NO145072B - PROCEDURE FOR PREPARING 4- (HYDROXYMETHYL) IMIDAZOLFOR COMPOUNDS. - Google Patents
PROCEDURE FOR PREPARING 4- (HYDROXYMETHYL) IMIDAZOLFOR COMPOUNDS. Download PDFInfo
- Publication number
- NO145072B NO145072B NO76762866A NO762866A NO145072B NO 145072 B NO145072 B NO 145072B NO 76762866 A NO76762866 A NO 76762866A NO 762866 A NO762866 A NO 762866A NO 145072 B NO145072 B NO 145072B
- Authority
- NO
- Norway
- Prior art keywords
- added
- hydroxymethyl
- ammonia
- imidazole
- carboxylic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 title description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical class O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 title 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 70
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 150000001340 alkali metals Chemical class 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- 239000011575 calcium Substances 0.000 claims description 8
- -1 4-(hydroxymethyl)imidazole compound Chemical class 0.000 claims description 7
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- 229910021529 ammonia Inorganic materials 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 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 16
- 229910052708 sodium Inorganic materials 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-UHFFFAOYSA-N 0.000 description 11
- QDYTUZCWBJRHKK-UHFFFAOYSA-N imidazole-4-methanol Chemical class OCC1=CNC=N1 QDYTUZCWBJRHKK-UHFFFAOYSA-N 0.000 description 11
- VLDUBDZWWNLZCU-UHFFFAOYSA-N ethyl 5-methyl-1h-imidazole-4-carboxylate Chemical compound CCOC(=O)C=1NC=NC=1C VLDUBDZWWNLZCU-UHFFFAOYSA-N 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229910052744 lithium Inorganic materials 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical class OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LGDSHSYDSCRFAB-UHFFFAOYSA-N Methyl isothiocyanate Chemical compound CN=C=S LGDSHSYDSCRFAB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960003151 mercaptamine Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- BLPWCLBWWYDASB-UHFFFAOYSA-N (4-ethyl-1h-imidazol-5-yl)methanol Chemical compound CCC=1N=CNC=1CO BLPWCLBWWYDASB-UHFFFAOYSA-N 0.000 description 1
- IETWVRUKWUZOSV-UHFFFAOYSA-N (4-propan-2-yl-1h-imidazol-5-yl)methanol Chemical compound CC(C)C=1NC=NC=1CO IETWVRUKWUZOSV-UHFFFAOYSA-N 0.000 description 1
- UBHDUFNPQJWPRQ-UHFFFAOYSA-N (5-methyl-1h-imidazol-3-ium-4-yl)methanol;chloride Chemical compound Cl.CC=1NC=NC=1CO UBHDUFNPQJWPRQ-UHFFFAOYSA-N 0.000 description 1
- DCYCQZSHGUXYGP-UHFFFAOYSA-N 2-methyl-1h-imidazole-4,5-dicarboxylic acid Chemical compound CC1=NC(C(O)=O)=C(C(O)=O)N1 DCYCQZSHGUXYGP-UHFFFAOYSA-N 0.000 description 1
- VQBKMIRKTBSHDB-UHFFFAOYSA-N 5-(hydroxymethyl)-2-methyl-1h-imidazole-4-carboxylic acid Chemical compound CC1=NC(C(O)=O)=C(CO)N1 VQBKMIRKTBSHDB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KDFQYGBJUYYWDJ-UHFFFAOYSA-N azane;sodium Chemical compound N.[Na] KDFQYGBJUYYWDJ-UHFFFAOYSA-N 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- IULFXBLVJIPESI-UHFFFAOYSA-N bis(methylsulfanyl)methylidenecyanamide Chemical compound CSC(SC)=NC#N IULFXBLVJIPESI-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RIMGDBZXWSGBQN-UHFFFAOYSA-N burimamide Chemical compound CNC(=S)NCCCCC1=CN=C[N]1 RIMGDBZXWSGBQN-UHFFFAOYSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- HCGFHTQCEAGFGW-UHFFFAOYSA-N ethyl 5-ethyl-1h-imidazole-4-carboxylate Chemical compound CCOC(=O)C=1N=CNC=1CC HCGFHTQCEAGFGW-UHFFFAOYSA-N 0.000 description 1
- DDTZMTIDAGDXRZ-UHFFFAOYSA-N ethyl 5-propan-2-yl-1h-imidazole-4-carboxylate Chemical compound CCOC(=O)C=1N=CNC=1C(C)C DDTZMTIDAGDXRZ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- LBVZYUZDHIPGLN-UHFFFAOYSA-N imidazol-1-ylmethanethiol Chemical compound SCN1C=CN=C1 LBVZYUZDHIPGLN-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011877 solvent mixture 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
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
Description
Oppfinnelsen vedrorer en forbedret fremgangsmåte for fremstilling av 4-(hydroksymetyl)imidazolforbindelser ved reduksjon av 4-imidazolkarboksylsyreestere under anvendelse av alkalimetall eller kalsium i flytende ammoniakk, idet en ytterligere protonkilde tilveiebringes under reaksjonen eller etter opparbeiding. The invention relates to an improved process for the production of 4-(hydroxymethyl)imidazole compounds by reduction of 4-imidazole carboxylic acid esters using alkali metal or calcium in liquid ammonia, an additional proton source being provided during the reaction or after work-up.
4-(hydroksymetyl)imidazolforbindelser kan fremstilles ved reduksjon av 4-imidazolkarboksylsyreestere under anvendelse av litium-aluminiumhydrid. Denne fremgangsmåten er kostbar, især for fremstilling av 4-(hydroksymetyl)imidazoler i stor målestokk. 4-(Hydroxymethyl)imidazole compounds can be prepared by reduction of 4-imidazole carboxylic acid esters using lithium aluminum hydride. This method is expensive, especially for the production of 4-(hydroxymethyl)imidazoles on a large scale.
Tamamushi, J. Pharm. Soc. Japan 53: 664-8 (1933), C.A. 28:20049 Tamamushi, J. Pharm. Soc. Japan 53: 664-8 (1933), C.A. 28:20049
(1934), har oppgitt at forsok på reduksjon av 2-metylimidazol-4,5-dikarboksylsyre og estere derav ved hjelp av forskjellige metoder ikke var vellykkede. Med 5-monokloridet resulterer reduksjon med Sn og HC1 i dannelsen av 2-metyl-5-hydroksymetylimidazol-4-karboksylsyre: Det er kjent at heterocykliske ringsystemer kan reduseres ved hjelp av metaller i flytende ammoniakk via en reaksjon av Birch-typen. F.eks. omtaler Remers et al., J. Amer. Chem Soc. 89:5513-4 (1934), have stated that attempts to reduce 2-methylimidazole-4,5-dicarboxylic acid and its esters by various methods were not successful. With the 5-monochloride, reduction with Sn and HC1 results in the formation of 2-methyl-5-hydroxymethylimidazole-4-carboxylic acid: It is known that heterocyclic ring systems can be reduced by means of metals in liquid ammonia via a Birch-type reaction. E.g. reviews Remers et al., J. Amer. Chem Soc. 89:5513-4
(1967), at indol og kinolinringer reduseres ved anvendelse av (1967), that indole and quinoline rings are reduced by the use of
litium og metanol i flytende ammoniakk. Videre beskriver O'Brien et al., J. Chem. Soc. 4609-4611, (1960), at en indol- og karba-zolring, men ikke pyrrolring, kan reduseres ved hjelp av metaller i flytende ammoniakk i nærvær av alkohol. Ved fremgangsmåten ifolge oppfinnelsen reduseres karboksylsyreestergruppen i en 4-. imidazolkarboksylsyreester selektivt til hydroksymetyl uten reduksjon av imidazolringen ved anvendelse av et alkalimetall eller kalsium i flytende ammoniakk samt en ytterligere protonkilde. lithium and methanol in liquid ammonia. Furthermore, O'Brien et al., J. Chem. Soc. 4609-4611, (1960), that an indole and carbazole ring, but not a pyrrole ring, can be reduced by metals in liquid ammonia in the presence of alcohol. In the method according to the invention, the carboxylic acid ester group is reduced in a 4-. imidazole carboxylic acid ester selectively to hydroxymethyl without reduction of the imidazole ring using an alkali metal or calcium in liquid ammonia as well as an additional proton source.
Fremgangsmåten ifolge den foreliggende oppfinnelse er fordelaktig, især i forbindelse med de foretrukne alkalimetaller, dvs. natrium, kalium og litium, fordi de til reduksjon av imidazolkarboksylsyreestere benyttede materialer ikke er dyre, og fordi det oppnås hoye utbytter av hydroksymetylimidazoler med hoy renhetsgrad, The method according to the present invention is advantageous, especially in connection with the preferred alkali metals, i.e. sodium, potassium and lithium, because the materials used for the reduction of imidazole carboxylic acid esters are not expensive, and because high yields of hydroxymethylimidazoles with a high degree of purity are obtained,
dvs. minst 90% renhet. i.e. at least 90% purity.
Fremgangsmåten ifolge oppfinnelsen kan illustreres som folger: The method according to the invention can be illustrated as follows:
hvori in which
R er hydrogen eller lavere alkyl med 1-4 karbonatomer, fortrinnsvis metyl, og R' er lavere alkyl med 1-4 karbonatomer, fortrinnsvis metyl eller etyl. R is hydrogen or lower alkyl with 1-4 carbon atoms, preferably methyl, and R' is lower alkyl with 1-4 carbon atoms, preferably methyl or ethyl.
Ifolge ovennevnte fremgangsmåte reduseres en lavere alkylester av en 4-imidazolkarboksylsyre under anvendelse av et alkalimetall eller kalsium i flytende•amnoniakk med en ytterligere protonkilde til å gi et 4-(hydroksymetyl)imidazol. Fortrinnsvis anvendes et alkalimetall, idet natrium eller litium er særlig foretrukket. Fire ekvivalenter av alkalimetallet eller to ekvivalenter kalsium kreves for hver ekvivalent av esteren. Fortrinnsvis er litt mer enn 4 ekvivalenter av alkalimetallet eller litt mer enn 2 ekvivalenter kalsium til stede. According to the above procedure, a lower alkyl ester of a 4-imidazole carboxylic acid is reduced using an alkali metal or calcium in liquid•ammonia with an additional proton source to give a 4-(hydroxymethyl)imidazole. An alkali metal is preferably used, sodium or lithium being particularly preferred. Four equivalents of the alkali metal or two equivalents of calcium are required for each equivalent of the ester. Preferably, slightly more than 4 equivalents of the alkali metal or slightly more than 2 equivalents of calcium are present.
En protonkilde som det ved fremgangsmåten ifolge oppfinnelsen kreves, her et materiale som avgir et hydrogenion. I alt tre ekvivalenter protoner pr. ekvivalent ester skal tilveiebringes for isolering av den fri hydroksymetylimidazolforbindelsen. De kan oppnås under reaksjonen, under opparbeidelsen eller under en kombinasjon av begge. De ytterligere protonkilder, som anvendes for fremgangsmåten ifolge oppfinnelsen, er med fordel i handelen tilgjengelige materialer. A proton source that is required by the method according to the invention, here a material that emits a hydrogen ion. A total of three equivalents of protons per equivalent ester must be provided for isolation of the free hydroxymethylimidazole compound. They can be obtained during the reaction, during the work-up or during a combination of both. The further proton sources used for the method according to the invention are advantageously commercially available materials.
En alkohol, som fortrinnsvis en lavere alkanol som inneholder 1-6, men helst 2-4, karbonatomer, eller en cykloalkanol som fortrinnsvis inneholder 5-6 karbonatomer, er mest hensiktsmessig å benytte for å oppnå to av de 3 nodvendige ekvivalente protoner. Den. An alcohol, preferably a lower alkanol containing 1-6, but preferably 2-4, carbon atoms, or a cycloalkanol preferably containing 5-6 carbon atoms, is most conveniently used to obtain two of the 3 required equivalent protons. It.
kan være tilstede i reaksjonsblandingen i en hver mengde inntil ca. 2 ekvivalenter alkohol pr. ekvivalent ~ ester. Storre mengder kan anvendes, men forårsaker hurtigere tap av alkali- eller jord-alkalimetallet som folge av dannelse av hydrogengass. Alternativt kan 2 ekvivalenter eller mer av alkoholen tilsettes under opparbeiding. I stedet for disse alkoholer kan forbindelser med en pKa-verdi i intervallet 16-35, fortrinnsvis 16-18, hvor materialene ikke reduseres under fremgangsmåten, anvendes for tilforing av de forste to protoner. F.eks. tilforer den opplosende ammoniakken til å begynne med protoner, når en ytterligere protonkilde som en alkohol, ikke tilsettes for opparbeidingsfasen. can be present in the reaction mixture in any amount up to approx. 2 equivalents of alcohol per equivalent ~ ester. Larger amounts can be used, but cause more rapid loss of the alkali or alkaline earth metal due to formation of hydrogen gas. Alternatively, 2 equivalents or more of the alcohol can be added during work-up. Instead of these alcohols, compounds with a pKa value in the range 16-35, preferably 16-18, where the materials are not reduced during the process, can be used to supply the first two protons. E.g. supplies the dissolving ammonia with protons to begin with, when an additional proton source such as an alcohol is not added for the work-up phase.
Ved opparbeiding og etter alkoholtilsetningen tilsettes 4 ekvivalenter protoner pr. ekvivalent ester fra en protonkilde som er mer sur enn hydroksymetylimidazol, slik som vann, ammoniumsulfat, eddiksyre eller fortrinnsvis ammoniumklorid. 3 av disse ekvi-vanlenter tjener til noytralisering av de 2 forut dannede ekvivalenter alkoksyd (eller annen base) pluss den ene ekvivalent alkoksyd som dannes av imidazolesteren under reduksjonen. Den fjerde ekvivalent tilforer den siste ekvivalent protoner til hydroksymetylimidazolanionene, som er til stede på dette tidspunkt. Hvis man onsker å isolere imidazolalkoholen som syreaddisjonssaltet, må en femte ekvivalent protoner tilfores fra en passende sterk syre, slik som hydrogenklorid. During processing and after the addition of alcohol, 4 equivalents of protons are added per equivalent ester from a proton source more acidic than hydroxymethylimidazole, such as water, ammonium sulfate, acetic acid or preferably ammonium chloride. 3 of these equivalents serve to neutralize the 2 previously formed equivalents of alkoxide (or other base) plus the one equivalent of alkoxide formed from the imidazole ester during the reduction. The fourth equivalent supplies the last equivalent of protons to the hydroxymethylimidazolane anions, which are present at this point. If one wishes to isolate the imidazole alcohol as the acid addition salt, a fifth equivalent of protons must be supplied from a suitable strong acid, such as hydrogen chloride.
Metaller som anvendes ved fremgangsmåten, er f.eks. alkali Metals used in the method are e.g. alkali
metaller, som natrium, kalium eller litium og kalsium. metals, such as sodium, potassium or lithium and calcium.
Imidlertid foretrekkes natrium eller litium ut fra et økonomisk standpunkt til drift i stor målestokk og med henblikk på However, sodium or lithium is preferred from an economic point of view for large-scale operation and with a view to
lett utførelse av fremgangsmåten. easy execution of the procedure.
Reaksjonen utfores ved eller .under kokepunktet for ammoniakk-opplosningen eller -blandingen, hensiktsmessig ved en temperatur i intervallet fra ca. 25°C til ca. -70°C, fortrinnsvis fra ca. -35°C til ca. -50°C. Alternativt kan reaksjonen utfores ved en hoyere temperatur under et trykk, hvorved ammoniakken er flytende. The reaction is carried out at or below the boiling point of the ammonia solution or mixture, suitably at a temperature in the interval from approx. 25°C to approx. -70°C, preferably from approx. -35°C to approx. -50°C. Alternatively, the reaction can be carried out at a higher temperature under pressure, whereby the ammonia is liquid.
Det foretrekkes ved fremgangsmåten ifolge oppfinnelsen å opplose metallet i flytende ammoniakk og til denne opplosning tilsette imidazolkarboksylsyreesteren og en alkohol. Fortrinnsvis tilsettes esteren og alkoholen samtidig, enten separat eller forut blandet, eller også, hvilket er mest hensiktsmessig, tilsettes alkoholen øyeblikkelig fulgt av esteren. Den sistnevnte metode er særlig hensiktsmessig ved drift i stor målestokk. Når alkoholen tilsettes forst fulgt av esteren, foretrekkes det å anvende en mindre sur alkohol som t-butanol, n-butanol eller isopropanol i stedet for en lavere alkanol som metanol. It is preferred in the method according to the invention to dissolve the metal in liquid ammonia and to this solution add the imidazole carboxylic acid ester and an alcohol. Preferably, the ester and the alcohol are added simultaneously, either separately or pre-mixed, or, which is most appropriate, the alcohol is added immediately followed by the ester. The latter method is particularly suitable for operations on a large scale. When the alcohol is added first followed by the ester, it is preferred to use a less acidic alcohol such as t-butanol, n-butanol or isopropanol instead of a lower alkanol such as methanol.
Den alkaliske reaksjonsblandingen opparbeides fortrinnsvis ved kjoling under reaksjonen, f.eks. ved tilsetning av en alkohol, hvorpå den mere sure protonkilde tilsettes, slik som ammoniumklorid, og ammoniakken deretter avdampes. Filtrering og inndampning resulterer i en rest som inneholder 4-(hydroksymetyl) imidazolforbindelsen med formelen II. The alkaline reaction mixture is preferably worked up by cooling during the reaction, e.g. by adding an alcohol, after which the more acidic proton source is added, such as ammonium chloride, and the ammonia is then evaporated. Filtration and evaporation result in a residue containing the 4-(hydroxymethyl)imidazole compound of formula II.
Alternativt kan man kjole reaksjonen ved tilsetning av vann. Derpå ekstraheres 4-(hydroksymetyl)imidazoler med formel II med en alkohol med 3-6 karbonatomer, som n-butanol, n-pentanol eller fortrinnsvis t-butanol. Avdampning av alkoholen fra ekstraktene resulterer i en rest som inneholder 4-(hydroksymetyl)imidazoler. Alternatively, the reaction can be quenched by adding water. 4-(Hydroxymethyl)imidazoles of formula II are then extracted with an alcohol with 3-6 carbon atoms, such as n-butanol, n-pentanol or preferably t-butanol. Evaporation of the alcohol from the extracts results in a residue containing 4-(hydroxymethyl)imidazoles.
4-(hydroksymetyl)imidazolforbindelsen isoleres fortrinnsvis som et syreaddisjonssalt, fortrinnsvis hydrokloridsaltet, ved behandling med en syre under opparbeiding, f.eks med behandling med hydrogenklorid og kcystallisasjon fra et passende losnings- The 4-(hydroxymethyl)imidazole compound is preferably isolated as an acid addition salt, preferably the hydrochloride salt, by treatment with an acid during work-up, for example by treatment with hydrogen chloride and crystallization from a suitable solution
middel som isopropanol eller fortrinnsvis fra en opplosnings-middelblanding som isopropano1/aceton/etyleter. agent such as isopropanol or preferably from a solvent mixture such as isopropanol/acetone/ethyl ether.
4-(hydroksymetyl)imidazolene er nyttige som mellomprodukter for fremstilling av farmakologisk aktive forbindelser, især histamin-^-antagonister, f. eks. N-metyl-N'*-[ 2- ( (5-R-4-imidazolyl) metyl-tio) -etyl Jtiourea samt N-cyano-N'-metyl-N"-[2-((5-R-4-imidazolyl) metyltio)etylJguanidinforbindelser. Histamin-f^-antagonister virker som histamin-f^-reseptorer, som , slik beskrevet av Black et al. (Nature 1972, 236, 385), kan defineres som de histamin-reseptorer, som ikke blokkeres av "antihistaminer", som mepyramii, men blokkeres av burimamid. Blokkeringen av histamin-I^-resptorer er nyttig ved inhibering av de biologiske virkninger av histamin, som ikke inhiberes av "antihistaminer". Histamin-H2-antagonister er nyttige, f.eks. som inhibitorer av mavestyresekresjon. The 4-(hydroxymethyl)imidazoles are useful as intermediates for the preparation of pharmacologically active compounds, especially histamine-^-antagonists, e.g. N-methyl-N'*-[ 2-( (5-R-4-imidazolyl) methyl-thio)-ethyl Jthiourea and N-cyano-N'-methyl-N"-[2-((5-R- 4-imidazolyl)methylthio)ethylguanidine compounds Histamine β-antagonists act as histamine β-receptors, which, as described by Black et al. (Nature 1972, 236, 385), can be defined as those histamine receptors which is not blocked by "antihistamines", such as mepyramii, but is blocked by burimamide. The blocking of histamine I^ receptors is useful in inhibiting the biological effects of histamine, which are not inhibited by "antihistamines". Histamine H2 antagonists are useful, eg as inhibitors of gastric secretion.
N-metyl-N'-[ 2-(( 5--R-4-imidazolyl) metyltio)-etyl Jtiourea. fremstilles ut fra 5-R-4-(hydroksymetyl)-imidazolene med formelen II ved omsetning av hydroksymetylforbindelsen med cysteamin og deretter omsetning av den resulterende 5-R-4-[(2-aminoetyl) tiometylJimidazol med metylisotiocyanat. N-Methyl-N'-[2-((5--R-4-imidazolyl)methylthio)-ethyl Jthiourea. is prepared from the 5-R-4-(hydroxymethyl)-imidazoles of formula II by reacting the hydroxymethyl compound with cysteamine and then reacting the resulting 5-R-4-[(2-aminoethyl)thiomethylimidazole with methyl isothiocyanate.
N-cyano-N<1->metyl-N"-[2-((5-R-4-imidazolyl)-metyltio)etyl] guanidiner fremstilles ut fra 5-R-4(hydroksymetyl)imidazolene med formelen II ved omsetning av hydroksymetylforbindelsen med cysteamin og derpå omsetning av den resulterende 5-R-4-[(2-amino-etyl) tiometyl Jimidazol med N-cyano-N", S-dimetylisotiourea eller ved omsetning av 5-R-4-[(2-aminoetyl)tiometylJimidazol-forbindelsen med dimetyl-N-cyanoimidoditiokarbonat og omsetning av det resulterende N-cyano-N<1->[2-((5-R-4-imidazolyl)metyltio) etylJ-S-metylisotiourea med metylamin. N-cyano-N<1->methyl-N"-[2-((5-R-4-imidazolyl)-methylthio)ethyl] guanidines are prepared from the 5-R-4(hydroxymethyl)imidazoles of the formula II by reaction of the hydroxymethyl compound with cysteamine and then reaction of the resulting 5-R-4-[(2-amino-ethyl)thiomethyl Jimidazole with N-cyano-N",S-dimethylisothiourea or by reaction of 5-R-4-[(2 -aminoethyl)thiomethylJimidazole compound with dimethyl-N-cyanoimidodithiocarbonate and reaction of the resulting N-cyano-N<1->[2-((5-R-4-imidazolyl)methylthio)ethylJ-S-methylisothiourea with methylamine.
Disse tiourea- og cyanoguanidinforbindelser, som fremstilles These thiourea and cyanoguanidine compounds, which are prepd
ut fra 4-(hydroksymetyl)imidazolene med formelen II, er beskrevet i britisk patentskrift 1.333.169 og i US patentskriftene from the 4-(hydroxymethyl)imidazoles with the formula II, is described in British patent document 1,333,169 and in the US patent documents
nr. 3.950.333 og nr. 3.950.353. No. 3,950,333 and No. 3,950,353.
4-(hydroksymetyl)imidazolene anvendes fortrinnsvis i form av syreaddisjonssalter som hydrokloridsalter ved de ovennevnte fremgangsmåter for fremstilling av tiourea- og cyanoguanidinfor-bindelsene. The 4-(hydroxymethyl)imidazoles are preferably used in the form of acid addition salts as hydrochloride salts in the above-mentioned methods for producing the thiourea and cyanoguanidine compounds.
De etterfølgende eksempler illustrerer fremgangsmåten ifølge oppfinnelsen. The following examples illustrate the method according to the invention.
I de etterfølgende eksempler refererer dé anforte utbytter seg til rå isolerte produkter. I samtlige tilfelle med mindre annet er angitt, er produktene minst 90% rene. Den vesentligste til-stedeværende urenhet ved denne fremgangsmåten er ammoniumklorid, som vanligvis er til stede i en mengde på ca. 1-7 vekt-%. 5-R-imidazol-4-karboksylsyre er til stede i en mengde på ca. 1% eller mindre, forutsatt at de foretrukne fremgangsmåter folges, men man kan regne .25-50%, hvis tilsetningsrekkefolgen for' ester til alkalimetall/kalsium-ammoniakk snus (eksempel 4). Ikke i noe tilfelle forefantes produkter som skrev seg fra ..reduksjon av imidazolringen. Når man onsker å oppnå et produkt med den hoyeste renhet, især når store mengder 5-R-imidazol-4-karboksylsyre er til stede, foretrekkes opparbeidelsesfremgangsmåten ifolge eksemp-lene 2 og 4. In the following examples, the given yields refer to crude isolated products. In all cases, unless otherwise stated, the products are at least 90% pure. The most significant impurity present in this process is ammonium chloride, which is usually present in an amount of approx. 1-7% by weight. 5-R-imidazole-4-carboxylic acid is present in an amount of approx. 1% or less, provided that the preferred methods are followed, but one can calculate .25-50%, if the order of addition is for' ester to alkali metal/calcium-ammonia snuff (Example 4). In no case were there any products arising from ..reduction of the imidazole ring. When it is desired to obtain a product of the highest purity, especially when large amounts of 5-R-imidazole-4-carboxylic acid are present, the work-up method according to examples 2 and 4 is preferred.
FJcsemrjel_l FJcsemrjel_l
En 2 liters kolbe ble utstyrt med en ovenfor anbrakt rorer samt A 2 liter flask was equipped with an above placed stirrer as well
et nitrogeninnlop og fylt med 600 ml vannfri ammoniakk.. Et torrisacetonkjolebad ble anvendt for å lette oppsamlingen av ammoniakk og for kjoling under reaksjonen. Etter at ammoniakken var oppsamlet ble natrium (33g , 1,435 M) tilsatt porsjonsvis og opplost, hvilket resulterte i en dypblå farge. t-butanol (25 ml, O,266 M) ble satt til denne opplosningen. 5-metyl-4-imidazolkarboksylsyreetylester (50 g, 0,32 M) ble tilsatt porsjonsvis. Etter tilsetning av esteren ble den blå opplosningen omrort i 5 min. og metanol (100 ml) ble tilsatt dråpevis, hvilket fikk den blå fargen til å forsvinne etter at noen få milliliter var blitt tilsatt. Ammoniumklorid (78 g, 1,458 M) ble tilsatt i porsjoner. Ammoniakken ble avdampet og isopropanol (700 ml) a nitrogen inlet and filled with 600 ml of anhydrous ammonia.. A dry ice acetone dressing bath was used to facilitate the collection of ammonia and for dressing during the reaction. After the ammonia was collected, sodium (33g, 1.435 M) was added portionwise and dissolved, resulting in a deep blue color. t-Butanol (25 mL, 0.266 M) was added to this solution. 5-Methyl-4-imidazole carboxylic acid ethyl ester (50 g, 0.32 M) was added portionwise. After addition of the ester, the blue solution was stirred for 5 min. and methanol (100 mL) was added dropwise, causing the blue color to disappear after a few milliliters had been added. Ammonium chloride (78 g, 1.458 M) was added in portions. The ammonia was evaporated and isopropanol (700 ml)
ble satt til resten, og blandingen ble oppvarmet under tilbakelop i 30 min. med kraftig roring. Blandingen ble kjolt til 40°C og surgjort (pH ca. 1) med hydrogenkloridgass. Vann (10 ml) ble tilsatt, og blandingen ble rort ved 50°C i 30 min. Blandingen ble filtrert, og filterkaken ble vasket med 200 ml varm (40-50°C) isopropanol. Losningen ble inndampet til 100 ml og fortynnet med aceton (400 ml) og eter (100 ml). Produktet ble oppsamlet og torket og gav 46,0 g (96%) 4-(hydroksymetyl)-5-metylimidazol-hydroklorid. was added to the residue, and the mixture was heated under reflux for 30 min. with vigorous rowing. The mixture was cooled to 40°C and acidified (pH approx. 1) with hydrogen chloride gas. Water (10 ml) was added and the mixture was stirred at 50°C for 30 min. The mixture was filtered, and the filter cake was washed with 200 ml of warm (40-50°C) isopropanol. The solution was evaporated to 100 mL and diluted with acetone (400 mL) and ether (100 mL). The product was collected and dried to give 46.0 g (96%) of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
Eksempel 2 Example 2
Ved fremgangsmåten ifolge eksempel 1 kan 4-(hydroksymetyl)-5-metyl-imidazolet alternativt isoleres som base ved hjelp av folgende fremgangsmåte: Etter at ammoniakken er fjernet ved hjelp av fordampning under fremgangsmåten ifolge eksempel 1 tilsettes isopropanol (700 ml) In the method according to example 1, the 4-(hydroxymethyl)-5-methyl-imidazole can alternatively be isolated as a base using the following method: After the ammonia has been removed by means of evaporation during the method according to example 1, isopropanol (700 ml) is added
til resten, og det oppvarmes under tilbakelop i 30 min. ved kraftig roring, hvoretter den resulterende blandingen filtreres, og isopropanolen fjernes ved inndampning i vakuum for å gi 4-(hydroksymetyl) -5-metylimidazol som rest. to the rest, and it is heated under reflux for 30 min. with vigorous stirring, after which the resulting mixture is filtered, and the isopropanol is removed by evaporation in vacuo to give 4-(hydroxymethyl)-5-methylimidazole as a residue.
Eksempel 3 Example 3
En 12-liters kolbe ble utstyrt med en ovenfor anbrakt omrorer A 12-liter flask was equipped with a stirrer placed above
og et nitrogeninnlop og påfylt med 6 1 ammoniakk. Et torris-aceton«-kjolebad ble anvendt for å lette oppsamlingen av ammoniakk og for frembringe kjoling under reaksjonen. Etter at ammoniakken var oppsamlet, ble natrium (335 g, 15,23 M) tilsatt i porsjoner og lost i ammoniakken, hvilket resulterte i en dypblå losning. Tilsetningen av natrium krever ca. 15 min. 5-metyl-4-imidazol-karboksylsyreetylester (500 g, 3,25 M) ble satt til 400 ml torr etanol for å oppnå et vått pulver. Dette våte pulveret ble porsjonsvis med forsiktighet satt til natriumammoniakkopplosning i lbpet av et tidsrom på ca. 30 min. Etter at tilsetningen var av-sluttet, ble 1 1 metanol forsiktig tilsatt. Ammoniumklorid (810 g, 15,28 M) ble meget forsiktig tilsatt inntil den blå and a nitrogen inlet and topped up with 6 1 ammonia. A dry ice-acetone dressing bath was used to facilitate the collection of ammonia and to produce dressings during the reaction. After the ammonia was collected, sodium (335 g, 15.23 M) was added in portions and dissolved in the ammonia, resulting in a deep blue solution. The addition of sodium requires approx. 15 min. 5-Methyl-4-imidazole carboxylic acid ethyl ester (500 g, 3.25 M) was added to 400 mL of dry ethanol to obtain a wet powder. This wet powder was carefully added in portions to sodium ammonia solution in lbpet over a period of approx. 30 min. After the addition was complete, 1 L of methanol was carefully added. Ammonium chloride (810 g, 15.28 M) was very carefully added until blue
fargen var forsvunnet, hvoretter den resterende mengden ammoniumklorid kunne tilsettes hurtigere. Etter tilsetningen av ammoniumkloridet, ble ammoniakken avdampet under anvendelse av et koldt-vannsvarmebad. Etter som blandingens volum avtok, ble oppvarmings-badet gjort varmere. Da nesten all ammoniakk var forsvunnet, the color had disappeared, after which the remaining amount of ammonium chloride could be added more quickly. After the addition of the ammonium chloride, the ammonia was evaporated using a cold-water heating bath. As the volume of the mixture decreased, the heating bath was made hotter. When almost all the ammonia had disappeared,
ble blandingen oppvarmet med damp under et vakuum for fjerning av de siste spor av ammoniakk. Fjerningen av ammoniakk krever 7-15 timer. Isopropanol (6 1) ble satt til resten, og det oppvarmet under tilbakelop i 1 time under kraftig roring. Vann (100 ml) ble så tilsatt, og roringen ble fortsatt i 10 min. Blandingen ble kjolet til ca. 40°C og surgjort med hydrogenkloridgass samt filtrert. Filterkaken ble vasket med varm isopropanol, og det samlede filtrat ble inndampet til ca. 1 1 og fortynnet med 4 1 aceton og 2 1 etyleter. Produktet ble oppsamlet og torket ved 50°C under vakuum for å gi 4-(hydroksymetyl)5-metylimidazol, hydroklorid i et utbytte på 97%. the mixture was heated with steam under a vacuum to remove the last traces of ammonia. The removal of ammonia requires 7-15 hours. Isopropanol (6 L) was added to the residue and heated under reflux for 1 hour with vigorous stirring. Water (100 ml) was then added and stirring was continued for 10 min. The mixture was stirred until approx. 40°C and acidified with hydrogen chloride gas and filtered. The filter cake was washed with hot isopropanol, and the combined filtrate was evaporated to approx. 1 1 and diluted with 4 1 acetone and 2 1 ethyl ether. The product was collected and dried at 50°C under vacuum to give 4-(hydroxymethyl)5-methylimidazole hydrochloride in 97% yield.
Eksempel_4 Example_4
En suspensjon av 5-metyl-4-imidazolkarboksylsyreetylester (3,0 g, 0,02 M) og absolutt etanol (10 ml) ble rort ved torristemperatur i en torr 200 ml kolbe som var utstyrt med en torristilbakelops-kjoler, mens 60-80 ml ammoniakk ble tilsatt. (Alternativt kan 10 ml t-butanol anvendes i stedet for etanol). A suspension of 5-methyl-4-imidazole carboxylic acid ethyl ester (3.0 g, 0.02 M) and absolute ethanol (10 mL) was stirred at oven temperature in a dry 200 mL flask equipped with an oven still back-loop condenser, while 60- 80 ml of ammonia was added. (Alternatively, 10 ml of t-butanol can be used instead of ethanol).
Små biter natrium (fra xylen) ble tilsatt i lopet av 15-20 min,. Opplosningen ble klar under tilsetningen, hvoretter en blå Small pieces of sodium (from xylene) were added over the course of 15-20 min. The solution became clear during the addition, after which a blue
farge holdt seg i et minutt og opplosningen ble uklar. Dette krever 2,2-2,7 g natrium. Reaksjonen tar 20-30 min.. color persisted for a minute and the solution became cloudy. This requires 2.2-2.7 g of sodium. The reaction takes 20-30 min..
Ammoniakken fikk anledning til å fordampe, og vann (50 ml) og The ammonia was allowed to evaporate, and water (50 ml) and
fast natriumklorid ble tilsatt. Den vandige losningen ble ekstrahert med flere 40 ml porsjoner t-butanol. Natriumklorid ble tilsatt under ekstraksjonens forlop. solid sodium chloride was added. The aqueous solution was extracted with several 40 mL portions of t-butanol. Sodium chloride was added during the course of the extraction.
Alkoholskiktet ble avdampet. 4-(hydroksymetyl)-5-metylimidazolet, som var til stede i resten, ble omdannet til hydrokloridsaltet ved behandling med eter og isopropanol samt ved å fore hydrogenkloridgass inn i den bråkjolte losningen. 4-(hydroksymetyl)-5-metylimidazol,hydrokloridet (1,6 g, 55%) ble isolert ved hjelp av filtrering. The alcohol layer was evaporated. The 4-(hydroxymethyl)-5-methylimidazole, which was present in the residue, was converted to the hydrochloride salt by treatment with ether and isopropanol and by passing hydrogen chloride gas into the quenched solution. The 4-(hydroxymethyl)-5-methylimidazole hydrochloride (1.6 g, 55%) was isolated by filtration.
Eksempel 5 Example 5
Ved hjelp av fremgangsmåten ifolge eksempel 1, med ved å anvende etylesteren av 4-imidazolkarboksylsyre i stedet for 5-metyl-4-imidazolkarboksylsyreetylester, oppnås 4-(hydroksymetyl)imidazol som produkt. Using the method according to example 1, with using the ethyl ester of 4-imidazole carboxylic acid instead of 5-methyl-4-imidazole carboxylic acid ethyl ester, 4-(hydroxymethyl)imidazole is obtained as product.
Ennvidere resulterer reduksjonen av 5-etyl-4-imidazolkarboksyl-syreetylester i 5-etyl-4-(hydroksymetyl)imidazol ved fremgangsmåten ifolge eksempel 1, og reduksjon av 5-isopropyl-4-imidazol-karboksylsyreetylester resulterer i 4-(hydroksymetyl)-5-isopropyl-imidazol ved den samme fremgangsmåte^Furthermore, the reduction of 5-ethyl-4-imidazole carboxylic acid ethyl ester results in 5-ethyl-4-(hydroxymethyl)imidazole by the method according to Example 1, and reduction of 5-isopropyl-4-imidazole carboxylic acid ethyl ester results in 4-(hydroxymethyl)- 5-isopropyl-imidazole by the same procedure^
Eksempel 6 Example 6
Én 1 liters kolbe, som var utstyrt med en ovenfor anbrakt omrorer og et nitrogeninnlop, ble fylt med 300 ml vannfri ammoniakk. Kalium (26,0 g, 0,66 M) ble tilsatt. t-butanol (12.5 ml, 0,122 M) , hvoretter 5-metyl-4-imidazolkarboksylsyreetylester (25.0 g, 0,16 M) ble tilsatt porsjonsvis i lopet av 20 min. Reaksjonsblandingen ble orarort i 5 min. og deretter kjolt med 50 ml metanol. Ammoniumklorid (40,0 g, 0,74 M) og isopropanol (400 ml) ble tilsatt, og One 1 liter flask, which was equipped with a stirrer as above and a nitrogen inlet, was filled with 300 ml of anhydrous ammonia. Potassium (26.0 g, 0.66 M) was added. t-butanol (12.5 ml, 0.122 M), after which 5-methyl-4-imidazole carboxylic acid ethyl ester (25.0 g, 0.16 M) was added portionwise over the course of 20 min. The reaction mixture was stirred for 5 min. and then quenched with 50 ml of methanol. Ammonium chloride (40.0 g, 0.74 M) and isopropanol (400 mL) were added, and
ammoniakken ble fjernet ved destillasjon. Hydrogenkloridgass ble tilsatt til ca. pH 1, og de faste stoffer ble frafiltrert. Filtratet ble inndampet til 60 ml og aceton (300 ml) ble til- the ammonia was removed by distillation. Hydrogen chloride gas was added to approx. pH 1, and the solids were filtered off. The filtrate was evaporated to 60 mL and acetone (300 mL) was added
satt. Produktet ble oppsamlet ved hjelp av filtrering og torket for å gi 24 g (93%) 4-(hydroksymetyl)-5-metylimidazol,hydroklorid. sat. The product was collected by filtration and dried to give 24 g (93%) of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
E ksempel 7 Example 7
En 2 liters kolbe, som var utstyrt med en ovenfor anbrakt omrorer og et nitrogeninnlop, ble fylt med 700 ml vannfri ammoniakk. Kalsium (29,0 g, 0,723 M) ble forsiktig tilsatt i porsjoner, t-butanol (25 ml, 0,266 M) ble tilsatt i en porsjon, og 5-metyl-4-imidazolkarboksylsyreetylester (50 g, 0,32 M) ble porsjonsvis tilsatt i lopet av 30 min. Den blå opplesningen ble rort i 40 A 2 liter flask, which was equipped with a stirrer placed above and a nitrogen inlet, was filled with 700 ml of anhydrous ammonia. Calcium (29.0 g, 0.723 M) was carefully added in portions, t-butanol (25 mL, 0.266 M) was added in one portion, and 5-methyl-4-imidazole carboxylic acid ethyl ester (50 g, 0.32 M) was added in portions over the course of 30 min. The blue reading was rowed in 40
min. og metanol (120 ml) ble tilsatt dråpevis. Ammoniumklorid (80,0 g, 1,48 M) og isopropanol (800 ml) ble tilsatt, og ammoniakken ble fjernet. Hydrogenkloridgass ble tilsatt (pH ca. 1), my. and methanol (120 mL) was added dropwise. Ammonium chloride (80.0 g, 1.48 M) and isopropanol (800 mL) were added and the ammonia was removed. Hydrogen chloride gas was added (pH approx. 1),
og de faste stoffer ble frafiltrert. • Filtratet ble inndampet til 100 ml, og aceton (500 ml) ble tilsatt. Produktet ble oppsamlet og torket for å gi 4-hydroksymetyl-5-metylimidazol,hydroklorid (23.0 g 65% rent materiale, utbytte 30%). and the solids were filtered off. • The filtrate was evaporated to 100 ml, and acetone (500 ml) was added. The product was collected and dried to give 4-hydroxymethyl-5-methylimidazole hydrochloride (23.0 g 65% pure material, yield 30%).
Eksempel 8 Example 8
En 2 liters kolbe ble utstyrt med et nitrogeninnlop og et rore-verk plassert ovenfor. Ved hjelp av kjoling og et torris-aceton-bad ble ca. 500 ml flytende ammoniakk oppsamlet i kolben. Metallisk litium (6,3 g, 0,895 M, ca. 25% overskudd) ble lost i flytende ammoniakk for å danne en blå opplosning. Under kontinuerlig kjoling og roring ble 5-metyl-4-imidazolkarboksylsyreetylester (27,58 g, 0,179 M) tilsatt i meget små porsjoner. Etter at esteren var blitt tilsatt, forble reaksjonslosningen blå, og den ble rort i 5 min.. Den blå opplosningen ble så kjolt ved dråpevis tilsetning av 60 ml metanol. Derpå tilsattes oksalsyrepulver A 2 liter flask was fitted with a nitrogen inlet and a stirrer placed above. With the help of dressing and a dry ice-acetone bath, approx. 500 ml of liquid ammonia collected in the flask. Lithium metal (6.3 g, 0.895 M, ca. 25% excess) was dissolved in liquid ammonia to form a blue solution. With continuous stirring and stirring, 5-methyl-4-imidazole carboxylic acid ethyl ester (27.58 g, 0.179 M) was added in very small portions. After the ester was added, the reaction solution remained blue, and it was stirred for 5 min. The blue solution was then quenched by dropwise addition of 60 ml of methanol. Oxalic acid powder was then added
(41 g, 0,45 M) forsiktig. Ammoniakken ble avdampet på et vannbad til en tyktflytende væske ble oppnådd, som ble tatt opp i 500 ml isopropanol. Blandingen ble i en halv time oppvarmet til 60-75°C og kjolt for filtrering. Filtratet ble surgjort til pH 1 med (41 g, 0.45 M) carefully. The ammonia was evaporated on a water bath until a viscous liquid was obtained, which was taken up in 500 ml of isopropanol. The mixture was heated to 60-75°C for half an hour and cooled before filtration. The filtrate was acidified to pH 1 with
hydrogenkloridgass og igjen filtrert. Dette andre filtratet ble inndampet til en tyktflytende væske og fortynnet med aceton. Produktet ble oppsamlet og torket for å gi 20,7 g (78%) 4-(hydroksymetyl)-5-metylimidazolhydroklorid. hydrogen chloride gas and again filtered. This second filtrate was evaporated to a viscous liquid and diluted with acetone. The product was collected and dried to give 20.7 g (78%) of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
E ksem<p>el 9 Example 9
En 5 liters kolbe ble utstyrt med et ovenfor anbrakt rorverkt og spylt med nitrogen. Beholderen ble fylt med 2,7 1 vannfri, flytende ammoniakk uten ytre kjbling. Etter at ammoniakken var oppsamlet, ble natrium (112 g, 4,87 M) tilsatt i små porsjoner. A 5 liter flask was equipped with a stirrer placed above and flushed with nitrogen. The container was filled with 2.7 1 anhydrous, liquid ammonia without external coupling. After the ammonia was collected, sodium (112 g, 4.87 M) was added in small portions.
Etter at natriumet var blitt opplost, ble langsom omroring igangsatt, og 5-metyl-4-imidazolkarboksylsyreetylester (150 g, 0,974 M, i form av 0,5 g tabletter) tilsatt i porsjoner på 2 g med 25-30 sekunders mellomrom. Temperaturen forble rundt -28°C under denne tilsetningen. Etter tilsetningen av esteren forble opplosningen blå. Metanol, 300 ml, ble forsiktig tilsatt dråpevis for å fjerne den blå fargen (hvis den blå farge ikke forsvinner etter metanoltilsetningen, bor omroring fortsettes inntil fargen forsvinner). Etter metanoltilsetningen ble ammoniumklorid (265 g, 4,97 M, ca. 2% overskudd i forhold til M natrium) tilsatt porsjonsvis forsiktig. Etter tilsetningen av ammoniumkloridet ble ammoniakken avdampet til en tyktflytende væske ble oppnådd. Temperaturen på beholderens vegger bor ikke overstige 50°C. Isopropanol (2,1 1) ble tilsatt, og blandingen ble kraftig rort under oppvarming av blandingen til 75°C. Blandingen ble så surgjort med hydrogenkloridgass (til pH ca. 1), og 30 ml vann ble tilsatt. Blandingen ble rort i 15 min. og kjolt til 40-50°C og filtrert. Resten ble vasket med varm isopropanol (2 x 300 ml). Filtratet og vaskevæskene ble inndampet nesten til torrhet (tyktflytende væske), og fortynnet med aceton (1,5 1). Produktet ble oppsamlet og torket for å gi 125,8 g, (87%)4-(hydroksymetyl)-5-metylimidazolhydroklorid. After the sodium had dissolved, slow stirring was initiated and 5-methyl-4-imidazole carboxylic acid ethyl ester (150 g, 0.974 M, in the form of 0.5 g tablets) was added in 2 g portions at 25-30 second intervals. The temperature remained around -28°C during this addition. After the addition of the ester, the solution remained blue. Methanol, 300 ml, was carefully added dropwise to remove the blue color (if the blue color does not disappear after the methanol addition, stirring should be continued until the color disappears). After the methanol addition, ammonium chloride (265 g, 4.97 M, approx. 2% excess in relation to M sodium) was added carefully in portions. After the addition of the ammonium chloride, the ammonia was evaporated until a viscous liquid was obtained. The temperature of the walls of the container must not exceed 50°C. Isopropanol (2.1 L) was added and the mixture was vigorously stirred while heating the mixture to 75°C. The mixture was then acidified with hydrogen chloride gas (to pH about 1), and 30 ml of water was added. The mixture was stirred for 15 min. and cooled to 40-50°C and filtered. The residue was washed with hot isopropanol (2 x 300 ml). The filtrate and washings were evaporated almost to dryness (viscous liquid), and diluted with acetone (1.5 L). The product was collected and dried to give 125.8 g, (87%) of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
E ksempel_10 Example_10
En 5 liters kolbe ble utstyrt med et rorverk plassert ovenfor og spylet med nitrogen. Beholderen ble påfylt med 2,3 1 vannfri, flytende ammoniakk uten ytre kjoling. Etter at ammoniakken var oppsamlet, ble natrium (97 g, 4,22 M, 25% molært overskudd) tilsatt i porsjoner. Etter at natriumet var opplost, ble omroring igangsatt, og 5-metyl-4-imidazolkarboksylsyreetylester (130 g, 0,844 M og i form av 0,5 g tabletter) ble tilsatt i 2 g porsjoner med ca. 30 sek. mellomrom. Etter tilsetningen av esteren ble den blå opplosningen rort i 5 min.. n-propanol (260 ml) ble forsiktig tilsatt dråpevis for fjerning av den blå farge (hvis den blå farge ikke forsvinner under n-propanol-tilsetningen, bor roringen fortsettes, inntil fargen forsvinner!. Ammoniumkloridet (232 g, 4,34 M, et 2% overskudd i forhold til A 5 liter flask was fitted with an agitator placed above and flushed with nitrogen. The container was filled with 2.3 1 of anhydrous, liquid ammonia without outer dressing. After the ammonia was collected, sodium (97 g, 4.22 M, 25% molar excess) was added in portions. After the sodium had dissolved, stirring was initiated and 5-methyl-4-imidazole carboxylic acid ethyl ester (130 g, 0.844 M and in the form of 0.5 g tablets) was added in 2 g portions of approx. 30 sec. space. After the addition of the ester, the blue solution was stirred for 5 min. n-propanol (260 ml) was carefully added dropwise to remove the blue color (if the blue color does not disappear during the n-propanol addition, stirring should be continued, until the color disappears! The ammonium chloride (232 g, 4.34 M, a 2% excess over
M natrium) ble porsjonsvis tilsatt i lopet av 20-30 min. med forsiktighet. Den resulterte ammoniakkblanding ble inndampet til en tyktflytende væske. Beholderens vegger bor. ikke komme over 50°C. n-propanol (2,0 1) ble derpå tilsatt, og blandingen ble oppvarmet under tilbakelop i ca. 10 min for fjerning av det meste av den tilbakeblevene ammoniakk. Blandingen ble surgjort til pH ca. 1 med konsentrert saltsyre og rort i 15 min., mens den ble kjolt til ca. 40°C. Blandingen ble filtrert, og kaken ble vasket med 2 x 300 ml varm (ca. 40°C) n-propanol. Filtratet ble under redusert trykk inndampet til 300 ml, og blandingen fikk stå ved ca. 20°C i 12 timer. Produktet ble oppsamlet og torket for å .gi 90,0 g (72%) 4-(hydroksymetyl)-5-metylimidazolhydroklorid. M sodium) was added in portions over the course of 20-30 min. with caution. The resulting ammonia mixture was evaporated to a viscous liquid. The walls of the container live. do not exceed 50°C. n-propanol (2.0 L) was then added, and the mixture was heated under reflux for approx. 10 min to remove most of the residual ammonia. The mixture was acidified to a pH of approx. 1 with concentrated hydrochloric acid and stirred for 15 min., while it was boiled to approx. 40°C. The mixture was filtered, and the cake was washed with 2 x 300 ml of warm (approx. 40°C) n-propanol. The filtrate was evaporated under reduced pressure to 300 ml, and the mixture was allowed to stand at approx. 20°C for 12 hours. The product was collected and dried to give 90.0 g (72%) of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
Eksempel 11 Example 11
600 ml flytende ammoniakk ble oppsamlet i en 1 liters 3-hals kolbe som var forsynt med nitrogeninnlop og et rorverk basert ovenfor. Under nitrogen ble 18 g metallisk natrium opplost i den, flytende ammoniakken, og 30,2 g 5-metyl-4-imidazolkarboksylsyre-etylester ble tilsatt i små porsjoner i lopet av 25 min.. Reaksjonsblandingen forble lyseblå. Ammoniumklorid, 43,4 g, ble forsiktig tilsatt i små porsjoner, inntil den blå fargen forsvant. Tilsetningshastigheten ble oket således at ammoniakken ble oppvarmet under tilbakelop. Ved avslutningen av tilsetningen ble 400 ml isopropanol tilsatt, og blandingen ble oppvarmet under tilbakelop i 1 1/2 time. Suspensjonen ble kjolt og surgjort med hydrogenklorgass og filtrert. Filtratet ble inndampet til en tyktflytende væske og fortynnet med aceton. Produktet ble torket i en vakuumovn for å gi 23,2 g 4-(hydroksymetyl)-5-metylimidazol-hydroklorid. 600 ml of liquid ammonia was collected in a 1 liter 3-necked flask which was fitted with a nitrogen inlet and a stirrer based on above. Under nitrogen, 18 g of metallic sodium was dissolved in the liquid ammonia, and 30.2 g of 5-methyl-4-imidazole carboxylic acid ethyl ester was added in small portions over 25 min. The reaction mixture remained pale blue. Ammonium chloride, 43.4 g, was carefully added in small portions until the blue color disappeared. The rate of addition was increased so that the ammonia was heated during reflux. At the end of the addition, 400 ml of isopropanol was added, and the mixture was heated under reflux for 1 1/2 hours. The suspension was cooled and acidified with hydrogen chloride gas and filtered. The filtrate was evaporated to a viscous liquid and diluted with acetone. The product was dried in a vacuum oven to give 23.2 g of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
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US60627075A | 1975-08-20 | 1975-08-20 | |
US05/690,476 US4063023A (en) | 1975-08-20 | 1976-05-27 | Process for preparing 4-(hydroxymethyl)imidazole compounds |
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NO762866L NO762866L (en) | 1977-02-22 |
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NO145072C NO145072C (en) | 1982-01-06 |
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JP (1) | JPS6025428B2 (en) |
AT (1) | AT358574B (en) |
AU (1) | AU496917B2 (en) |
CA (1) | CA1064940A (en) |
DD (1) | DD126871A5 (en) |
DE (1) | DE2637670C2 (en) |
DK (1) | DK143749C (en) |
EG (1) | EG12426A (en) |
ES (1) | ES450371A1 (en) |
FI (1) | FI64356C (en) |
FR (1) | FR2321490A1 (en) |
GB (1) | GB1562811A (en) |
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HU (1) | HU177508B (en) |
IE (1) | IE44020B1 (en) |
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NO (1) | NO145072C (en) |
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NZ184893A (en) * | 1976-09-21 | 1980-11-28 | Smith Kline French Lab | Pure crystalline form of cimetidine a(n-methyl-n-cyano-n-(-2-(5-methyl-4imidazolyl) methylthio) ethyl)-guanidine andpharmaceutical compositions containing it |
DE2800148A1 (en) | 1978-01-03 | 1979-07-12 | Basf Ag | PROCESS FOR THE PRODUCTION OF 4-METHYL-5-CHLOROMETHYL-IMIDAZOLE |
DE2825547A1 (en) * | 1978-06-10 | 1979-12-20 | Basf Ag | 1-HYDROXYMETHYLIMIDAZOLE AND ITS USE AS CHEMICAL INTERMEDIATES |
JPS5914460B2 (en) * | 1978-12-27 | 1984-04-04 | 相互薬工株式会社 | Production method of cimetidine, an anti-H↓2 receptor |
JPS63117318U (en) * | 1987-01-24 | 1988-07-29 | ||
JPH0619559U (en) * | 1992-03-16 | 1994-03-15 | 加藤 利夫 | toothbrush |
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1976
- 1976-07-14 CA CA256,981A patent/CA1064940A/en not_active Expired
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- 1976-08-11 FI FI762306A patent/FI64356C/en not_active IP Right Cessation
- 1976-08-13 AT AT606376A patent/AT358574B/en active
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- 1976-08-16 FR FR7624871A patent/FR2321490A1/en active Granted
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- 1976-08-19 JP JP51099204A patent/JPS6025428B2/en not_active Expired
- 1976-08-19 NO NO76762866A patent/NO145072C/en unknown
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1977
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