药物详细合成路线
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: |
![](http://image28.360doc.com/DownloadImg/2011/05/0322/11432235_1.gif) |
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 |
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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. |
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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) |
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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 |
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Intermediates: |
Serial No. |
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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 |
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Intermediates: |
Serial No. |
3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-4-phenyl-1,4-dihydropyridine |
(II) |
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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 |
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Intermediates: |
Serial No. |
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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 |
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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) |
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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 |
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Intermediates: |
Serial No. |
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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 . |
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