DK174201B1 - Substituerede 2-mercoptoimidazoler eller syreadditionssalte deraf samt fremgangsmåde til fremstilling af disse forbindelser - Google Patents
Substituerede 2-mercoptoimidazoler eller syreadditionssalte deraf samt fremgangsmåde til fremstilling af disse forbindelser Download PDFInfo
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- DK174201B1 DK174201B1 DK198404713A DK471384A DK174201B1 DK 174201 B1 DK174201 B1 DK 174201B1 DK 198404713 A DK198404713 A DK 198404713A DK 471384 A DK471384 A DK 471384A DK 174201 B1 DK174201 B1 DK 174201B1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000002253 acid Substances 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 6
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims abstract description 10
- 229940116357 potassium thiocyanate Drugs 0.000 claims abstract description 7
- KEQUNHIAUQQPAC-UHFFFAOYSA-N Dihydroxyacetone (dimer) Chemical compound OCC1(O)COC(O)(CO)CO1 KEQUNHIAUQQPAC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 101100037762 Caenorhabditis elegans rnh-2 gene Proteins 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- AJDIPXJCUNPHHS-UHFFFAOYSA-N 4-(hydroxymethyl)-1,3-dihydroimidazole-2-thione Chemical class OCC1=CNC(=S)N1 AJDIPXJCUNPHHS-UHFFFAOYSA-N 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
- -1 1-substituted-5-hydroxymethyl-2-mercapto-imidazoles Chemical class 0.000 abstract description 8
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 abstract description 4
- 150000001412 amines Chemical class 0.000 abstract description 3
- 150000002460 imidazoles Chemical class 0.000 abstract description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract description 3
- 125000003158 alcohol group Chemical group 0.000 abstract 1
- 125000003172 aldehyde group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 229910052736 halogen Chemical group 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- 239000011777 magnesium Substances 0.000 abstract 1
- 229910052749 magnesium Inorganic materials 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 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
- RHDJRPPFURBGLQ-UHFFFAOYSA-N detomidine Chemical group CC1=CC=CC(CC=2NC=NC=2)=C1C RHDJRPPFURBGLQ-UHFFFAOYSA-N 0.000 description 6
- 229960001894 detomidine Drugs 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 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
- 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
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical class SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 description 1
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 1
- 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
- OIWRDXKNDCJZSM-UHFFFAOYSA-N 5-[(2,3-dimethylphenyl)methyl]-1h-imidazole;hydron;chloride Chemical compound Cl.CC1=CC=CC(CC=2NC=NC=2)=C1C OIWRDXKNDCJZSM-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 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
- 230000000202 analgesic effect Effects 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013078 crystal Substances 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
- 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
- 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
- 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
- 229910001023 sodium amalgam Inorganic materials 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
i DK 174201 B1
Den foreliggende opfindelse angår hidtil ukendte 1-substituerede-5-hydroxymetyl-2-mercaptoimidazoler med den almene formel 5 //-! 1
H
j ^ CH2OH R
10 hvor R har den i krav 1's kendetegnende del angivne betydning, og syreadditionssalte deraf.
Disse forbindelser er vigtige mellemprodukter ved fremstilling af terapeutisk værdifulde 1,5- og 4(5)-imidazol-15 derivater som fx 4(5)-(2,3-dimetylbenzyl)-imidazol, hvis generiske navn som hydroklorid er detomidin, som er offentliggjort i 1981, se EP patentskrift nr. 24829, og som i form af base har formlen
< y "--R
N s' ™ CH-,
H
25
Forbindelserne med formel I er som nævnt hidtil ukendte. En forbindelse svarende til den almene formel I, men hvor R er et hydrogenatom, er kendt fra publikationen R.A.F. Buller-well et al., J. Chem. Soc. 1951, 3030, hvor den l-osubstituere-^ de forbindelse vindes ved omsætning af serin med kaliumtio-cyanat og natriumamalgam.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 2's kendetegnende del angivne. Den er baseret på en tilpasning af to i forvejen kendte reaktioner.
Disse er Art Lobry de Bruyn - Alberda von Ekenstein omlejring 35 til fremstilling af D-glucosaminderivater (L. Sattier, Adv. Carbohydr. Chemistry 3 (1948) 113 og K. Heynes et al., Z.
DK 174201 B1 2
Naturforsch. 76 {1952) 486), og fremgangsmåden til fremstilling af α-mercaptoglucimidazoler ud fra glucosamin og ka-liumtiocyanat (IF Garcia Gonzales og J. Fernandez Bolanoz,
Anales Real. Soc. Espan. Fis. y Quim. 44 B (1948) 233; G.
5 von Huber et al., Helv. Chim. Acta 43 (1960) 713 og 1787) .
Ved fremgangsmåden ifølge opfindelsen omsættes dihy-droxyacetone-dimer, der har formel III, med en amin til dannelse af aminoaldehydet II, der ringsluttes i nærværelse af en syre med kaliumtiocyanat til dannelse af imidazolderiva-10 ter med formel I i glimrende udbytte.
Beskrevet ved et reaktionsskema er denne fremgangsmåde som følger: 15 0v.CH20H RNH2 'f*10 /'"'-i H0 Jj* OH KSCN 1 CH-NHR —► HS —$ | lavere alkohol J, \N \ hoch2 h Θ ch2oh I ch2oh
L J
R
20 III II I
Forbindelserne ifølge opfindelsen kan forekomme som frie baser eller være omdannet til syreadditionssalte som fx hydroklorider, acetater og sulfater.
25 Ved fremstilling af forbindelser af medicinsk inter esse fjernes mercaptogruppen fra mercaptoimidazolerne ved oxy-dation med salpetersyre og den dannede alkohol oxyderes med mangandioxyd til det tilsvarende aldehyd. Det herved vundne N-substituerede imidazol-karboxaldehyd omsættes med Grignard-30 reagenser til fremstilling af 1,5-imidazolderivater, og når beskyttelsesgruppen på N-atomet fjernes vindes der 4 (5)-monosubstituerede imidazoler.
Syntesen af forbindelserne I finder sted i ét trin. Dihydroxyacetone-dimer, en amin med formlen RNH2 35 og kal iumtiocyanat forenes i en lavere alkohol og omsættes i nærværelse af en syre. Reaktionstemperaturen DK 174201 B1 3 er fra 10 til 100°C.
Detomidin, der har sedative og analgetiske egenskaber er især egnet som sedativ til store husdyr såsom heste og køer og dets fremstilling er beskrevet i 5 europæisk, patentansøgning nr. 0024829. Detomidin fremstilles ud fra forbindelserne med formel I ved at mercaptogruppen fjernes i første trin fra en forbindelse med formel I i fortyndet salpetersyre ved omrøring ved omkring 30-35°C. I det næste trin oxyderes alkoholen 10 til aldehyd, fx ved kogning i dioxan i 6 timer. I tredie trin omsættes et substitueret fenylmagnesium-bromid i tetrahydrofuran med det ovennævnte aldehyd, hvorved der vindes detomidin.
Nedenstående eksempel 1 belyser fremstilling af for-15 bindeiserne med formel I mens eksempel 2 belyser anvendelse af en forbindelse med formel I ifølge opfindelsen til fremstilling af detomidin.
2g Eksempel 1 l-Benzyl-2-merkapto-5-hydroxymetylimidazol 50 ml n-butanol, 25 g iseddikesyre, 21,0 g dihydroxy- acetone-dimer, 34,1 g kaliumtiocyanat og 28,0 g benzylamin sammenblandes ved stuetemperatur. Blandingen omrøres ved 25 stuetemperatur i 50 timer hvorpå produktet filtreres.
13C NMR <DMSO-d6, TMS): 46,35, 53,22, 112,46, 112,61, 126,69, 127,02, 128,20, 130,20, 136,92, 162,53.
Der vindes et lysebrunt produkt i en mængde på 35,0 g (68,2%) og smp. 229-231°C.
30 e
Ved anvendelse af samme fremgangsmåde fremstilles følgende produkter: l-(4-Klorbenzyl)-2-mercapto-5-hydroxymetylimidazol, smp. 217-222°C.
l-(2-Fenylætyl)-2-mercapto-5-hydroxymetylimidazol, *) r smp. 202-208°C.
DK 174201 B1 4 1-(2-Pyridylmetyl)-2-mercapto-5-hydroxymetylimidazol, smp. 181-285°C.
l-Ætyl-2-mercapto-5-hydroxymetylimidazol, smp. 175-250°C (sønderdeling).
5
Eksempel 2 4-(2,3-Dimetylbenzyl)-imidazol-hydroklorid (detomidin-HCl) 7,5 g l-benzyl-2-mercapto-5-hydroxymetylimidazol sættes 10 i små portioner til en blanding af 18 ml vand og 7,5 g koncentreret salpetersyre ved 35°C. Derefter omrøres der i 3 timer og reaktionsblandingens pH-værdi reguleres til 9-10 med natriumhydroxyd. Der vindes 3,8 g (60%) l-benzyl-5-hydroxymetyl-imidazol med smp. 131-135°C.
15 4,5 g l-benzyl-5-hydroxymetylimidazol, 8,5 g aktiveret
MnO- og 25 ml dioxan bringes sammen. Derefter omrøres blandin-gen ved 90°C i 6 timer, filtreres og inddampes til tørhed. Produktet, (1-benzyl-imidazol-5-yl)-karboxaldehyd, krystalliseres fra acetone som hvide krystaller.
20 Udbytte 3,58 g (80%), smp. 52-54°C.
40 g 2,3-dimethylfenylmagnesiumbromid, fremstillet ved kendte metoder, i 500 ml tetrahydrofuran sættes dråbevis til en opløsning i tetrahydrofuran af 12 g (1-benzyl-imidazol-5-yl)-karboxaldehyd. Reaktions-25 blandingen omrøres i 5 timer og udhældes i 170 ml isvand. Derefter omrøres der og filtreres. Der vindes hvidt l-benzyl-5-[α(2,3-dimetylfeny1)-metyl]-imidazol-HCl-salt på denne måde i en mængde på 18,2 g (85%). Produktet kan omkrystalliseres fra fx isopropanol.
30 1 -Benzyl-5-[a(2,3-dimetylfeny1)-metyl]- imidazol-hydroklorid (17 g), 190 ml IN HCl-opløsning og Pd/C katalysator bringes sammen. Der hydrogeneres på sædvanlig måde ved normalt tryk og 60°C indtil der ikke forbruges mere hydrogen. Katalysatoren frafiltreres og filtratet gøres alka-35 DK 174201 B1 5 lisk ved hjælp af natriumhydroxyd. Produktet filtreres og tør res. Produktet kan omdannes til hydrokloridsaltet med HCl-isopropanol i ætylacetat og har smp. 154-159°C. Udbytte 8 g (70%).
Claims (4)
1. Substituerede 5-hydroxymetyl-2-mercaptoimidazoler, kendetegnet ved at de har den almene formel 5 /,N-_ HS_^ | 1 '*1 '^Ss*CH2OH R 10 hvor R betegner en pyridylmetylgruppe, en C1-4 alkyl-gruppe eller en gruppe med formlen
15 R hvor R1 er et hydrogen- eller halogenatom og n et helt tal 1-3, eller er syreadditionssalte deraf.
2. Fremgangsmåde til fremstilling af forbindelser med den almene formel I som er angivet i krav 1 eller syread- 20 ditionssalte deraf, kendetegnet ved at man omsætter dihydroxyacetone-dimer med formel III /O^^CH2OH III HOvM n OH
25 HOCH^"'0 med kaliumtiocyanat med formlen KSCN (IV) og en primær amin med den almene formel RNH2 (V) , hvor R har den i krav 1 an-30 givne betydning, i en lavtkogende alkohol i nærværelse af en syre ved en temperatur på 10-100°C, hvorpå den dannede forbindelse om ønsket omdannes til et syreadditionssalt deraf. 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI833794A FI833794A0 (fi) | 1983-10-18 | 1983-10-18 | Substituerade 2-merkapto-imidazoler |
| FI833794 | 1983-10-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK471384D0 DK471384D0 (da) | 1984-10-02 |
| DK471384A DK471384A (da) | 1985-04-19 |
| DK174201B1 true DK174201B1 (da) | 2002-09-16 |
Family
ID=8517935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198404713A DK174201B1 (da) | 1983-10-18 | 1984-10-02 | Substituerede 2-mercoptoimidazoler eller syreadditionssalte deraf samt fremgangsmåde til fremstilling af disse forbindelser |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4584383A (da) |
| EP (1) | EP0146228B1 (da) |
| JP (1) | JPS60149568A (da) |
| AT (1) | ATE32064T1 (da) |
| AU (1) | AU566437B2 (da) |
| DD (1) | DD236730A1 (da) |
| DE (1) | DE3468869D1 (da) |
| DK (1) | DK174201B1 (da) |
| ES (1) | ES536186A0 (da) |
| FI (1) | FI833794A0 (da) |
| HU (1) | HU191960B (da) |
| IE (1) | IE57591B1 (da) |
| IL (1) | IL73255A (da) |
| NO (1) | NO159167C (da) |
| NZ (1) | NZ209896A (da) |
| SU (1) | SU1301313A3 (da) |
| UA (1) | UA5972A1 (da) |
| ZA (1) | ZA848112B (da) |
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 |
| NO159167B (no) | 1988-08-29 |
| 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 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |