NO159167B - Nye 1-substituerte-5-hydroksymetyl-2-merkapto-imidazol-derivater og fremgangsmaate for fremstilling derav. - Google Patents
Nye 1-substituerte-5-hydroksymetyl-2-merkapto-imidazol-derivater og fremgangsmaate for fremstilling derav. Download PDFInfo
- Publication number
- NO159167B NO159167B NO844139A NO844139A NO159167B NO 159167 B NO159167 B NO 159167B NO 844139 A NO844139 A NO 844139A NO 844139 A NO844139 A NO 844139A NO 159167 B NO159167 B NO 159167B
- Authority
- NO
- Norway
- Prior art keywords
- substituted
- hydroxymethyl
- group
- imidazole
- mercapto
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- -1 1-SUBSTITUTED-5-HYDROXYMETHYL-2-MERCAPTO IMIDAZOLE Chemical class 0.000 title claims description 4
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 7
- 229940116357 potassium thiocyanate Drugs 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- KEQUNHIAUQQPAC-UHFFFAOYSA-N Dihydroxyacetone (dimer) Chemical compound OCC1(O)COC(O)(CO)CO1 KEQUNHIAUQQPAC-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 239000000047 product Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- GQZILHANXWXTIW-UHFFFAOYSA-N (3-benzylimidazol-4-yl)methanol Chemical compound OCC1=CN=CN1CC1=CC=CC=C1 GQZILHANXWXTIW-UHFFFAOYSA-N 0.000 description 2
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical class SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IIQWCVZBUKMFBS-UHFFFAOYSA-N 3-benzyl-4-(hydroxymethyl)-1h-imidazole-2-thione Chemical compound OCC1=CNC(=S)N1CC1=CC=CC=C1 IIQWCVZBUKMFBS-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- NPLFBOPCFNSVDK-UHFFFAOYSA-N 3-[(4-chlorophenyl)methyl]-4-(hydroxymethyl)-1h-imidazole-2-thione Chemical compound OCC1=CN=C(S)N1CC1=CC=C(Cl)C=C1 NPLFBOPCFNSVDK-UHFFFAOYSA-N 0.000 description 1
- JRGDGGYXZKWDFN-UHFFFAOYSA-N 3-ethyl-4-(hydroxymethyl)-1h-imidazole-2-thione Chemical compound CCN1C(S)=NC=C1CO JRGDGGYXZKWDFN-UHFFFAOYSA-N 0.000 description 1
- MVGDQHAJWDHHLG-UHFFFAOYSA-N 4-(hydroxymethyl)-3-(2-phenylethyl)-1h-imidazole-2-thione Chemical compound OCC1=CN=C(S)N1CCC1=CC=CC=C1 MVGDQHAJWDHHLG-UHFFFAOYSA-N 0.000 description 1
- PSKXKHYBLYMSAP-UHFFFAOYSA-N 4-(hydroxymethyl)-3-(pyridin-2-ylmethyl)-1h-imidazole-2-thione Chemical compound OCC1=CN=C(S)N1CC1=CC=CC=N1 PSKXKHYBLYMSAP-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical class N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- RHDJRPPFURBGLQ-UHFFFAOYSA-N detomidine Chemical compound CC1=CC=CC(CC=2NC=NC=2)=C1C RHDJRPPFURBGLQ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PJYPCKZZTIAODG-UHFFFAOYSA-M magnesium;1,2-dimethylbenzene-6-ide;bromide Chemical compound [Mg+2].[Br-].CC1=CC=C[C-]=C1C PJYPCKZZTIAODG-UHFFFAOYSA-M 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical class Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001023 sodium amalgam Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Epoxy Resins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Denne oppfinnelse angår tidligere ukjente l-substituerte-5-hydroksymetyl-2-merkapto-imidazoler med den generelle formel (I)
hvor R er en substituert eller usubstituert arylalkyl-, heteroarylalkyl- eller lavere alkylgruppe, som er viktige mellomprodukter ved fremstilling av terapeutisk verdifulle 1,5- og 4(5)-imidazol-derivater, som for eksempel 4(5)-(2,3-dimetylbenzyl)-imidazol som i form av base har formelen
Forbindelsene med formel (I) er nye. En forbindelse med formel (I) hvor R=H er kjent fra publikasjonen RAF Bullerwell et al., J.Chem.Soc. 1951, 3030, hvor den 1-substituerte forbindelse oppnåes ved omsetning av serin med kaliumtiocyanat og natrium-amalgam.
Fremstillingen av de nye 2-merkapto-imidazol-derivater (I) ifølge oppfinnelsen er basert på en ny tilpasning av to tidligere kjente reaksjoner. De er Art Lobry de Bruyn - Alberda von Ekenstein omleiringen for fremstilling av D-glukosamin-derivater
(L Sattler, Adv. Carbohydr. Chemistry 3 (1948) 113 og K Heynes et al., Z Naturforsch. 76 (1952) 486), og fremgangsmåten for fremstilling av alfa-merkaptoglukimidazoler fra glukosamin og kaliumtiocyanat (IF Garcia Gonzåles og J Fernåndéz Bolanos, Anales Real. Soc. Espan. Fis. y Quim. 44 B (1948) 233; G von Huber et al.,
Heiv. Chim. Acta 43 (1960) 713 og 1787).
Ved fremgangsmåten ifølge oppfinnelsen anvendes dihydroksyaceton-dimer som utgangsmateriale og omsettes med et amin til aminoaldehydet (II) , som ringsluttes i nærvær av en syre med kaliumtiocyanat til de ønskede imidazol-derivater. Fremgangsmåten fører til imidazol-derivater (I) i meget godt utbytte.
Illustrert ved formler er den nye fremgangsmåte som følger:
Forbindelsene ifølge oppfinnelsen kan forekomme som frie baser eller syreaddisjonssalter som for eksempel hydroklorider, acetater, sulfater, osv.
Ved fremstilling av forbindelser av medisinsk interesse fjernes merkaptogruppen fra merkaptoimidazolene ved oksydasjon med salpetersyre, og den oppnådde alkohol oksyderes med mangan-dioksyd til det tilsvarende aldehyd. Det oppnådde N-substituerte imidazol-karboksaldehyd omsettes med Grignard reagens for fremstilling av 1,5-imidazol-derivater, og hvis beskyttelsesgruppen på N-atomet fjernes, oppnåes 4(5)-monosubstituerte imidazoler.
Syntesen av forbindelsene (I) finner sted i ett trinn. Dihydroksyaceton-dimer, et passende amin og kaliumtiocyanat blandes i en lavere alkohol, og de omsettes i nærvær av en syre. Reaksjonstemperaturen kan variere mellom 10 og 100°C.
For fremstilling av de farmakologisk aktive imidazol-forbindelser, som er beskrevet i de europeiske patentansøkninger 0024829 og 0058047, fjernes merkaptogruppen i første trinn fra en forbindelse med formel (I) i fortynnet salpetersyre ved omrøring ved ca. 30-35°C. I det følgende trinn oksyderes alkoholen til aldehyd, for eksempel ved kokning i dioksan i 6 timer. I tredje trinn omsettes et substituert fenylmagnesiumbromid i tetrahydrofuran med det ovennevnte aldehyd slik at man får de farmakologisk interessante 1,5-imidazol-derivater. Når 1-substituenten er en hydrogenolyserbar substituent eller en usubstituert benzylgruppe, oppnåes 4(5)-substituerte imidazoler efter hydrogenering. Hydrogeneringen kan for eksempel foretas i en fortynnet syre-oppløsning ved forhøyet temperatur.
Eksempel 1
l- benzyl- 2- merkapto- 5- hydroksymetyl- imidazol
n-butanol (50 ml), iseddik (25 g), dihydroksyaceton-dimer (21,0 g), kaliumtiocyanat (34,1 g) og benzylamin (28,0 g) blandes ved romtemperatur. Blandingen omrøres ved romtemperatur i 50
timer, og produktet filtreres.
13C NMR (DMS0-d6, TMS): 46.35, 53.22, 112.46, 112.61, 126.69, 127.02, 128.20, 130.20, 136.92, 162.53
Man får et lysebrunt produkt, 35,0 g (68,2%), smp.229-231°C.
Ved å anvende den samme fremgangsmåte kan de følgende produkter fremstilles: 1-(4-klorbenzyl)-2-merkapto-5-hydroksymetyl-imidazol, smp. 217-222°C. 1-(2-fenyletyl)-2-merkapto-5-hydroksymetyl-imidazol, smp. 202-208°C. 1-(2-pyridylmety1)-2-merkapto-5-hydroksymetyl-imidazol, smp. 181-185°C. l-etyl-2-merkapto-5-hydroksymety1-imidazol, smp. dekomp.
(175-250°C).
Eksempel 2
4- ( 2, 3- dimetylbenzyl)- imidazol- hydroklorid
l-benzyl-2-merkapto-5-hydroksymetyl-imidazol (7,5 g) settes
i små porsjoner til en blanding av vann (18 ml) og konsentrert salpetersyre (7,5 g) ved 35°C. Derefter omrøres i 3 timer, og reaksjonsblandingens pH reguleres til 9-10 med natriumhydroksyd.
l-benzyl-5-hydroksymety1-imidazol får man, 3,8 g (60%),
smp. 131-135°C.
l-benzyl-5-hydroksymetyl-imidazol (4,5 g), aktivert Mn 0^
(8,5 g) og dioksan (25 ml) blandes. Derefter omrøres ved 90°C i 6 timer, filtreres og inndampes til tørrhet. Produktet, 1-benzyl-5- karboksaldehyd, krystalliserer fra aceton som hvite krystaller. Utbytte 3.58 g (80%), smp. 52-54 °C
2,3-dimetylfenylmagnesiumbromid (40 g) fremstilt i henhold til vanlige metoder, i 500 ml tetrahydrofuran settes dråpevis til en tetrahydrofuranoppløsning av l-benzyl-5-karboksyaldehyd (12 g). Reaksjonsblandingen omrøres i 5 timer og helles i isvann (170 ml). Derefter omrøres og filtreres. Hvitt l-benzyl-5-[a-(2,3-dimetylfenyl)hydroksymetyl]-imidazol- HCl-salt oppnåes på denne måte, 18,2 g (85%). Produktet kan omkrystalliseres, f.eks. fra isopropanol. l-benzyl-5-[a-(2,3-dimetylfenyl)hydroksymetyl]-imidazol-hydroklorid (17 g), IN HCl oppløsning (190 ml) og Pd/C-katalysator blandes. Derefter foretas hydrogenering på vanlig måte ved normalt trykk ved 60 °C inntil ikke mer hydrogen opptas. Katalysatoren frafiltreres, og filtratet gjøres alkalisk med natriumhydroksyd. Produktet filtreres og tørkes. Produktet kan omdannes til hydrokloridsalt med HCl-isopropanol i etylacetat,
smp. 154-159°C. Utbytte 8 g (70%).
Claims (7)
- L. l-substituerte-5-hydroksymetyl-2-merkapto-imidazoler, karakterisert ved den generelle formelhvor R er R^ er et hydrogen- eller halogenatom, og n er 1-3, en pyridylmetylgruppe eller en alkylgruppe med 1-4 C-atomer.
- 2. Substituerte imidazoler ifølge krav 1, karakterisert ved at R er en benzylgruppe.
- 3. Substituerte imidazoler ifølge krav 1, karakterisert ved at R er en 4-klorbenzylgruppe.
- 4. Substituerte imidazoler ifølge krav 1, karakterisert ved at R er en 2-fenyletylgruppe.
- 5. Substituerte imidazoler ifølge krav 1, karakterisert ved at R er en 2-pyridylmetylgruppe.
- 6. Substituerte imidazoler ifølge krav 1, karakterisert ved at R er en etylgruppe.
- 7. Fremgangsmåte for fremstilling av forbindelser med formel (I),karakterisert ved at dihydroksyaceton-dimer (III) omsettes med kaliumtiocyanat (IV) og et primært amin (V)hvor R er som ovenfor angitt,i en lavere alkohol i nærvær av en syre ved en temperatur på 10 - 100°C, for å danne en forbindelse med formel (I).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI833794A FI833794A0 (fi) | 1983-10-18 | 1983-10-18 | Substituerade 2-merkapto-imidazoler |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO844139L NO844139L (no) | 1985-04-19 |
| NO159167B true NO159167B (no) | 1988-08-29 |
| NO159167C NO159167C (no) | 1988-12-07 |
Family
ID=8517935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO844139A NO159167C (no) | 1983-10-18 | 1984-10-17 | Nye 1-substituerte-5-hydroksymetyl-2-merkapto-imidazol-derivater og fremgangsmaate for fremstilling derav. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4584383A (no) |
| EP (1) | EP0146228B1 (no) |
| JP (1) | JPS60149568A (no) |
| AT (1) | ATE32064T1 (no) |
| AU (1) | AU566437B2 (no) |
| DD (1) | DD236730A1 (no) |
| DE (1) | DE3468869D1 (no) |
| DK (1) | DK174201B1 (no) |
| ES (1) | ES536186A0 (no) |
| FI (1) | FI833794A0 (no) |
| HU (1) | HU191960B (no) |
| IE (1) | IE57591B1 (no) |
| IL (1) | IL73255A (no) |
| NO (1) | NO159167C (no) |
| NZ (1) | NZ209896A (no) |
| SU (1) | SU1301313A3 (no) |
| UA (1) | UA5972A1 (no) |
| ZA (1) | ZA848112B (no) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4634711A (en) * | 1985-08-02 | 1987-01-06 | Smithkline Beckman Corporation | Pyridylalkyl imidazole-2-thiols |
| US5138069A (en) * | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
| FI91754C (fi) * | 1986-12-02 | 1994-08-10 | Tanabe Seiyaku Co | Analogiamenetelmä lääkeaineena käyttökelpoisen imidatsolijohdannaisen valmistamiseksi |
| US4882348A (en) * | 1987-12-29 | 1989-11-21 | Smithkline Beckman Corporation | 2-(aminoalkylthio)imidazoles as dopamine-β-hydroxylase inhibitors |
| CA1338238C (en) | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| US5210079A (en) * | 1988-01-07 | 1993-05-11 | E. I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists |
| US5354867A (en) * | 1988-12-06 | 1994-10-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
| WO1991000281A2 (en) * | 1989-06-30 | 1991-01-10 | E.I. Du Pont De Nemours And Company | Fused-ring aryl substituted imidazoles |
| US5073566A (en) * | 1989-11-30 | 1991-12-17 | Eli Lilly And Company | Angiotensin ii antagonist 1,3-imidazoles and use thereas |
| US5332820A (en) * | 1991-05-20 | 1994-07-26 | E. I. Du Pont De Nemours And Company | Dibenzobicyclo(2.2.2) octane angiotensin II antagonists |
| US5401851A (en) * | 1992-06-03 | 1995-03-28 | Eli Lilly And Company | Angiotensin II antagonists |
| US5612360A (en) * | 1992-06-03 | 1997-03-18 | Eli Lilly And Company | Angiotensin II antagonists |
| IT1295405B1 (it) | 1997-09-30 | 1999-05-12 | Merck Sharp & Dohme Italia S P | Uso di un antagonista recettoriale di angiotensina ii per la preparazione di farmaci per aumentare il tasso di sopravvivenza di |
| KR100567183B1 (ko) * | 1997-11-14 | 2006-06-13 | 론자 아게 | 포르밀이미다졸의제조방법 |
| CN1372551A (zh) * | 1999-09-06 | 2002-10-02 | 株式会社Lgci | 制备1－取代的5－羟甲基咪唑的方法 |
| KR100388788B1 (ko) * | 1999-09-06 | 2003-06-25 | 주식회사 엘지생명과학 | 1-치환된-5-하이드록시메틸 이미다졸의 신규 제조방법 |
| US6620939B2 (en) | 2001-09-18 | 2003-09-16 | General Electric Company | Method for producing bisphenol catalysts and bisphenols |
| US7112702B2 (en) * | 2002-12-12 | 2006-09-26 | General Electric Company | Process for the synthesis of bisphenol |
| FI116292B (fi) | 2003-01-08 | 2005-10-31 | Juvantia Pharma Ltd Oy | Menetelmä substituoitujen imidatsolijohdannaisten valmistamiseksi ja menetelmässä käytettäviä välituotteita |
| US7132575B2 (en) * | 2003-07-01 | 2006-11-07 | General Electric Company | Process for the synthesis of bisphenol |
| FI20050391A0 (fi) * | 2005-04-15 | 2005-04-15 | Orion Corp | Detomidiinihydrokloridin kiteytysmenetelmä |
| CN101747280B (zh) * | 2008-11-28 | 2011-11-09 | 上海迪赛诺医药发展有限公司 | 制备地托咪定及其中间体的方法 |
| US20210323929A1 (en) | 2018-07-18 | 2021-10-21 | Clexio Biosciences Ltd. | Purified Detomidine, Process of Preparing and Methods of Use |
| EP3782989A1 (en) | 2019-08-23 | 2021-02-24 | Andreas Sachse | Detomidine hydrochloride monohydrate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2541924A (en) * | 1948-09-17 | 1951-02-13 | Lilly Co Eli | Synthesis of substituted imidazoles |
| AU518569B2 (en) * | 1979-08-07 | 1981-10-08 | Farmos-Yhtyma Oy | 4-benzyl- and 4-benzoyl imidazole derivatives |
| GB2092569B (en) * | 1981-02-05 | 1984-09-19 | Farmos Oy | Substituted imidazole derivatives and their preparation and use |
-
1983
- 1983-10-18 FI FI833794A patent/FI833794A0/fi not_active Application Discontinuation
-
1984
- 1984-09-24 ES ES536186A patent/ES536186A0/es active Granted
- 1984-10-02 DK DK198404713A patent/DK174201B1/da not_active IP Right Cessation
- 1984-10-16 IL IL73255A patent/IL73255A/xx not_active IP Right Cessation
- 1984-10-16 US US06/661,487 patent/US4584383A/en not_active Expired - Lifetime
- 1984-10-16 NZ NZ209896A patent/NZ209896A/en unknown
- 1984-10-16 JP JP59218160A patent/JPS60149568A/ja not_active Expired - Lifetime
- 1984-10-16 DD DD84268430A patent/DD236730A1/de not_active IP Right Cessation
- 1984-10-16 AU AU34263/84A patent/AU566437B2/en not_active Expired
- 1984-10-16 IE IE2652/84A patent/IE57591B1/en not_active IP Right Cessation
- 1984-10-16 EP EP84307095A patent/EP0146228B1/en not_active Expired
- 1984-10-16 DE DE8484307095T patent/DE3468869D1/de not_active Expired
- 1984-10-16 AT AT84307095T patent/ATE32064T1/de not_active IP Right Cessation
- 1984-10-17 HU HU843890A patent/HU191960B/hu unknown
- 1984-10-17 UA UA3801008A patent/UA5972A1/uk unknown
- 1984-10-17 SU SU843801008A patent/SU1301313A3/ru active
- 1984-10-17 NO NO844139A patent/NO159167C/no not_active IP Right Cessation
- 1984-10-17 ZA ZA848112A patent/ZA848112B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO159167C (no) | 1988-12-07 |
| ES8507507A1 (es) | 1985-09-01 |
| JPS60149568A (ja) | 1985-08-07 |
| DK471384D0 (da) | 1984-10-02 |
| FI833794A0 (fi) | 1983-10-18 |
| DD236730A1 (de) | 1986-06-18 |
| AU3426384A (en) | 1985-04-26 |
| IL73255A (en) | 1988-11-30 |
| DE3468869D1 (en) | 1988-02-25 |
| SU1301313A3 (ru) | 1987-03-30 |
| UA5972A1 (uk) | 1994-12-29 |
| ZA848112B (en) | 1985-06-26 |
| US4584383A (en) | 1986-04-22 |
| HUT35649A (en) | 1985-07-29 |
| IE842652L (en) | 1985-04-18 |
| DK174201B1 (da) | 2002-09-16 |
| ATE32064T1 (de) | 1988-02-15 |
| ES536186A0 (es) | 1985-09-01 |
| DK471384A (da) | 1985-04-19 |
| EP0146228B1 (en) | 1988-01-20 |
| EP0146228A1 (en) | 1985-06-26 |
| AU566437B2 (en) | 1987-10-22 |
| NZ209896A (en) | 1987-02-20 |
| NO844139L (no) | 1985-04-19 |
| IL73255A0 (en) | 1985-01-31 |
| IE57591B1 (en) | 1993-01-13 |
| HU191960B (en) | 1987-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO159167B (no) | Nye 1-substituerte-5-hydroksymetyl-2-merkapto-imidazol-derivater og fremgangsmaate for fremstilling derav. | |
| HU187478B (en) | Process for preparing new imidazolyl-phenyl-amidines and pharmaceutical compositions containing thereof | |
| EP0595111B2 (en) | Carbazolone derivatives and process for preparing the same | |
| NO135751B (no) | ||
| JP3378016B2 (ja) | カルバモイル基を有するイミダゾール誘導体の製造法 | |
| HU196377B (en) | Process for production of 2-substituated-amin-5-acethilimidasoles | |
| NO165104B (no) | Analogifremgangsmaate til fremstilling av terapeutisk aktive 1, 1-disubstituerte cyklopropanderivater. | |
| IL116384A (en) | Iliden assemblies and their preparation | |
| JPH0579061B2 (no) | ||
| HU206088B (en) | Process for produicng 4(5)-(aminoalkyl)-imidazole derivatives | |
| Bastiaansen et al. | 2-Aminomethylimidazole and imidazole-2-carboxaldehyde: two facile syntheses | |
| US2927110A (en) | Process for the preparation of azomethines of 5-nitro-2-formyl furan with hydrazine compounds | |
| EP0719280B1 (en) | Process for the preparation of compounds having ace inhibitory action as well as novel compounds useful as starting materials or intermediates in said process | |
| FI69302B (fi) | 1-substituerade-5-hydroximetyl-2-merkapto-imidazoler | |
| CA1248960A (en) | Substituted 2-mercapto-imidazoles | |
| NO784423L (no) | Fremgangsmaate for fremstilling av nye arylaminoimidazolinderivater | |
| JPH072746B2 (ja) | ベンゾピラノピラゾレン誘導体 | |
| NO850943L (no) | Fremgangsmaate ved fremstilling av dl-beta-arylaminosyrer | |
| NO312721B1 (no) | Fremgangsmåte ved fremstilling av 2-amin-2-imidazolin-, guanidin- og 2-amin-3,4,5,6-tetrahydropyrimidin-derivater | |
| NO833422L (no) | Fremgangsmaate for fremstilling av 4(eller 5)-(1-hydroksyalkyl)imidazol-derivater | |
| KR100393744B1 (ko) | 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1ｈ-이미다졸-1-일)메틸]-4ｈ-카바졸-4-온의 제조방법 | |
| JPS5855459A (ja) | 光学活性トリプトフアン誘導体の製造法 | |
| JP2585283B2 (ja) | イミダゾ−ル誘導体の製造法 | |
| JPS63192747A (ja) | ホルムアミジンのギ酸塩 | |
| Braña et al. | Synthesis of 1, 2‐di‐(4‐pyridyl) ethylenediamine and related compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |