NO774407L - Fremgangsmaate for fremstilling av imidazolderivater - Google Patents
Fremgangsmaate for fremstilling av imidazolderivaterInfo
- Publication number
- NO774407L NO774407L NO774407A NO774407A NO774407L NO 774407 L NO774407 L NO 774407L NO 774407 A NO774407 A NO 774407A NO 774407 A NO774407 A NO 774407A NO 774407 L NO774407 L NO 774407L
- Authority
- NO
- Norway
- Prior art keywords
- mol
- methyl
- formula
- give
- methylimidazol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- -1 4,5-disubstituted imidazoles Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 4
- 229940116357 potassium thiocyanate Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- RXECVOHEVVDTIV-UHFFFAOYSA-N n-(5-benzamido-6-oxoheptyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC(C(=O)C)CCCCNC(=O)C1=CC=CC=C1 RXECVOHEVVDTIV-UHFFFAOYSA-N 0.000 description 3
- FOACJRMZCSTLKP-UHFFFAOYSA-N n-[3-(5-oxo-2-phenyl-2h-1,3-oxazol-4-yl)propyl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NCCCC(C(O1)=O)=NC1C1=CC=CC=C1 FOACJRMZCSTLKP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- PIACAFBPVPICSU-UHFFFAOYSA-N 4-(2-aminoethyl)-5-methylimidazole-2-thione Chemical compound CC1=NC(=S)N=C1CCN PIACAFBPVPICSU-UHFFFAOYSA-N 0.000 description 2
- XFZLAEXVWQCHMU-UHFFFAOYSA-N 4-(5-methyl-1h-imidazol-4-yl)butan-1-amine Chemical compound CC=1NC=NC=1CCCCN XFZLAEXVWQCHMU-UHFFFAOYSA-N 0.000 description 2
- UGYXPZQILZRKJJ-UHFFFAOYSA-N 4-methylhistamine Chemical compound CC=1NC=NC=1CCN UGYXPZQILZRKJJ-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- VAKQTQZJNALDGU-UHFFFAOYSA-N n-(4-benzamido-5-oxohexyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC(C(=O)C)CCCNC(=O)C1=CC=CC=C1 VAKQTQZJNALDGU-UHFFFAOYSA-N 0.000 description 2
- GXRVVGDHUPSBFV-UHFFFAOYSA-N n-(5-amino-6-oxoheptyl)benzamide;hydrochloride Chemical compound Cl.CC(=O)C(N)CCCCNC(=O)C1=CC=CC=C1 GXRVVGDHUPSBFV-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WZWYZPFOTAVDKN-KRWDZBQOSA-N (2s)-2,6-dibenzamidohexanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)CCCNC(=O)C1=CC=CC=C1 WZWYZPFOTAVDKN-KRWDZBQOSA-N 0.000 description 1
- XTBZYMOXUSCADZ-UHFFFAOYSA-N 1-methylsulfanyl-1-methylsulfinyl-2-nitroethene Chemical compound CSC(S(C)=O)=C[N+]([O-])=O XTBZYMOXUSCADZ-UHFFFAOYSA-N 0.000 description 1
- YZWJQAVCKRVMSW-UHFFFAOYSA-N 2-(4-ethylimidazol-4-yl)ethanamine Chemical compound NCCC1(CC)C=NC=N1 YZWJQAVCKRVMSW-UHFFFAOYSA-N 0.000 description 1
- YQFOVQZWQMRWRW-UHFFFAOYSA-N 3,7-diaminoheptan-2-one;dihydrochloride Chemical compound Cl.Cl.CC(=O)C(N)CCCCN YQFOVQZWQMRWRW-UHFFFAOYSA-N 0.000 description 1
- KBRWWPALPLHJSW-UHFFFAOYSA-N 3-(5-methyl-1h-imidazol-4-yl)propan-1-amine Chemical compound CC=1NC=NC=1CCCN KBRWWPALPLHJSW-UHFFFAOYSA-N 0.000 description 1
- SMEQHTVSLUGXQD-UHFFFAOYSA-N 4,8-diaminooctan-3-one Chemical compound CCC(=O)C(N)CCCCN SMEQHTVSLUGXQD-UHFFFAOYSA-N 0.000 description 1
- HHCOPJPYNNOYRH-UHFFFAOYSA-N 4-(3-aminopropyl)-5-methylimidazole-2-thione Chemical compound CC1=NC(=S)N=C1CCCN HHCOPJPYNNOYRH-UHFFFAOYSA-N 0.000 description 1
- YHUXHRFSJXVCGK-UHFFFAOYSA-N 4-(4-aminobutyl)-5-methylimidazole-2-thione Chemical compound CC1=NC(=S)N=C1CCCCN YHUXHRFSJXVCGK-UHFFFAOYSA-N 0.000 description 1
- GJTJGTBTGJSMKT-UHFFFAOYSA-N 4-(4-aminobutyl)-5-methylimidazole-2-thione;hydrochloride Chemical compound Cl.CC1=NC(=S)N=C1CCCCN GJTJGTBTGJSMKT-UHFFFAOYSA-N 0.000 description 1
- PMRUVDKVWYLPTC-UHFFFAOYSA-N 4-(5-aminopentyl)-5-methylimidazole-2-thione Chemical compound CC1=NC(=S)N=C1CCCCCN PMRUVDKVWYLPTC-UHFFFAOYSA-N 0.000 description 1
- MIJBBFKFBGTVOT-UHFFFAOYSA-N 4-(5-methyl-1h-imidazol-4-yl)-n-(1-methylsulfanyl-2-nitroethenyl)butan-1-amine Chemical group [O-][N+](=O)C=C(SC)NCCCCC=1N=CNC=1C MIJBBFKFBGTVOT-UHFFFAOYSA-N 0.000 description 1
- DKFZSUMRXILROO-UHFFFAOYSA-N 4-(5-methyl-1h-imidazol-4-yl)butan-1-amine;dihydrochloride Chemical compound Cl.Cl.CC=1NC=NC=1CCCCN DKFZSUMRXILROO-UHFFFAOYSA-N 0.000 description 1
- UKUMBWIAJWVEDN-UHFFFAOYSA-N 4-Methylburimamide Chemical compound CNC(=S)NCCCCC=1N=CNC=1C UKUMBWIAJWVEDN-UHFFFAOYSA-N 0.000 description 1
- BUGDFCKTOJKKHR-UHFFFAOYSA-N 5-(5-methyl-1h-imidazol-4-yl)pentan-1-amine Chemical compound CC=1NC=NC=1CCCCCN BUGDFCKTOJKKHR-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- NTRBNFOLBJWRAO-INIZCTEOSA-N N(2),N(5)-dibenzoyl-L-ornithine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)CCNC(=O)C1=CC=CC=C1 NTRBNFOLBJWRAO-INIZCTEOSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IULFXBLVJIPESI-UHFFFAOYSA-N bis(methylsulfanyl)methylidenecyanamide Chemical compound CSC(SC)=NC#N IULFXBLVJIPESI-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKUWZQLFGPGEPY-UHFFFAOYSA-N methyl n-cyano-n'-[4-(5-methyl-1h-imidazol-4-yl)butyl]carbamimidothioate Chemical compound N#CNC(SC)=NCCCCC=1N=CNC=1C UKUWZQLFGPGEPY-UHFFFAOYSA-N 0.000 description 1
- MHMXKYAPSNZETH-UHFFFAOYSA-N n-(5-benzamido-6-oxooctyl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC(C(=O)CC)CCCCNC(=O)C1=CC=CC=C1 MHMXKYAPSNZETH-UHFFFAOYSA-N 0.000 description 1
- OAXJHEFFWAWQAA-UHFFFAOYSA-N n-[4-(5-methyl-1h-imidazol-4-yl)butyl]benzamide Chemical compound N1C=NC(CCCCNC(=O)C=2C=CC=CC=2)=C1C OAXJHEFFWAWQAA-UHFFFAOYSA-N 0.000 description 1
- MBLFAFYQWSREDG-UHFFFAOYSA-N n-[4-(5-methyl-2-sulfanylideneimidazol-4-yl)butyl]benzamide Chemical compound CC1=NC(=S)N=C1CCCCNC(=O)C1=CC=CC=C1 MBLFAFYQWSREDG-UHFFFAOYSA-N 0.000 description 1
- CNCODGORBRKJLO-UHFFFAOYSA-N n-[4-(5-oxo-2-phenyl-2h-1,3-oxazol-4-yl)butyl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NCCCCC(C(O1)=O)=NC1C1=CC=CC=C1 CNCODGORBRKJLO-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 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
- ZRQJSWOPZOITNN-UHFFFAOYSA-N urea;dihydrochloride Chemical compound Cl.Cl.NC(N)=O ZRQJSWOPZOITNN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
"Analogifremgangsmåte for fremstilling av
farmakologisk a ktive imidazolderivater"
Denne oppfinnelse angår :en fremgangsmåte for fremstilling av. visse 4,5-disubstituerté imidazoler.med den generelle formel I: .
hvor R er metyl eller.etyl; n er 2, 3, 4 eller 5; Q er hydrogen eller en aroylgruppe, og syreaddisjonssaltene derav. I henhold til oppfinnelsen avsvovles en forbindelse med den generelle formel II
hvor R, n og Q har de ovenfor angitte betydninger. Forbindelsene
med formel I kan eksistere som syreaddisjonssalter, men av praktiske grunner vil de her bli omtalt som utgangsforbindelsene.
Forbindélsene med formel I hvor n er 2 og Q er hydrogen, dvs. 4-metylhistamin og- 4-etylhistamin, er farmakologisk aktive
som ^-antagonister. Forbindelsene med formel I kan også omdannes til forbindelser med I^-antagonistvirkning, f.eks. de som er
beskrevet i våre britiske patenter 1.305.546, 1.307.539, 1.397.436 og 1.431.589.
Særlig nyttige forbindelser er de hvor R er metyl og Q er hydrogen. Forbindelser hvor n er 4 foretrekkes også.
Ved foreliggende fremgangsmåte foretas avsvovlingen fortrinnsvis under anvendelse av Raney-nikkel, hensiktsmessig i etanol.
Forbindelsene med formel II kan fremstilles fra de til-svarende 'diaminosyrer med formel III: hvor n er 2, 3, 4 eller 5, ved det følgende reaksjonsskjema hvor X er halogen, Ar er en arylgruppe så som fenyl, og R, n og Q har de ovenfor angitte betydninger.
Diaminosyren med formel III omsettes først med aroylhalogenid eller -anhydrid for å gi diaroylaminoforbindelsen IV som derefter omsettes med et ringslutningsmiddel så som eddiksyreanhydrid eller fortrinnsvis dicykloheksylkarbodiimid (D.C.C.) for å gi oksazolonet V..Omsetning av dette oksazolon med acetyi- eller propionylhalogenid eller -anhydrid gir forbindelsen VI, og når
denne underkastes mild hydrolyse, f.eks. med eddiksyre, og påfølgende spontan dekarboksylering av produktet, dannes forbindelsen med formel VII, som underkastes kraftige betingelser, f.eks. med konsentrert saltsyre, for å fjerne en av eller begge de beskyttende aroylgrupper, og omsetning av den resulterende forbindelse VIII med tiocyanat, f.eks. kaliumtiocyanat, gir forbindelsen med formel II
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere.
Eksempel 1
4-( 4- aminobuty1)- 5- metylimidazol- 2- tion- hydroklorid
(i) N,N'-dibenzoy1-lysin (140,4 g, 0,36 mol) oppløst i dioksan . (350 ml) ble i løpet av 45 minutter satt til dicyklo-heksy lkarbodiimid (88,0 g, 0,43 mol) i dioksan (193 ml). Efter omrøring i 2 timer ble blandingen satt til side natten over, dicykloheksylurinstoff (88,1 g) ble frafiltrert, oppløsningen ble konsentrert til halvt volum og satt til' f^O. Bunnfallet ble
oppsamlet og omkrystallisert fra metylal for å gi 4-(4-benzamido-butyl)-2-fenyl-5-oksazolon (104 g, 86%), sm.p. 118-122°.
C20H20N2°3 krever: C 71'4'H 6'0'N 8'3-
funnet: C 71,1, H6,2, N 8,7.
(ii) En blanding av oksazolonet (1,69 g, 0,005 mol), 4-dimetylaminopyridin (0,025 g), eddiksyreanhydrid (1 ml) og trietylamin (1 ml) ble omrørt inntil man fikk en oppløsning
(1 time). Eddiksyre (7,5 ml) ble tilsatt, og oppløsningen ble satt til side natten over og inndampet til. tørrhet. Residuet ble oppløst i kloroform og vasket med fortynnet NaOH, fortynnet HC1
og derefter tørret over MgSO^. Konsentrering ga råproduktet som kunne renses ved tørrkolonne-kromatografi på aluminiumoksyd med
etylaéetat som oppløsningsmiddel for å gi 3,7-dibenzamidoheptan-2-on (0,60 g, 34%),
6 (60 MHz DMS0-d6) 8,5 (t, NH) ,^8,3 (bred s, NH),^7,8, 7,4
(m, C6H5) , 4,4 (m, CH) , 3,2 (m, NCH2) , 2,1 (s, CH3) , 1,.5 (m, (CH2>3). (iii) Rått 3,7-dibenzamidoheptan-2-on (123 g, 0,35 mol) ble hydrolysert ved oppvarmning under tilbakeløpskjøling med konsentrertHC1 i 18 timer for å gi 3,7-diaminoheptan-2-on-dihydroklorid (49 g, 65%) , sm.p. 160-166° ■ (MeCN) .
6 (.60 MHz D20) 4,3 (t, CH) , 3,1 (t, NHC2), 2,35 (s, CH )', 1,7
(m,. (CH2) 3) .
(iv) En oppløsning av aminoketon-dihydrokloridet (21,7 g,
0,10 mol) og kaliumtiocyanat.(19,40 g, 0,20 mol) i vann ble oppvarmet under tilbakeløpskjøling i 7 timer og ble derefter inndampet .til tørrhet. Residuet ble ekstrahert med varm AcOH,
og de filtrerte ekstrakter ble avkjølt. Det erholdte produkt ble omrkystallisert■fra eddiksyre for å gi 4-(4-aminobutyl)-5-metylimidazol-2-tion-hydroklorid (14,1 g, 64%), sm.p. 279-280°.• C8H15<N>3<S*>HC1krever: C 43,4, H 7,3, N 18,9, S 13,9 ;funnet: C .43,1, H 7,2, N. 18,5, S 13,9. ;Eksempel 2;(i) 3,7-dibenzamidoheptan-2-on (91,11. g, 0,258 mol) ble hydrolysert i-et lukket^.rør med konsentrert HC1 i 3 timer ved 160° (oljebad). Oppløsningen ble ekstrahert med eter og inndampet til tørrhet for å gi 3-amino-7-benzamidoheptan-2-on-hydroklorid (25,01 g, 34,2%).. (ii) En oppløsning av 3-amino-7-benzamidoheptan-2-on-hydroklorid (16,39 g, 0,0576 mol) og kaliumtiocyanat (7,30 g, 0,0755 mol, overskudd) i vann ble oppvarmet under tilbakeløps-kjøling i 20 timer. Den vandige fase ble avdekantert, og den organiske fase ble vasket med vann og omkrystallisert fra aceto- . nitril for å gi 4-(4-benzamidobuty1)-5-metylimidazol-2-tion (4,18 g, 25%), sm.p. 180-184°. C15H19N3OS krever: c 43'3/H 7' 3' N 18,9, S 13,9 .funnet: C 62,01, H 6,46, N 14,39, S 11,55%. ;Eksempel 3 ;4-( 4- aminobuty1)- 5- etylimidazol- 2- tion- hydroklorid;Omsetning av 4-(4-benzmidobuty1)-2-feny1-5-oksazolon;ved fremgangsmåten ifølge eksempel 1 (ii) , men under anvendelse av propionsyreanhydrid istedenfor eddiksyreanhydrid, gir 4,8-dibenzamidooktan-3-on, som ved hydrolyse ved fremgangsmåten ifølge eksempel l(iii) gir 4,8-diaminooktan-3-on. Omsetning av ;dette produkt med kaliumtiocyanat ved fremgangsmåten ifølge eksempel 1(iv) gir tittelforbindelsen. ;Eksempel 4 ;4-( 3- benzamidopropyl)- 2- feny1- 5- oksazolon;(i) N, N1-dibenzoylornitin (29,09 g, 0,0855 mol) oppløst i dioksan -(1160 ml) ble behandlet ved dråpevis tilsetning over 85 min. med dicykloheksylkarbodiimid (20,95 g, 0,102 mol) ;oppløét i dioksan (460 ml). Suspensjonen ble omrørt i 22 timer, dicykloheksylurinstoff ble frafiltrert (17,49 g), oppløsningen ;ble konsentrert til halv volum og satt til f-^O. Bunnfallet ble oppsamlet og omkrystallisert fra toluen/petroleter (60-80°) for å gi 4-(3-benzamidopropyl)-2-feny1-5-oksazolon (18,55 g, 67%), sm.p. 135-138°C. (ii) . N,N'-dibenzoylornitin (0,05 g, 0,147 mmol) og eddiksyreanhydrid (0,16 g, 1,57 mmol) ble oppvarmet ved 155°C i 7 min.'Oppløsningen'ble inndampet til tørrhet, og det gjenværende, faste, hvite stoff ble omkrystallisert fra benzen/petroleter (40-60°) for å gi 4-(3-benzamidopropyl)-2-feny1-5-oksazolon (0,02 g, 43%), sm.p.,135-138°C. ;Eksempel 5;3, 6- dibenzamidoheksan- 2- on;En blanding av 4-(3-benzamidopropyl)-2-feny1-5-oksazolon (1,0 g, 3,1 mmol), 4-dimetylaminopryidin (0,016 g), éddiksyre-anhydrid (0,62 ml) og trietylamin. (0,62 ml) ble omrørt i 1 time. Eddiksyre (4,7 ml) ble tilsatt, og oppløsningen ble satt til side natten over og inndampet til tørrhet. Residuet ble oppløst i kloroform og vasket med fortynnet NaOH, fortynnet HC1 og derefter ;tørret over MgSO^. Konsentrering ga råproduktet som kunne renses ved tørrkolonne-kromatografi på aluminiumoksyd med etylacetat som oppløsningsmiddel.for å gi 3,6-dibenzamidoheksan-2-on. ;Eksempel 6;Når det ved fremgangsmåten ifølge eksempel 1 ble anvendt de følgende utgangsmaterialer istedenfor lysin: 2,4-dibenzoylamidosmørsyre ;2,7-dibenzoylamidoheptansyre,;får man de følgende forbindelser: 4-(2-aminoetyl)-5-metylimidazol-2-tion, ;4-(5-aminopentyl)-5-metylimidazol-2-tion.;Eksempel 7 ;Når det ved fremgangsmåten ifølge eksempel .1 (iii) og;(iv) anvendes ;3,6-dibenzamidoheksan-2-on;som utgangsmateriale, får man ;4-(3-aminopropyl)-4-metylimidazol-2-tion.... ;E ksempel 8;Omsetning av 4-(2-aminoetyl)-5-metylimidazol-2-tipn;med Raney-nikkel i etanol ga 4-metylhistamin.;Eksempel 9;(i) 4-(4-aminobutyl)-5-metylimidazol-2-tion (14,1 g,;0,064 mol) i absolutt etanol (250.ml) ble avsvovlet med Raney-nikkel (ca'. 25 g) i 30 minutter. Filtrering -fulgt av konsentrering under redusert trykk og behandling av resiudet med HC1 ;ga 4-(4-aminobutyl)-5-metylimidazol-dihydroklorid (8,2 g), sm.p. 206-208° (fra eddiksyre). ;<C>8<H>15N3*2HC1 krever: C 42,5, ■ H 7,6, N 18,6, Cl 31,4,
funnet: ; C 42,4, H 7>5, N 18,2, Cl' 31,1.
(ii) En oppløsning av aminet (erholdt fra dihydrokloridet
(9,60 g, 0,049 mol) ved alkalisering med K2C03) og metyl-'isotiocyanat (4,0 g, 0,055 mol) i EtOH (100 ml) inneholdende
noen få dråper t^O ble oppvarmet under tilbakeløpskjøling i 30 minutter. Filtrering, fulgt av inndampning under redusert trykk
og omkrystallisering av residuet fra MeCN ga N-metyl-N'.-[4-(5-metyl-4-imidazolyl)butyl]tiourinstoff, sm.p..110-112°C (fra akrylnitril).
Eksempel 10
4-(4-benzamidobuty1)-5-metylimidazol-2-tion (4,12 g,
0,01425 mol) i absolutt etanol (80 ml) ble avsvovlet med Raney-
nikkel (ca. 18 g). Filtrering fulgt av konsentrering under redusert trykk ga 4-(4-benzamidobuty1)-5-metylimidazol (3,23 g, . 88%) , sm.p. 124-128°.
Eksempel 11 v
Omsetning av 4-(4-aminobutyl)-5-metylimidazol (se
eksempel 9 (ii) , 2,71 g, 0,012 mol) med dimetylcyanoditioimido-karbonat (1,75 g, 0,013 mol) ga S-metyl-N-cyano-N'-[4-(5-mety1-4-imidazolyl)butyl]isotiourinstoff (2,27 g) som- ble behandlet direkte med metylamin for å gi N-cyano-N<1->metyl-N"-[4-(5-metyl-4-imidazoly1)butyl]guanidin (1,35 g), sm.p. 152-154 C (fra akrylnitril).
Eksempel 12
Når 4-(3-aminopropyl)-5-metylimidazol-2-tion og 4-(5-aminopentyl)-5-metylimidazol-2-tion avsvovles ved fremgangsmåten ifølge eksempel 9(i), er produktene henholdsvis 4-(3-aminopropyl)-5-metylimidazol og 4-(5-aminopentyl)-5-metylimidazol. Ved fremgangsmåten ifølge eksempel 11 kan disse forbindelser omdannes til henholdsvis N-cyano-N1-metyl-N"-[3-(5-metyl-4-imidazo'lyl) propyl] guanidin og N-cyano-N'-metyl-N"-i [5- (5-mety 1-4-imidazolyl) pentyl] guanidin.
Eksempel 13
Omsetning av 4-(4-aminobutyl)-5-metylimidazol (se
eksempel 9 (ii) , 0,765 g, 0.,005 mol) med 1-metylsulfinyl-1-metyl.tio-2-nitroeten (0,91 g, 0,005 mol), ga 1-metyltio-l-[4-(5-metylimidazol-4-yl)butylamino]-2-nitroetylen . (0,69 g, 51%)
som ble behandlet direkte med metylamin for å gi 1-metylamino-1-[4-(5-metylimidazol-4-yl)butylamino]-2-nitroeten (0,40 g, 61,9%). Denne forbindelsen ble omsatt med pikrinsyre for å gi 1-metyl-amino-1- [4-^ (5-metylimidazol-4-yl) butylamino] -2-nitroeten-pikrat-hemihydrat (0,33 g, 26,3%, siste trinn), sm.p. 185-187°.
Claims (3)
1. Analogifremgangsmåte for fremstilling av farmakologisk aktive forbindelser med formelen:
hvor R er metyl eller etyl; n er 2, 3, 4 eller 5; og Q er hydrogen eller en aroylgruppe, og syreaddisjonssaltene derav, karakterisert ved at en forbindelse med formelen
hvor R, n og Q har de ovenfor angitte betydninger, avsvovles.
2. Fremgangsmåte som angitt i krav 1, karakterisert ved at det anvendes et utgangsmateriale med formel II hvor R er metyl og Q er hydrogen.
.
3. Fremgangsmåte som angitt i krav 1 eller 2, karakterisert ved at det anvendes et utgangsmateriale med formel II hvor n er 4.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB53538/76A GB1596376A (en) | 1976-12-22 | 1976-12-22 | 4,5-disubstituted imidazole-2-thiones processes for their preparation and their use as intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO774407L true NO774407L (no) | 1978-06-23 |
Family
ID=10468162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO774407A NO774407L (no) | 1976-12-22 | 1977-12-21 | Fremgangsmaate for fremstilling av imidazolderivater |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4166184A (no) |
| JP (1) | JPS5379863A (no) |
| AU (1) | AU514770B2 (no) |
| BE (1) | BE862095A (no) |
| CA (1) | CA1096388A (no) |
| DE (1) | DE2755749A1 (no) |
| DK (1) | DK559877A (no) |
| ES (1) | ES465346A1 (no) |
| FI (1) | FI773592A (no) |
| FR (1) | FR2375219A1 (no) |
| GB (1) | GB1596376A (no) |
| HU (1) | HU177745B (no) |
| IE (1) | IE46493B1 (no) |
| IL (1) | IL53350A (no) |
| LU (1) | LU78725A1 (no) |
| NL (1) | NL7714261A (no) |
| NO (1) | NO774407L (no) |
| PH (1) | PH14357A (no) |
| PT (1) | PT67276B (no) |
| SE (1) | SE7714123L (no) |
| ZA (1) | ZA776538B (no) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0170872B1 (de) * | 1984-07-13 | 1989-08-23 | Bayer Ag | Verfahren zur Herstellung, von 3,7-Bisacetaminoheptanon-2 |
| EP0428849A3 (en) * | 1989-09-28 | 1991-07-31 | Hoechst Aktiengesellschaft | Retroviral protease inhibitors |
| US7767826B2 (en) * | 2007-10-05 | 2010-08-03 | Pharmatech International, Inc. | Process for the synthesis of L-(+)-ergothioneine |
| CN109956881A (zh) * | 2017-12-26 | 2019-07-02 | 上海凯赛生物技术研发中心有限公司 | 一种苯甲酰戊二胺及其制备和应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2585388A (en) * | 1948-11-17 | 1952-02-12 | Lilly Co Eli | Preparation of 2-mercaptoimidazoles |
| GB1054708A (no) * | 1964-10-02 |
-
1976
- 1976-12-22 GB GB53538/76A patent/GB1596376A/en not_active Expired
-
1977
- 1977-11-03 ZA ZA00776538A patent/ZA776538B/xx unknown
- 1977-11-10 IL IL53350A patent/IL53350A/xx unknown
- 1977-11-14 PT PT67276A patent/PT67276B/pt unknown
- 1977-11-22 PH PH20461A patent/PH14357A/en unknown
- 1977-11-28 FI FI773592A patent/FI773592A/fi not_active Application Discontinuation
- 1977-12-08 US US05/858,488 patent/US4166184A/en not_active Expired - Lifetime
- 1977-12-13 SE SE7714123A patent/SE7714123L/xx unknown
- 1977-12-14 DE DE19772755749 patent/DE2755749A1/de not_active Withdrawn
- 1977-12-14 FR FR7737607A patent/FR2375219A1/fr active Granted
- 1977-12-14 AU AU31572/77A patent/AU514770B2/en not_active Expired
- 1977-12-15 DK DK559877A patent/DK559877A/da unknown
- 1977-12-15 JP JP15159477A patent/JPS5379863A/ja active Pending
- 1977-12-16 IE IE2568/77A patent/IE46493B1/en unknown
- 1977-12-20 LU LU78725A patent/LU78725A1/xx unknown
- 1977-12-21 NO NO774407A patent/NO774407L/no unknown
- 1977-12-21 CA CA293,537A patent/CA1096388A/en not_active Expired
- 1977-12-21 BE BE183657A patent/BE862095A/xx unknown
- 1977-12-21 HU HU77SI1607A patent/HU177745B/hu unknown
- 1977-12-22 ES ES465346A patent/ES465346A1/es not_active Expired
- 1977-12-22 NL NL7714261A patent/NL7714261A/xx not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA1096388A (en) | 1981-02-24 |
| IL53350A0 (en) | 1978-01-31 |
| ZA776538B (en) | 1978-08-30 |
| FR2375219B1 (no) | 1981-02-27 |
| PH14357A (en) | 1981-06-03 |
| NL7714261A (nl) | 1978-06-26 |
| US4166184A (en) | 1979-08-28 |
| IL53350A (en) | 1981-10-30 |
| IE46493B1 (en) | 1983-06-29 |
| SE7714123L (sv) | 1978-06-23 |
| AU3157277A (en) | 1979-06-21 |
| FI773592A (fi) | 1978-06-23 |
| GB1596376A (en) | 1981-08-26 |
| HU177745B (en) | 1981-12-28 |
| IE46493L (en) | 1978-06-22 |
| PT67276B (en) | 1979-04-18 |
| PT67276A (en) | 1977-12-01 |
| LU78725A1 (no) | 1978-04-17 |
| FR2375219A1 (fr) | 1978-07-21 |
| JPS5379863A (en) | 1978-07-14 |
| DK559877A (da) | 1978-06-23 |
| BE862095A (fr) | 1978-06-21 |
| DE2755749A1 (de) | 1978-06-29 |
| AU514770B2 (en) | 1981-02-26 |
| ES465346A1 (es) | 1978-09-16 |
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