CS237849B1 - Processing of1-/3-chlorine-2-hydroxyropyl/-2methyl-5-nitroimidazole - Google Patents

Abstract

The invention relates to a process for the preparation of 1- (3- chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole formula I, oH a C H 3 CH-CH 3 (IΪ which is used in medicine to treat protozoal infections. It is an object of the invention Reaction of 2-methyl-4 (5-nitroimidazole with epichlorohydrin) in the presence of a Lewis acid characterized by being realized in carboxylic acid esters of a number carbon atoms 1 to 7 with alcohols having carbons 1 to 7, in ketones having carbon numbers 3 to 6 or in ethers or polyethers with carbons 2 to 8 or mixtures thereof or in the presence of a Lewis complex acids with ethers or polyethers the number of carbons 2 to 20 in the above solvents, or mixtures thereof, at temperature -20 ° C to +70 ° C for 0.1 to 10 hrs using 0.1 to 5 moles of Lewis acid or a complex thereof with ethers or polyethers with carbon numbers of 2 to 20 per liter mole -methyl-4 (5-nitroimidazole.

Description

The invention relates to a process for the preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole of the formula I, OH and CH3CH-CH3.

The invention relates to the reaction of 2-methyl-4- (5'-nitroimidazole with epichlorohydrin in the presence of Lewis acid, characterized in that it is carried out in carboxylic acid esters having a carbon number of 1 to 7 seconds. alcohols having a carbon number of 1 to 7, ketones having a carbon number of 3 to 6, or ethers or polyethers having a carbon number of 2 to 8 or mixtures thereof, or in the presence of a Lewis acid complex with ethers or polyethers having a carbon number of 2 to 20 above of said solvents, or mixtures thereof, at a temperature of -20 to + 70 ° C for 0.1 to 10 hours, using 0.1 to 5 moles of Lewis acid or a complex thereof with ethers or polyethers having a carbon number of 2 to 20 per 1 mol 2-methyl-4 (5'-nitroimidazole).

The invention relates to a process for the preparation of a compound of formula I which is used in medicine for the treatment of protozoal diseases.

OH Cl i I

CH5CH-CH _a

(H

To date, this compound has been prepared by reacting 2-methyl-4 (S) -nitroimidazole with epichlorohydrin in 85% formic acid in 40% yield (M. Hoffer, E. Grundberg: J. Med. Chem. 17, 1019 (1974)), alkylation of 2-methyl-4 (S) -nitroimidazole with bis- (3-chloro-2-hydroxypropyl) sulfate in 25% yield (U.S. Patent 3519637) or reaction of 2-methyl-4 (S) -nitroimidazole with epichlorohydrin in nitrobenzene Lewis acid in 45% yield (AO 211414).

The present invention relates to the reaction of 2-methyl-4 (S) -nitroimidazole with epichlorohydrin in the presence of a Lewis acid, characterized in that it is carried out in carboxylic acid esters of 1 to 7 with alcohols of 1 to 7, in ketones with a number of carbons of 3 to 6 or ethers or polyethers of 2 to 8 or mixtures thereof or in the presence of a Lewis acid complex of ethers or polyethers of 2 to 20 in the abovementioned solvents or mixtures thereof at -20 to +70 degrees Celsius, for 0.1 to 10 hours, using 0.1 to 5 moles of Lewis acid or a complex thereof with the above ethers or polyethers and 1 to 6 moles of epichlorohydrin per mole of 2-methyl-4 (5) - nitroimidazole.

As the organic solvent, esters of lower aliphatic carboxylic acids having a carbon number of 1 to 7 with lower aliphatic alcohols having a carbon number of 1 to 7 can be used, for example methyl formate, ethyl acetate, butyl formate and the like. or ketones having a carbon number of 3 to 6 such as acetone, methyl ethyl ketone and the like. or ethers or polyethers having a carbon number of 2 to 8, for example ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dioxane and the like or mixtures thereof, preferably using ethyl acetate.

The reaction is carried out in the presence of a Lewis acid, for example aluminum chloride, zinc chloride, ferric chloride and the like. preferably the use of aluminum chloride or in the presence of a Lewis acid complex with an ether or polyether having a carbon number of 2 to 20, for example, diethyl ether, ethylene glycol dimethyl ether, dioxane, 18-crown-6, can be prepared in the reaction without isolation.

The process according to the invention is carried out by adding 0.1 to 5 moles of Lewis acid, preferably 0.9 to 1.75 moles, to a suspension of 1 mole of 2-methyl-4 (S) -nitroimidazole in anhydrous organic solvent, and 1 to 6 moles, preferably 1 to 2 moles, of epichlorohydrin is added at a temperature of -20 to + 70 ° C, preferably of -10 to + 5 ° C. The reaction mixture is stirred at said temperature for 0.1 to 10 hours, preferably 0.1 to 0.5 hours. After completion of the reaction, the reaction mixture was poured onto ice. After dissolution, the unreacted 2-methyl-4 (S) -nitroimidazole is filtered off. The filtrate was extracted with 2-40% mineral acid. Dichloromethane was added to the acid extract, and the pH was adjusted to pH 3-7 with an aqueous ammonia solution at a maximum of +5 ° C. The precipitated solid was filtered off and the pH of the filtrate was adjusted to pH 7.5 with an aqueous ammonia solution. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The dichloromethane extracts are combined, washed with water, dried chemically and the dichloromethane is distilled off under vacuum at a maximum of 50 ° C. The crude product was recrystallized from ethyl acetate.

The advantage of this process over the previous processes is the replacement of toxic nitrobenzene, easier isolation or higher reaction yields.

The invention is further described in the examples without being limited thereto.

Example 1

To a suspension of 127.1 g of 2-methyl-4- (5-nitroimidazole in 1200 ml of anhydrous ethyl acetate at 238C) was added 238 g of anhydrous aluminum chloride, followed by 166 g of epichlorohydrin with stirring at such a rate that the temperature did not rise. After addition of epichlorohydrin, the reaction mixture is stirred at -5 ° C for 0.5 hours, then poured onto 500 g of ice, and the resulting unreacted 2-methyl-4 (S) -nitroimidazole is filtered off with suction. The organic layer was extracted with dilute sulfuric acid, dichloromethane was added to the aqueous extracts, and the pH was adjusted to 3 to 3.5 with aqueous ammonia solution, and the crystallized ammonium aluminum sulfate was filtered off with suction, and the pH of the filtrate was adjusted to 7.5 with aqueous ammonia solution. The product is extracted into dichloromethane, the dichloromethane is distilled off under vacuum at a maximum of 50 ° C and the residue is recrystallized from ethyl acetate to give 145 g of product, 66%.

To a suspension of 127.1 g of 2-methyl-4 (5) -nitroimidazolu of anhydrous methyl formate at a temperature of ^about -5 C was added 136.3 g of anhydrous zinc chloride. 166 g of epichlorohydrin are then added with stirring at such a rate that the temperature does not exceed 0 ° C. After addition of epichlorohydrin, the reaction mixture was stirred at -5 ° C for 0.5 hours. The reaction mixture was then poured onto 500 g of ice. The resulting unreacted 2-methyl-4- (5'-nitroimidazole is filtered off with suction. The aqueous layer is separated from the filtrate and the organic is extracted with dilute hydrochloric acid. Dichloromethane is added to the aqueous extracts and the pH is adjusted to 7.5 with aqueous ammonia solution. The product was extracted into dichloromethane, the dichloromethane layer was washed with water and dried over anhydrous sodium sulfate, the dichloromethane was distilled off in vacuo at a maximum of 50 ° C and the residue was recrystallized from ethyl acetate to give 55 g of product, 25%.

Example 3

To a suspension of 127.1 g of 2-methyl-4 (S) -nitroimidazole in 1500 ml of anhydrous acetone at -5 ° C was added 150 g of anhydrous zinc chloride. Then 185 g of epichlorohydrin are added at a rate such that the temperature does not exceed 0 ° C. After addition of epichlorohydrin, the reaction mixture was stirred at 0 ° C for 1 hour. 1500 ml of water are then added. The precipitated unreacted 2-methyl-4 (S) -nitroimidazole is filtered off with suction. The filtrate is adjusted to pH 7.5 with aqueous ammonia solution and after filtration the product is extracted into dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate, and the dichloromethane was distilled off in vacuo at a maximum of 50 ° C. The distillation residue is recrystallized from ethyl acetate. 44 g of product are obtained, i.e. 20%.

Example 4

To a suspension of 127.1 g of 2-methyl-4 (S) -nitroimidazole in 1000 ml of ethylene glycol dimethyl ether at 0 ° C was added 133.3 g of anhydrous aluminum chloride. It is then added at 0 ° C

92.5 g of epichlorohydrin and the reaction mixture is stirred for 1 hour. Water (500 ml) was then added to the reaction mixture. The precipitated unreacted 2-methyl-4 (S) -nitroimidazole is filtered off with suction. The aqueous layer was separated from the filtrate and the organic layer was extracted with dilute hydrochloric acid. Dichloromethane was added to the aqueous extracts and the pH was adjusted to 7.5. The precipitated solid is filtered off and the product is extracted into dichloromethane. The dichloromethane extract is washed with water, dried over anhydrous sodium sulfate and the dichloromethane is distilled off under vacuum at a maximum of 50 ° C. The distillation residue is recrystallized from ethyl acetate. 77 g of product are obtained, i.e. 35%.

Example 5

150 g of anhydrous aluminum chloride are added to 500 ml of ethylene glycol dimethyl ether. The resulting white precipitate is filtered off with suction. The precipitate is added at 0 ° C to a suspension of 127.1 g of 2-methyl-4- (5-nitroimidazole in 1200 ml of anhydrous ethyl acetate), then 92.5 g of epichlorohydrin are added at 0 ° C and the reaction mixture is stirred at The reaction mixture is poured onto 500 grams of ice and the precipitated unreacted 2-methyl-4 (5'-nitroimidazole is filtered off with suction. The procedure is as in Example 1. 88 grams of product are obtained. %.

Claims (4)

237849 5 zinc chloride. Then, 166 g of epichlorohydrin is added with stirring at a rate such that the temperature does not exceed 0 ° C. Addition of epichlorohydrin is stirred at -5 ° C for 0.5 hours. Then, the reaction mixture is poured onto 500 g of ice. The unreacted 2-methyl-4 (5-nitro-imidazole is filtered off with suction. The aqueous layer is separated from the filtrate and the organic is extracted with dilute hydrochloric acid. Dichloromethane is added to the aqueous extracts and the pH is adjusted to 7 with aqueous ammonia solution). The solid was filtered off with suction, extracted into dichloromethane, the dichloromethane layer washed with water and dried over anhydrous sodium sulfate, and the dichloromethane was distilled off under vacuum at a maximum of 50 DEG C. and the distillation residue was recrystallized from ethyl acetate. 55 g of product are obtained, i.e. 25% Example 3 150 g of anhydrous chlorine are added to a suspension of 127.1 g of 2-methyl-4 (5) -nitro-imidazole in 1500 ml of anhydrous acetone. Then, 185 g of e-pichlorohydrin are added at a rate such that the temperature does not rise above 0 DEG C. After the addition of epichlorohydrin, the reaction mixture is stirred at 0 DEG C. for 1 hour, then 1500 ml of water are added. methyl- The 4 (5) -nitro-imidazole is filtered off with suction, the filtrate is adjusted to pH 7.5 with ammonia solution, and after filtration the product is extracted into dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate, and dichloromethane was distilled off at a maximum of 50 ° C. The distillation residue is recrystallized from ethyl acetate. 44 g of product are obtained, i.e. 20%. EXAMPLE 4 133.3 g of anhydrous aluminum chloride are added to a suspension of 127.1 g of 2-methyl-4 (5) -nitro-imidazole in 1000 ml of ethylene glycol dimethyl ether (0 DEG C.). Then, at 0 ° C, 92.5 g of epichlorohydrin are added and the reaction mixture is stirred for 1 hour. Then, 500 mL of water was added to the reaction mixture. The precipitated unreacted 2-methyl-4 (5) -nitroimidazole is filtered off with suction. The aqueous layer is separated from the filtrate and the organic layer is extracted with dilute hydrochloric acid. Dichloromethane was added to the aqueous extracts and the pH was adjusted to 7.5. The precipitated solid was filtered off and the product was extracted into dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate, and dichloromethane was distilled off under vacuum at a maximum of 50 ° C. The distillation residue is recrystallized from ethyl acetate. 77 g of product are obtained, i.e. 35%. EXAMPLE 5 150 g of anhydrous aluminum chloride are added to 500 ml of ethylene glycol dimethyl ether. The resulting white precipitate is filtered off with suction. The precipitate is added to a suspension of 127.1 g of 2-methyl-4 (5-nitroimidazole in 1200 ml of anhydrous ethyl acetate at 0 ° C. Then, 92.5 g of epichlorohydrin is added at 0 ° C and the reaction mixture is stirred at 0 ° C). The reaction mixture is poured onto 500 grams of 1 hour and the precipitated unreacted 2-methyl-4 (5'-nitroimidazole is filtered off with suction. Next, proceed as in Example 1. 88 grams of product is obtained, that is 40% OBJECT A process for the preparation of 1- (3-chloro-2-hydroxy-propyl) -2-methyl-5-nitroimidazole of formula I, OH 1 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 (1 / by reaction of 2-methyl-4 ( 5) -nitroimidazole with epi-chlorohydrin in the presence of a Lewis acid characterized in that the reaction is carried out in carboxylic acid esters of carbon numbers 1 to 7 with alcohols counting from 1 to 7, in ketones having carbon numbers of 3 to 6 or in ethers or in polyethers having carbon numbers of 2 to 8 or mixtures thereof or in the presence of a Lewis acid complex with ethers or polyethers having carbon numbers of 2 to 20 in the abovementioned solvents or mixtures thereof, at a temperature of -20 to +70 ° C, for 0.1 to 10 hours using 0.1 to 5 moles of a Lewis acid or complex thereof with the aforementioned ethers or polyethers; and 1 to 6 moles of epichlorohydrin per mole of 2-methyl-4 (5-nitroimidazole) . 2. A process according to claim 1 wherein the solvent is an ester of an organic carboxylic acid having carbon numbers 1-7 of an alcohol having a carbon number of 1-7, preferably ethyl acetate. 3. A process according to claim 1 wherein the solvent is ether or polyether having a carbon number of from 2 to 8, preferably ethylene glycol dimethyl ether. 4. A process according to claim 1, wherein the reaction is carried out in the presence of a Lewis acid complex with a ether or polyether having a carbon number of 2 to 20, preferably in the presence of aluminum complex-ethylene glycol dimethyl ether.