Metronidazole
From The Cure For The Needy
Contents |
Metronidazole (Flagyl)
Effective Against
Metronidazole is selectively taken up by anaerobic bacteria and sensitive protozoa, making it an effective anti-infective medication.
"All but the most severe cases of Amoebiasis can be treated with short cycles of medication. Abscesses throughout the body are first treated, using Metronidazole or a related drug, for 5-10 days. As abscesses cause most symptoms, treatment should show near-immediate increases in health including solid/bloodless stool, increase in appetite, and decrease in liver swelling. Metronidazole is only given to patients who present with severe illness. Both asymptomatic and symptomatic (after Metronidazole cycle) patients are given a second antibiotic such as Iodoquinol for 10-20 days to clear the remaining E. histolytica in the intestine and colon to prevent recurrence of abscesses. "
Study of Metronidazole
A succinct paper on Amebiasis and drugs used to treat it, focusing on Metronidazole, by a Rice University student
Cost
To Cosumers: Walmart offers a prescription for $4 a month which includes 28 250mg tablets. This correlates to about 14 cents a tablet. Walmart $4 Prescriptions
From Sigma-Aldrich: 48.20 USD (5g)
Reported Routes of Synthesis
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.
Abbott GmbH & Co. KG. Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407
Abbott GmbH & Co. KG. Production of 1-hydroxyalkyl-5-nitroimidazoles. GB 1481349, DE 2359625, FR 2253019
M. Ya. Kraft, P. M. Kochergin, A. M. Tsyganova, and V. S. Shlikhunova. Synthesis of Metronidazole from Ethylenediamine. Pharmaceutical Chemistry Journal, 1989 23(10), 1
Alternative Description:
(I) Diaminoethane is prepared and reacted with (II) Acetic Acid under high temperatures to maximize process efficiency. (III) is an intermediate which is treated with lime to deprotonate N (forming Ca(OH)2, very exothermic) and causing a ring-formation reaction. (IV)The 2-Methyl, Dinitrogen ring is treated with Raney Nickel, which surprisingly forms an additional double bond*, forming (V) 2-Methyimidazole. (V) is reacted with Nitric Acid, Sulfuric Acid, and Sodium Sulfate to add a nitro group meta to the methyl. (VI) 2-Methly-5-Nitroimidazole is then treated with an epoxide (VII) and acid to substitute ethanol onto N1. (VIII) Alternatively, (VI) can undergo reflux substitution with 2-Chloroethan-1-ol.
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.
Sunjic, V.; Fajdiga, T.; Kajfez, F.; Process for preparation of 1 - (2'-hydroxyethyl)-2-methyl-5-nitroimidazole. DE 1695321; GB 1138805; US 3520900
Cost of Starting Materials and Selected Reagents:
Starting Material Bromoethyl imidazole pricing not available from Sigma-Aldrich
Formic acid (1 M in H2O) from Sigma-Aldrich: 124 USD (100 ml)
Formamide from Sigma-Aldrich: 39 USD (100 mL)
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.
Lavigne, M.; Mandard-Cazin, B. (Aventis Pharma SA); Process for preparing hydroxyalkyl-1 nitro-5 imidazoles. WO 9113877
Cost of Starting Materials and Selected Reagents:
Starting Material 1-(acetoxymethyl)-2-methyl-4-nitroimidazole pricing not available from Sigma-Aldrich
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Ethylene oxide from Sigma-Aldrich: 498.5 USD (227 g)
Sulfur trioxide from Sigma-Aldrich: 97.3 USD (40 g)
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.
Buforn, A.; Massonneau, V.; Mulhauser, M. (Aventis SA); Process for the preparation of 1-hydroxyalkyl-2-methyl-5-nitro-imidazoles. EP 0325513; FR 2625999
Cost of Starting Materials and Selected Reagents:
Starting Material 1-(acetoxymethyl)-2-methyl-4-nitroimidazole pricing not available from Sigma-Aldrich
Ethylene glycol diacetate from Sigma-Aldrich: 26.5 USD (500 mL)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Acetic anhydride from Sigma-Aldrich: 16.2 USD (5 g)
Ethanol from Sigma-Aldrich: 37.6 USD (100 mL)
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
Reference: Lavigne, M.; Mandard-Cazin, B. (Aventis Pharma SA); Process for preparing hydroxyalkyl-1 nitro-5 imidazoles. WO 9113877
Cost of Starting Materials and Selected Reagents:
Starting Material 2-methyl-4-nitroimidazole pricing not available from Sigma-Aldrich
Acetic anhydride from Sigma-Aldrich: 16.2 USD (5 g)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Ethylene oxide from Sigma-Aldrich: 498.5 USD (227 g)
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
Massonneau, V.; Mulhauser, M.; Buforn, A.; Madard-Cazin, B. (Aventis Pharma SA); Process for the preparation of 1-hydroxyalkyl-5-nitro-imidazoles. EP 0324691
Sanofi-aventis (FR) Process for the preparation of hydroxyalkylating agents, the agents so prepared and their use. EP 0324692
Cost of Starting Materials and Selected Reagents:
Starting Material 1-(acetoxymethyl)-2-methyl-4-nitroimidazole pricing not available from Sigma-Aldrich
Ethylene glycol diacetate from Sigma-Aldrich: 26.5 USD (500 mL)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
1,3,2-Dioxathiolane 2,2-dioxide (ethylene sulfate) from Sigma-Aldrich: 63.7 USD (5 g)
from Sigma-Aldrich: USD ()
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.
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
Available in Vardnayan, R and Hruby, V. Synthesis of Essential Drugs. Elsevier:2006. pg. 576
Cost of Starting Materials and Selected Reagents:
Starting Material 2-Methylimidazole from Sigma-Aldrich: 17 USD (100 g)
Sulfuric acid from Sigma-Aldrich: 67.2 USD (100 mL)
Nitric Acid from Sigma-Aldrich: 83.1 USD (25 mL)
Acetic anhydride from Sigma-Aldrich: 16.2 USD (5 g)
Iron(III) nitrate nonahydrate from Sigma-Aldrich: 201.5 USD (25 g)
2-chloroethanol from Sigma-Aldrich: 15.1 USD (1 g)
Ethylene oxide from Sigma-Aldrich: 498.5 USD (227 g)
Formic acid (1 M in H2O) from Sigma-Aldrich: 124 USD (100 ml)