydroklorid, toluenfasen tørkes med natriumsulfat og deretter avdestilleres oppløsningsmidlet og overskytende butyramin. 24.7 g of 3-chloroacetylamino-2-carbomethoxy-4-methylthiophene (prepared from 3-amino-2-carbomethoxy-4-methylthiophene (m.p. 84-85°C) and chloroacetyl chloride, m.p. 118°C (from methanol) ), dissolve in 200 ml of toluene. 22 g of n-butylamine are then added and heated to boiling for 6-7 hours. After cooling, the formed butylamine hydrochloride is washed out with water, the toluene phase is dried with sodium sulphate and then the solvent and excess butyramine are distilled off.
Det oljeaktige residuum opptas i eter. Ved innføring av hydrogenkloridgass eller ved metanolisk saltsyre får man 3-n-butylamino-acetylamino-2- karbometoksy-4-metyltiofen-hydroklorid, utbytte 92$. Por rensing omkrystalliseres stoffet fra vann og smelter ved 154-156°C. The oily residue is taken up in ether. By introducing hydrogen chloride gas or by methanolic hydrochloric acid, 3-n-butylamino-acetylamino-2-carbomethoxy-4-methylthiophene hydrochloride is obtained, yield 92$. Por cleaning, the substance is recrystallized from water and melts at 154-156°C.
På analog måte får man under anvendelse av tilsvarende aminer: In an analogous way, using corresponding amines, one obtains:
3- dietylairiinoacetylamino-2-karbometoksy-4-metyltiof en-hydroklorid, 3-diethylairinoacetylamino-2-carbomethoxy-4-methylthiophene hydrochloride,
smp. 157-158°C, m.p. 157-158°C,
3-piperidino-acetylamino-2-karbometoksy-4-metyltiofen, smp. 110- 3-piperidino-acetylamino-2-carbomethoxy-4-methylthiophene, m.p. 110-
111°C (hydroklorid, smp. 188°C), 111°C (hydrochloride, m.p. 188°C),
3-pyrrolidino-acetylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 182-183°C, 3-pyrrolidino-acetylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 182-183°C,
3-isopropylamino-acetylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 93-99°C, 3-isopropylamino-acetylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 93-99°C,
av 3-kloracetylamino-4-karbometoksy-2-metyltiofen, of 3-chloroacetylamino-4-carbomethoxy-2-methylthiophene,
smp. 137-138°C, får man: m.p. 137-138°C, you get:
3-n-butylamino-acetylamino-4-karbometoksy-2-metyltiofen-hydroklorid som krystalliserer ved omkrystallisering fra vann og 1 mol krystall-vann, smp. l42-l43°C, 3-dietylamino-acetylamino-4-karbometoksy-2-metyltiofen-hydroklorid, smp. 163-164°C, av 3-kloracetylamino-5-karbometoksy-2,4-dimetyltiofen, smp. 142-143°C, får man: 3-n-butylamino-acetylamino-5-karbometoksy-2,4-dimetyltiofen-hydroklorid, smp. 234°C (under spaltning), 3-dietylamino-acetylamino-5-karbometoksy-2,4-dimetyltiofen-hydroklorid, smp. 112-ll4°C, av 3-c-klorpropionylamino-2-karbometoksy-4-metyltiofen, smp. 99-101°C, får man: 3-n-propylamino-a-propionylamino-2-karbometoksy-<i>Hmetyltiofen-hydroklorid, smp. 177-178°C, (basens kokepunkt: l62-l67°C/0,3 mm), 3-n-butylamino-a-propionylamino-2-karbometoksy-il-metyltiofen-hydroklorid, smp. 178-l80°C, 3-n-butylamino-acetylamino-4-carbomethoxy-2-methylthiophene hydrochloride which crystallizes by recrystallization from water and 1 mol of crystal water, m.p. 142-143°C, 3-diethylamino-acetylamino-4-carbomethoxy-2-methylthiophene hydrochloride, m.p. 163-164°C, of 3-chloroacetylamino-5-carbomethoxy-2,4-dimethylthiophene, m.p. 142-143°C, you get: 3-n-butylamino-acetylamino-5-carbomethoxy-2,4-dimethylthiophene hydrochloride, m.p. 234°C (under decomposition), 3-diethylamino-acetylamino-5-carbomethoxy-2,4-dimethylthiophene hydrochloride, m.p. 112-114°C, of 3-c-chloropropionylamino-2-carbomethoxy-4-methylthiophene, m.p. 99-101°C, one obtains: 3-n-propylamino-α-propionylamino-2-carbomethoxy-<i>Hmethylthiophene hydrochloride, m.p. 177-178°C, (base boiling point: 162-167°C/0.3 mm), 3-n-butylamino-α-propionylamino-2-carbomethoxy-yl-methylthiophene hydrochloride, m.p. 178-180°C,
3-dietylamino-a-propionylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 178-l80°C, 3-diethylamino-α-propionylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 178-180°C,
3-pyrrolidino-a-propionylamino-2-karbometoksy-4-metyltiofenklorid, 3-pyrrolidino-α-propionylamino-2-carbomethoxy-4-methylthiophene chloride,
smp. 190-195°C, 3-allylamino-a-propionylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 170-171°C, og m.p. 190-195°C, 3-allylamino-α-propionylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 170-171°C, and
3-butylamino-a-propionylamino-2-karbometoksy-it-metyltiof en-f osf at, 3-Butylamino-α-propionylamino-2-carbomethoxy-it-methylthiophene-phosphate,
smp. 193-194°C, m.p. 193-194°C,
av 3-S-klorpropionylamino-2-karbometoksy-4-metyltiofen, smp. 108-110°C, får man: of 3-S-chloropropionylamino-2-carbomethoxy-4-methylthiophene, m.p. 108-110°C, you get:
3-n-butylamino-0-propionylamino-2-karbometoksy-4-metyltiofen-hydroklorid med smp. 174-175°C, 3-n-propylamino-6-propionylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 200-202°C, 3-dietylamino-$-propionylamino-2-karbometoksy-4-metyltiofen-hydroklorid, smp. 101-102°C, 3-pyrrolidino-$-propionylamino-2-karbometoksy-'<-metyltiof en-hydroklorid, smp. 138-139°C, av 3-kloracetylamino-2-karbetoksy-4-metyltiofen, smp. 103-104°C, får man: 3-n-butylamino-acetylamino-2-karbetoksy-4-metyltiofen-hydroklorid, smp. 130-134°C, 3-n-butylamino-0-propionylamino-2-carbomethoxy-4-methylthiophene hydrochloride with m.p. 174-175°C, 3-n-propylamino-6-propionylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 200-202°C, 3-diethylamino-$-propionylamino-2-carbomethoxy-4-methylthiophene hydrochloride, m.p. 101-102°C, 3-pyrrolidino-$-propionylamino-2-carbomethoxy-'<-methylthiophene hydrochloride, m.p. 138-139°C, of 3-chloroacetylamino-2-carbethoxy-4-methylthiophene, m.p. 103-104°C, you get: 3-n-butylamino-acetylamino-2-carbethoxy-4-methylthiophene hydrochloride, m.p. 130-134°C,
3-dietylamino-acetylamino-2-karbetoksy-4-metyltiofen med kokepunktQ Qt-160-162°C (hydroklorid: smp. 13C~132°C). 3-diethylamino-acetylamino-2-carbethoxy-4-methylthiophene with boiling point Qt-160-162°C (hydrochloride: m.p. 13C~132°C).
Eksempel 2. Example 2.
17,6 g 3-kloracetylaminotiofen, som man får ved dekarboksylering av 3-amino-2-karboksytiofen og etterfølgende omsetning av det derved dannede 3-aminotiofen av kokepunkt 50°C/0,06 mm med kloracetylklorid, oppvarmes med 300 ml benzen og 23 ml n-butylamin i 7 timer til kokning. Etter avkjøling utvaskes med vann det dannede butylaminhydroklorid, benzenfasen tørkes med natriumsulfat og deretter avdestilleres oppløsningsmidlet overskytende butylamin. Det oljeaktige residuum som under tiden krystalliserer opptas i eter, og ved inn-føring av hydrogenkloridgass eller ved hjelp av metanolisk saltsyre utfelles hydrokloridet av 3-n-butylamino-acetylaminiotiofen. Utbytte: 19 g. Hydrokloridet smelter etter omkrystallisering fra i-propanol ved 219-220°C. 17.6 g of 3-chloroacetylaminothiophene, which is obtained by decarboxylation of 3-amino-2-carboxythiophene and subsequent reaction of the resulting 3-aminothiophene of boiling point 50°C/0.06 mm with chloroacetyl chloride, is heated with 300 ml of benzene and 23 ml of n-butylamine for 7 hours until boiling. After cooling, the formed butylamine hydrochloride is washed out with water, the benzene phase is dried with sodium sulphate and then the solvent excess butylamine is distilled off. The oily residue which in the meantime crystallizes is taken up in ether, and by introducing hydrogen chloride gas or with the aid of methanolic hydrochloric acid, the hydrochloride of 3-n-butylamino-acetylaminothiophene is precipitated. Yield: 19 g. The hydrochloride melts after recrystallization from i-propanol at 219-220°C.
På analog måte får man under anvendelse av tilsvarende aminer: av 3-kloracetylamino-4-metyltiofen (smp. 95-96°C),^som man får ved dekarboksylering av 3-amino-2-karboksy-4-metyltiofen (smp. 123°C) og etterfølgende omsetning av det derved dannede 3-amino-4-metyltiofen (kokepunkt 45°C70,05 mm) med kloracetylklorid, får man: 3-n-butylaminoacetylamino-4-metyltiofen, smp. l45-150°C/0,05 mm (hydrokloridets smp. 219-220°C), In an analogous way, using corresponding amines: from 3-chloroacetylamino-4-methylthiophene (m.p. 95-96°C),^ which is obtained by decarboxylation of 3-amino-2-carboxy-4-methylthiophene (m.p. 123°C) and subsequent reaction of the thereby formed 3-amino-4-methylthiophene (boiling point 45°C70.05 mm) with chloroacetyl chloride, one obtains: 3-n-butylaminoacetylamino-4-methylthiophene, m.p. l45-150°C/0.05 mm (m.p. of the hydrochloride 219-220°C),
3-n-propylaminoacetylamino-4-metyltiofen, smp. 144°C/0,15 mm (hydrokloridets smp. 2l8-219°C), 3-n-propylaminoacetylamino-4-methylthiophene, m.p. 144°C/0.15 mm (m.p. of the hydrochloride 2l8-219°C),
3-dietylamino-acetylamino-4-metyltiofen, smp. 52-55°C (hydrokloridets smp. 118-120°C), 3-diethylamino-acetylamino-4-methylthiophene, m.p. 52-55°C (m.p. of the hydrochloride 118-120°C),
3-cykloheksylaminoacetylamino-4-metyltiofen-hydroklorid, smp. 250°C, (spaltning), 3-cyclohexylaminoacetylamino-4-methylthiophene hydrochloride, m.p. 250°C, (decomposition),
av 3-kloracetylamino-2,4-dimetyltiofen (smp. 120-122°C), som man får ved omsetning av det ved forsåpning og dekarboksylering av 3-amino-5-karbometoksy-2,4-dimetyltiofen (smp. 82-84°C) dannede 3-amino-2,4-dimetyltiofen med kloracetylklorid, får man: 3-n-butylamino-acetylamino-2,4-dimetyltiofen-hydroklorid, smp. 230-223°C, of 3-chloroacetylamino-2,4-dimethylthiophene (m.p. 120-122°C), which is obtained by reacting it by saponification and decarboxylation of 3-amino-5-carbomethoxy-2,4-dimethylthiophene (m.p. 82- 84°C) formed 3-amino-2,4-dimethylthiophene with chloroacetyl chloride, one obtains: 3-n-butylamino-acetylamino-2,4-dimethylthiophene hydrochloride, m.p. 230-223°C,
3-dietylaminoacetylamino-2,4-dimetyltiofen-hydroklorid, smp. 174-176°C, 3-diethylaminoacetylamino-2,4-dimethylthiophene hydrochloride, m.p. 174-176°C,
av 3_a-klorpropionylamino-4-metyltiofen (smp. 74-75°C), som kan fremstilles av 3-amino-4-metyltiofen (kokepunkt 45°C70,05 mm) og ct-klorpropionylklorid får man: of 3_a-chloropropionylamino-4-methylthiophene (m.p. 74-75°C), which can be prepared from 3-amino-4-methylthiophene (boiling point 45°C70.05 mm) and ct-chloropropionyl chloride, one gets:
3-n-propylamino-a-propionylamino-4-metyltiofen, kokep. l40-l44°C7 3-n-propylamino-α-propionylamino-4-methylthiophene, bp. l40-l44°C7
0,1 mm (hydrokloridets smp. 2l8-219°C), 0.1 mm (m.p. of the hydrochloride 2l8-219°C),
3-n-butylamino-a-propionylamino-4-metyltiofen, smp. 66°C (hydrokloridets smp. 130-134°C), 3-n-butylamino-α-propionylamino-4-methylthiophene, m.p. 66°C (m.p. of the hydrochloride 130-134°C),
av 3-$-klorpropionylamino-4-metyltiofen, smp. 108-109°C, som man får av 3-amino-4-metyltiofen og 3-klorpropionylklorid får man: 3-n-butylamino-$-propionylamino-4-metyltiofen-hydroklorid, smp. 170-171°C, of 3-$-chloropropionylamino-4-methylthiophene, m.p. 108-109°C, which is obtained from 3-amino-4-methylthiophene and 3-chloropropionyl chloride: 3-n-butylamino-$-propionylamino-4-methylthiophene hydrochloride, m.p. 170-171°C,
3-n-propylamino-3-propionylamino-4-metyltiofen-hydroklorid, smp. 159,5-160,5°C, 3-n-propylamino-3-propionylamino-4-methylthiophene hydrochloride, m.p. 159.5-160.5°C,
3-pyrrolidino-3-propionylamino-4-metyltiofen-hydroklorid, smp. 169-170°C. 3-pyrrolidino-3-propionylamino-4-methylthiophene hydrochloride, m.p. 169-170°C.
Eksempel 3. Example 3.
3- dietylaminoacetylamino- 2- karbometoksy- 4- metyltiofen. 3- diethylaminoacetylamino- 2- carbomethoxy- 4- methylthiophene.
9 g 3-amino-2-karbometoksy-4-metyltiofen (smp. 84-85°C) innføres porsjonsvis under omrøring og avkjøling med isvann i en suspensjon av 15 g dietylaminoeddiksyreklorid-hydroklorid i 100 ml aceton og oppvarmes deretter i 30 minutter til kokning. Etter av-kjøling frasuges 3-dietylamino-acetylamino-2-karbometoksy-4-metyltio-fenhydroklorid. For rensing oppløser man hydrokloridet i vann, ut-ryster med eter og utfeller basen med kaliumkarbonatoppløsning. Man opptar deretter basen i eter, tørker med natriumsulfat og destillerer etter å ha fordampet eteren residuet i høy vakuum.- Man får således 6 g 3-dietylaminoacetylamino-2-karbometoksy-4-metyltiofen med kokepunkt l6l-l65°C/0,l mm Hg. Hydrokloridet smelter omkrystallisert fra isopropanol/diisopropyleter ved 157_158°C. 9 g of 3-amino-2-carbomethoxy-4-methylthiophene (m.p. 84-85°C) is introduced portionwise while stirring and cooling with ice water into a suspension of 15 g of diethylaminoacetic acid chloride-hydrochloride in 100 ml of acetone and is then heated for 30 minutes to boiling. After cooling, 3-diethylamino-acetylamino-2-carbomethoxy-4-methylthiophene hydrochloride is sucked off. For purification, the hydrochloride is dissolved in water, shaken out with ether and the base is precipitated with potassium carbonate solution. The base is then taken up in ether, dried with sodium sulfate and, after evaporating the ether, the residue is distilled under high vacuum.- You thus obtain 6 g of 3-diethylaminoacetylamino-2-carbomethoxy-4-methylthiophene with a boiling point of 161-165°C/0.l mm Hg. The hydrochloride melts recrystallized from isopropanol/diisopropyl ether at 157-158°C.
Eksempel 4. Example 4.
3- dietylaminoacetylamino- 2- karbometoksy- 4- metyltiofen. 3- diethylaminoacetylamino- 2- carbomethoxy- 4- methylthiophene.
14,3 g dietylaminoacetylamino-2-karbometoksy-4-metyl-4,5-dihydrotiofen (kokep. 156<1>l6l°C/0,05 torr) oppløses i 50 ml metylenklorid og blandes under omrøring ved -5 til -10°C dråpevis med en oppløsning av 8 g brom i 25 ml metylenklorid. Man lar det etteromrøre ved samme temperatur ennå i 1 time, fjerner overskytende brom og dannet bromhydrogen, idet man suger luft gjennom oppløsningen, og avdamper metylenkloridet deretter i vannstrålevakuum. 14.3 g of diethylaminoacetylamino-2-carbomethoxy-4-methyl-4,5-dihydrothiophene (boiling point 156<1>161°C/0.05 torr) are dissolved in 50 ml of methylene chloride and mixed while stirring at -5 to -10 °C dropwise with a solution of 8 g of bromine in 25 ml of methylene chloride. It is left to stir at the same temperature for a further 1 hour, excess bromine and hydrogen bromine formed are removed by sucking air through the solution, and the methylene chloride is then evaporated in a water jet vacuum.
Residuet oppløses i vann, den vandige oppløsning utrystes med eter. Etter eterens adskillelse utfeller man fra den brom-hydrogensure oppløsning basen med natriumkarbonatoppløsning, opptar den i eter og tørker den eteriske oppløsning med natriumsulfat. Etter eterens avdestillering destilleres residuet i høyvakuum ved l6l-l65°C og 0,1 mm Hg. Man får 7,7 g 3-dietylaminoacetylamino-3-karbometoksy-4- metyltiofen (hydrokloridets smeltepunkt: 157_158°C). The residue is dissolved in water, the aqueous solution is shaken with ether. After the separation of the ether, the base is precipitated from the bromine-hydrogen acid solution with sodium carbonate solution, taken up in ether and the ethereal solution is dried with sodium sulfate. After the ether has been distilled off, the residue is distilled in high vacuum at 161-165°C and 0.1 mm Hg. 7.7 g of 3-diethylaminoacetylamino-3-carbomethoxy-4-methylthiophene are obtained (melting point of the hydrochloride: 157-158°C).
Utgangsstoffet får man ved omsetning av 3-kloracetyl-amino-2-karbometoksy-4-metyl-4,5-dihydrotiofen (smp. 84-85°C, fremstilt ved omsetning av 2-karbometoksy-4-metyl-tiofanon-(3), kokepunkt 75°C/0,05 torr) og kloracetylklorid og dietylamin. The starting material is obtained by reacting 3-chloroacetyl-amino-2-carbomethoxy-4-methyl-4,5-dihydrothiophene (m.p. 84-85°C, prepared by reacting 2-carbomethoxy-4-methyl-thiophanone-(3 ), boiling point 75°C/0.05 torr) and chloroacetyl chloride and diethylamine.
Eksempel 5. Example 5.
3- dietylamino- acetylamino- 2- karbometoksy- 4- metyltiofen. 3- diethylamino- acetylamino- 2- carbomethoxy- 4- methylthiophene.
36 g 3-isocyan-2-karbometoksy-4-metyltiofen (smp. 107- 36 g of 3-isocyano-2-carbomethoxy-4-methylthiophene (m.p. 107-
108°C),, som man får av 3-formylamino-2-karbometoksy-4-metyltiofen (smp. 130-131°C) etter kjente metoder (se Neue Methoden der pråpa-rativen organischen Chemie, bind IV, side 43), 25,8 ml dietylamin, 25 ml 30%-ig formaldehyd, 100 ml aceton og 50 ml vann has sammen og blandes under avkjøling med 25 ml konsentrert saltsyre. Man lar det henstå i 60 timer ved værelsetemperatur og fordeler deretter mellom vann og eter. Den vandige fase gjøres alkalisk med natriumkarbonat-oppløsning og utrystes flere ganger med eter. Etter tørkning med natriumsulfat fjernes eteren og residuet destilleres i vakuum. Man får 42 g dietylamino-acetylamino-4-metyltiofen med kokepunkt l6l-165°C/0.,1 mm Hg. Hydrokloridets smeltepunkt: 157-158°C. 108°C), which is obtained from 3-formylamino-2-carbomethoxy-4-methylthiophene (m.p. 130-131°C) according to known methods (see Neue Methoden der pråparativen organischen Chemie, volume IV, page 43) , 25.8 ml of diethylamine, 25 ml of 30% formaldehyde, 100 ml of acetone and 50 ml of water are brought together and mixed while cooling with 25 ml of concentrated hydrochloric acid. It is allowed to stand for 60 hours at room temperature and then distributed between water and ether. The aqueous phase is made alkaline with sodium carbonate solution and shaken several times with ether. After drying with sodium sulphate, the ether is removed and the residue is distilled in vacuo. 42 g of diethylamino-acetylamino-4-methylthiophene with a boiling point of 161-165°C/0.1 mm Hg is obtained. Melting point of the hydrochloride: 157-158°C.
Eksempel 6. Example 6.
3- dietylamino- g- butyrylamino- 4- metyltiofen. 3- diethylamino- g- butyrylamino- 4- methylthiophene.
10,5 g 3-krotonylamino-4-metyltiofen (smp. 99-100°C) 10.5 g 3-crotonylamino-4-methylthiophene (m.p. 99-100°C)
som ble dannet av 3-amino-4-metyltiofen og krotonsyreklorid ble opp-løst i 34 ml dietylamin og oppvarmet i 20 timer i autoklav ved 140-150°C. Etter avkjøling avdestilleres det overskytende dietylamin, residuet oppløses i eter og utrystes med 2-n saltsyre. Etter eter-sjiktets adskillelse utfeller man fra det vandige sjikt basen med natriumkarbonatoppløsning, opptar den i eter, tørker den eteriske oppløsning med natriumsulfat. Ved tilsetning av eterisk saltsyre utfeller man hydrokloridet av 3-dietylamino-g-butyrylamino-4-metyltiofen som omkrystallisert fra etanol/eter smelter ved l64-l65°C. Utbytte: 5 g. which was formed from 3-amino-4-methylthiophene and crotonic acid chloride was dissolved in 34 ml of diethylamine and heated for 20 hours in an autoclave at 140-150°C. After cooling, the excess diethylamine is distilled off, the residue is dissolved in ether and shaken out with 2-n hydrochloric acid. After the separation of the ether layer, the base is precipitated from the aqueous layer with sodium carbonate solution, taken up in ether, the ethereal solution is dried with sodium sulfate. On addition of ethereal hydrochloric acid, the hydrochloride of 3-diethylamino-g-butyrylamino-4-methylthiophene is precipitated which, recrystallized from ethanol/ether, melts at 164-165°C. Yield: 5 g.
Eksempel 7• Example 7•
3- n- butylamino- acetylamino- 4- metyltiofen. 3-n-butylamino-acetylamino-4-methylthiophene.
9,5 g N-benzyloksykarbonyl-n-butylaminoeddiksyre og 5 ml trietylamin oppløses i 50 ml tetrahydrofuran, blandes dråpevis ved -5°C under omrøring med 3,4 ml klormaursyreetylester og etteromrøres i 15 minutter ved denne tid. Deretter tilsettes en likeledes til -5°C avkjølt oppløsning av 4 g 3-amino-4-metyltiofen i 20 ml tetrahydrofuran og omrøres i 2 timer. Under denne tid lar man blandingen opp-varme seg langsomt til værelsetemperatur. Deretter tilsettes vann for å utløse trietylaminhydrokloridet, den vandige fase utrystes igjen med eter og de forenede organiske oppløsninger tørkes med natriumsulfat. Det etter oppløsningsmidlets destillering gjenblivende residuum hensettes med 40 ml av en oppløsning av hydrogenbromidet i iseddik (ca. 371) i 1 time. Derved faller det ut hydrobromidet av 3-n-butylaminoacetylamino-4-metyltiofen, som suges fra og vaskes med eter. 9.5 g of N-benzyloxycarbonyl-n-butylaminoacetic acid and 5 ml of triethylamine are dissolved in 50 ml of tetrahydrofuran, mixed dropwise at -5°C with stirring with 3.4 ml of ethyl chloroformate and stirred for 15 minutes at this time. A solution of 4 g of 3-amino-4-methylthiophene in 20 ml of tetrahydrofuran, likewise cooled to -5°C, is then added and stirred for 2 hours. During this time, the mixture is allowed to warm up slowly to room temperature. Water is then added to precipitate the triethylamine hydrochloride, the aqueous phase is shaken again with ether and the combined organic solutions are dried with sodium sulphate. The residue remaining after the solvent has been distilled is treated with 40 ml of a solution of the hydrogen bromide in glacial acetic acid (approx. 371) for 1 hour. Thereby the hydrobromide of 3-n-butylaminoacetylamino-4-methylthiophene precipitates out, which is sucked off and washed with ether.
Utbytte: 7 g, smp. 200-202°C. Det innføres under omrøring i natrium-karbonatoppløsning og den frigjorte base opptas i eter. Etter den eteriske oppløsnings tørkning utfelles med eterisk saltsyre hydrokloridet av 3-n-butylamino-4-metyltiofenj smp. 219-220°C. Yield: 7 g, m.p. 200-202°C. It is introduced with stirring into sodium carbonate solution and the liberated base is taken up in ether. After drying the ethereal solution, the hydrochloride of 3-n-butylamino-4-methylthiophene is precipitated with ethereal hydrochloric acid, m.p. 219-220°C.
På analog måte vil man: Analogously, one would:
av N-benzyloksykarbonyl-n-butylaminoeddiksyre og of N-benzyloxycarbonyl-n-butylaminoacetic acid and
3-amino-5_karbometoksy-2,4-dimetyltiofen få 3-n-butylamino-acetylamino-5-karbometoksy-2,4-dimetyltiofen-hydroklorid, med smp. 234°C (under spaltning). 3-amino-5_carbomethoxy-2,4-dimethylthiophene get 3-n-butylamino-acetylamino-5-carbomethoxy-2,4-dimethylthiophene hydrochloride, m.p. 234°C (during decomposition).
Eksempel 8. Example 8.
3- n- butylaminoacetylamino- 4- metyltiofen. 3-n-butylaminoacetylamino-4-methylthiophene.
27 g 3_n-butylaminoacetylamino-2-karboksy-4-metylti6fen som fåes ved forsåpning av 3-n-butylaminoacetylamino-2-karbometoksy-4- metyltiofen med 4-n vandig natronlut ved værelsetemperatur, oppvarmes med 27 g kobberpulver og 300 ml chinolin langsomt til 190-200°C. Fra 130-l40°C kan det da iakttas en tydelig gassutvikling. 27 g of 3-n-butylaminoacetylamino-2-carboxy-4-methylthiophene, which is obtained by saponification of 3-n-butylaminoacetylamino-2-carbomethoxy-4-methylthiophene with 4-n aqueous caustic soda at room temperature, is slowly heated with 27 g of copper powder and 300 ml of quinoline to 190-200°C. From 130-140°C, a clear gas evolution can then be observed.
Det hensettes så lenge ved denne temperatur til COg-utviklingen stopper (ca. 2-3 timer). Etter avkjøling frafiltreres fra kobberpulver og chinolinet avdestilleres i vannstrålevakuum. Det blir tilbake 15 g av en olje som koker ved l45-150°C og 0,05 mm Hg. Det således dannede 3-n-butylamino-acetylamino-4-metyltiofen lar seg ved utrivning med 2-n vandig saltsyre overføre i hydrokloridet, som omkrystallisert fra etanol smelter ved 219-220°C. It is left at this temperature until COg evolution stops (approx. 2-3 hours). After cooling, the copper powder is filtered off and the quinoline is distilled off in a water jet vacuum. There remains 15 g of an oil which boils at 145-150°C and 0.05 mm Hg. The 3-n-butylamino-acetylamino-4-methylthiophene thus formed can be transferred by trituration with 2-n aqueous hydrochloric acid into the hydrochloride, which, recrystallized from ethanol, melts at 219-220°C.
Eksempel 9. Example 9.
3- dietylamino- acetylamino- 4- metyltiofen. 3- diethylamino- acetylamino- 4- methylthiophene.
1,7 g 3-aminoacetylamino-4-metyltiofen (smp. 73_74°C) oppvarmes til kokning med 3,9 g dietylsulfat og 3,4 g natrium-hydrogenkarbonat i 50 ml toluol i 5 timer. Etter avkjøling utrystes med 2-n saltsyre. Den saltsure fase ekstraheres gjentatt med metylenklorid, filtreres med aktivkull og gjøres alkalisk med 2-n natronlut. 3-dietylamino-acetylamino-4-metyltiofen frasuges, vaskes med isvann og tørkes (smp. 55°C). Med eterisk saltsyre får man herved hydrokloridet som smelter ved 118-120°C. 1.7 g of 3-aminoacetylamino-4-methylthiophene (m.p. 73-74°C) is heated to boiling with 3.9 g of diethyl sulfate and 3.4 g of sodium bicarbonate in 50 ml of toluene for 5 hours. After cooling, shake off with 2-N hydrochloric acid. The hydrochloric acid phase is extracted repeatedly with methylene chloride, filtered with activated carbon and made alkaline with 2-n caustic soda. 3-Diethylamino-acetylamino-4-methylthiophene is filtered off with suction, washed with ice water and dried (m.p. 55°C). With ethereal hydrochloric acid, the hydrochloride is obtained which melts at 118-120°C.
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DE4244069A1 (en) * | 1992-12-24 | 1994-06-30 | Hoechst Ag | Cephalosporin salts and process for their preparation |
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- 1968-07-05 CS CS528071A patent/CS150589B2/cs unknown
- 1968-07-05 CS CS527668A patent/CS150585B2/cs unknown
- 1968-07-05 DK DK330768A patent/DK120029B/en not_active IP Right Cessation
- 1968-07-05 AT AT616069A patent/AT284833B/en not_active IP Right Cessation
- 1968-07-05 CS CS527968A patent/CS150588B2/cs unknown
- 1968-07-05 CS CS527768A patent/CS150586B2/cs unknown
- 1968-07-05 AT AT615669A patent/AT281810B/en not_active IP Right Cessation
- 1968-07-05 FI FI194668A patent/FI50879C/en active
- 1968-07-05 CS CS498368A patent/CS150583B2/cs unknown
- 1968-07-05 AT AT615769A patent/AT282612B/en not_active IP Right Cessation
- 1968-07-05 CS CS527568A patent/CS150584B2/cs unknown
- 1968-07-05 AT AT615969A patent/AT282614B/en not_active IP Right Cessation
- 1968-07-06 ES ES355858A patent/ES355858A1/en not_active Expired
- 1968-07-08 GB GB3243868A patent/GB1234833A/en not_active Expired
- 1968-07-08 SE SE937268A patent/SE352639B/xx unknown
- 1968-07-08 FR FR1584764D patent/FR1584764A/fr not_active Expired
- 1968-07-08 NO NO271568A patent/NO122432B/no unknown
- 1968-07-08 BE BE717788D patent/BE717788A/xx not_active IP Right Cessation
- 1968-10-04 FR FR168764A patent/FR8214M/fr not_active Expired
-
1973
- 1973-09-27 YU YU256273A patent/YU33963B/en unknown
- 1973-09-27 YU YU256373A patent/YU34043B/en unknown
- 1973-09-27 YU YU256073A patent/YU33961B/en unknown
- 1973-09-27 YU YU256173A patent/YU33962B/en unknown
- 1973-09-27 YU YU256573A patent/YU33965B/en unknown
- 1973-09-27 YU YU256473A patent/YU33964B/en unknown
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