| Chemical Name： | 2-Methyl-5-nitro-1H-imidazole-1-ethanol | | Generic Name： | 甲硝唑;Metronidazole | | Other Names： | Metronidazole;IDR-90105(Ophthalmic);Rosased;Zidoval;Metrogel;Flagyl | | CAS： | 443-48-1 | | Related CAS： | 133884-00-1 (deleted CAS) | | Formula： | C6H9N3O3 | | Mole Weight： | 171.15693 | | structure： | | | Company： | Pfizer (Originator), 3M Pharmaceuticals (Not Determined), Novartis (Not Determined), Pierre Fabre (Not Determined), Institute for Drug Research (Licensee) | | Usage： | Acne Therapy, Antiamebics, Antibacterial Drugs, Antibacterial Ophthalmic Drugs, Antifungal Agents, ANTIINFECTIVE THERAPY, Antitrichomonals, DERMATOLOGIC DRUGS, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Treatment of Protozoal Diseases | | | |
| Route 1 | 2-Methylimidazole (I) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in Ac2O to produce 2-methyl-4-nitroimidazole (II) . In a variant of this procedure, 2-methylimidazole (I) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. Imidazole (II) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. Alternatively, the alkylation of (II) has been reported by treatment with ethylene oxide (III) under acidic conditions. | | | | Intermediates: | Serial No. | | 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-4-phenyl-1,4-dihydropyridine | (III) | | (3aR,6aS)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde | (I) | | ethyl (1R,2S,4R)-2-isopropenyl-1-methyl-4-vinylcyclohexanecarboxylate | (II) | | | Reference 1: Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . Reference 2: Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
Route 2 | In an alternative procedure, the title compound is obtained by hydrolysis of the bromoethyl imidazole (I) in the presence of formic acid in aqueous formamide | | | | Intermediates: | Serial No. | | | Reference 1: Sunjic, V.; Fajdiga, T.; Kajfez, F.; Process for preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole. DE 1695321; GB 1138805; US 3520900 . |
Route 3 | The title compound can be obtained by reaction of 1-(acetoxymethyl)-2-methyl-4-nitroimidazole (I) with ethylene oxide (II) in the presence of sulfur trioxide, followed by hydrolysis in aqueous H2SO4 | | | | Intermediates: | Serial No. | | 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-4-phenyl-1,4-dihydropyridine | (II) | | | Reference 1: Lavigne, M.; Mandard-Cazin, B. (Aventis Pharma SA); Process for preparing hydroxyalkyl-1 nitro-5 imidazoles. WO 9113877 . |
Route 4 | In a related procedure, 1-(acetoxymethyl)-2-methyl-4-nitroimidazole (I) is condensed with ethyleneglycol diacetate (II) in the presence of anhydrous H2SO4, followed by hydrolysis or alcoholysis under acidic conditions to produce the title compound | | | | Intermediates: | Serial No. | | | Reference 1: Buforn, A.; Massonneau, V.; Mulhauser, M. (Aventis SA); Process for the preparation of 1-hydroxyalkyl-2-methyl-5-nitro-imidazoles. EP 0325513; FR 2625999 . |
Route 5 | Alternatively, 2-methyl-4-nitroimidazole (I) is protected by acylation in hot acetic anhydride to give (II). Addition of ethylene oxide (III) to the N-acetyl imidazole (II) in the presence of SO3, followed by acidic hydrolysis furnishes the title compound | | | | Intermediates: | Serial No. | | 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-4-phenyl-1,4-dihydropyridine | (III) | | ethyl (1R,2S,4R)-2-isopropenyl-1-methyl-4-vinylcyclohexanecarboxylate | (I) | | | Reference 1: Lavigne, M.; Mandard-Cazin, B. (Aventis Pharma SA); Process for preparing hydroxyalkyl-1 nitro-5 imidazoles. WO 9113877 . |
Route 6 | The title compound can also be obtained by alkylation, in different solvents, of 1-(acetoxymethyl)-2-methyl-4-nitroimidazole (I) with either ethylene sulfate (II) or with bis-(2-acetoxyethyl) sulfate (III) -generated from ethyleneglycol diacetate (IV) and either dimethyl sulfate or H2SO4 - followed by hydrolysis or alcoholysis treatment | | | | Intermediates: | Serial No. | | | Reference 1: Massonneau, V.; Mulhauser, M.; Buforn, A. (Aventis Pharma SA); Process for the preparation of hydroxyalkylating agents, the agents so prepared and their use. EP 0324692 . Reference 2: Massonneau, V.; Mulhauser, M.; Buforn, A.; Madard-Cazin, B. (Aventis Pharma SA); Process for the preparation of 1-hydroxyalkyl-5-nitro-imidazoles. EP 0324691 . | | | |
