CS211414B1 - Method of preparation of 1-/3-chlor-2-hydroxypropyl/-2-methyl-5 nitroimidazole - Google Patents

Abstract

The invention relates to a method of preparation compounds of formula I, CH 2 -CH-CH 2 71 ' Oh Cl used in human medicine for treatment protozoal infections. So far this is the substance was prepared by reaction of 2-methyl-4/5 / - -nitroimidazole with epichlorohydrin in 85% formic acid, or by alkylation of 2-methyl- -4- [5-nitroimidazole bis- (3-chloro-2-hydroxypropyl) sulfate. It is an object of the invention a method for preparing a compound of formula I by reaction 2-methyl-4, 5-nitroimidazole with epichlorohydrin in anhydrous nitrobenzene in the presence Lewis acid.

Description

(54) Preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole

The invention relates to a process for the preparation of a compound of formula I,

CH ₂ -CH-CH ₂ ⁷¹ '

Oh Cl used in human medicine for the treatment of protozoal infections. To date, this compound has been prepared by reacting 2-methyl-4 (5) -nitroimidazole with epichlorohydrin in 85% formic acid, or by alkylating 2-methyl-4 (5) -nitroimidazole with bis- (3-chloro-2-hydroxypropyl) sulfate. The present invention provides a process for the preparation of a compound of formula (I) by reacting 2-methyl-4 (5) -nitroimidazole with epichlorohydrin in anhydrous nitrobenzene in the presence of Lewis acid.

/ 1 /

The invention relates to a process for the preparation of a compound of formula (I), ° ₂ n

from CHO

-N-CH-CH? ² II ²

OH Cl used in human medicine to treat pro-social infections. To date, this material has been prepared by reacting 2-methyl-4 (5) -nitroimidazole with epichlorohydrin in 85% formic acid in a yield of 40% [m. Hoffer, E. Grundberg, J. Med. Chem. 17, 1019, (1974)], or by alkylation of 2-methyl-1-4 (5) nitrimidazole with bis- (3-chloro-2-hydroxypropyl) sulfate in a yield of 25% (Amer.). No. 3 5 1 9 637].

The present invention provides the reaction of 2-methyl-4 (5) -nitroimidazole with epichlorohydrin under Lewis acid catalysis in anhydrous nitrobenzene. As the catalyst of the reaction - Lewis acid, it can be used. aluminum chloride, boron trifluoride etherate, boron trifluoride acetate, colorless. ferric chloride zinc chloride and the like, preferably aluminum chloride.

The process according to the invention is carried out by the suspension. 1 mole of 2-methyl-4 (5) -nitroimidazole in anhydrous nitrobenzene add 0.1 to 3 mol, preferably 0.9 to 1 mol, of Lewis acid, and 1 to 6 mol, preferably 1 to 2 mol, epichlorohydrin at -10 to + 70 ° C, preferably 5 ° C to 10 ° C. The reaction mixture is allowed to react at said temperature for 0.1 to 10 hours, preferably 0.1 to 1.5 hours.

After completion of the reaction, the reaction mixture is poured into dilute mineral acid, preferably 20 to 40% sulfuric acid, which is then neutralized with an aqueous ammonia solution to a pH of 6.5 to 7.5. Extracts the solution with an organic solvent _? e.g. dichloromethane, chloroform, benzene, ethyl acetate and the like. The extracts obtained are concentrated, preferably under vacuum, and the crude product is recrystallized from ethyl acetate.

This process has the advantage of significantly reducing the reaction time, lower energy costs, simplifying the isolation and higher yields of the reaction.

In the following, the course of the invention is described in the examples without being limited to these. He limited.

Example 1

To 100 ml of anhydrous nitrobenzene was added, with stirring, 12.7 g (0.1 mol) of 2-methyl-1-4 (5) -nitro-iridazole. Anhydrous aluminum chloride (13.3 g, 0.1 mol) was then added to the suspension at 15-20 ° C. After stirring for 0.5 h, 9.25 g (0.1 mol) of epichlorohydrin was added dropwise to the reaction mixture at 7-10 ° C with stirring. After stirring for 1 h, the reaction mixture was poured onto a previously prepared mixture of ice and conc. 2: 1 sulfuric acid. The nitrobenzene layer was separated and extracted once more with 20% sulfuric acid. The sulfuric acid extracts were combined and washed 2 times with toluene.

The acid solution is then neutralized with aqueous ammonia solution to pH 7.5. The precipitated product is then extracted with ethyl acetate. The ethyl acetate solution is concentrated to dryness under vacuum. The solid residue is suspended in dichloromethane, the unreacted 2-methyl-4 (5) -nitroimidazole is filtered off with suction and the filtrate is concentrated to dryness. An equal amount of ethyl acetate was added to the residue, and 1- [3-chloro-2-hydroxypropyl] -2-methyl-5-nitroimidazole crystallized with stirring and cooling.

which is aspirated and dried. 9.5 g, i.e. 45.5% of the product with a melting point of 84-87 DEG C., are obtained

Example 2

To a suspension of 12.7 g (0.1 mol) of 2-methyl-4 (5) -nitroimidazole in 150 ml of nitrobenzene at room temperature is added 15.4 g (0.095 mol) of anhydrous ferric chloride. After stirring for 0.5 h, 13.9 (0.15 mol) epichlorohydrin was added to the reaction mixture at 5-10 ° C. After 6 h at this temperature, the reaction mixture was poured into 40% sulfuric acid with stirring and cooling. The nitrobenzene layer was separated and shaken once more with 40% sulfuric acid.

Sulfuric acid extracts. joints, rupture 2 shocks with toluene and neutralize with aqueous ammonia solution to pH 7 to 7.5. The precipitated product is extracted with dichloromethane and the dichloromethane is distilled off. The residue was dissolved in an equal amount of ethyl acetate and 1- [3-chloro-2-hydroxypropyl] -2-methyl-5-nitroimidazole crystallized with stirring and cooling, which was filtered off with suction and dried. 4.7 g (21.5%) are obtained.

Example 3

To a suspension of 38.1 g / 0.3 mole / of 2-mety1-4 / 5 / -nitroimidazolu in 200 mL of anhydrous nitrobenzene at a temperature of 5 to 20 ^Q C with stirring was added 40.4 grams / 0.285 mol / boron trifluoride etherate. Subsequently, 55.5 g (0.6 mol) of epichlorohydrin was added to the reaction mixture with stirring at 0 to 10 ° C and the mixture was allowed to stir at this temperature for 2 hours. The reaction mixture is then added under cooling with 150 ml of 207 sulfuric acid and after thorough mixing, the nitrobenzene layer is separated and reextracted with 20% sulfuric acid, the acid extracts are combined, washed with toluene and neutralized with aqueous ammonia solution to pH 7 to 7.5 .

The precipitated product is extracted with dichloromethane and the extract is concentrated. The residue was dissolved in ethyl acetate and crystallized to give the first crystal. Concentration of the mother liquor and crystallization yields a second crystal which is combined with the first. The combined crystals were dried to give 14.0 g of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, i.e. 21%, mp 84-86 ° C.

Example 4

To a suspension of 12.7 g (0.1 mol) of 2-methyl-4 (5) -nitroimidazole in 100 ml of anhydrous nitrobenzene at 15 ° C was added 13.6 g (0.1 mol) of anhydrous zinc chloride and after 0 13.9 g (0.15 mol) of epichlorohydrin was added dropwise at 7-10 ° C. The reaction mixture was stirred at this temperature for 4 h and then poured into 20% sulfuric acid. After separation of the nitrobenzene, it is extracted once more with 20% sulfuric acid.

The acid layers were combined, washed with toluene and neutralized with 10 N NaOH to pH 7.5. The neutral mixture was extracted with dichloromethane. The dichloroethane was distilled off in vacuo, an equal amount of ethyl acetate was added to the distillation residue and the crystallizer was left. The precipitated crystal is filtered off with suction and dried. 4.5 g, i.e. 20% of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, melting at 84-87 ° C, is obtained.

Example 5

The reaction is carried out as in Example 1 with a different isolation. After stirring for 1 h, the reaction mixture was poured into ice water and stirred for a further 10 min, then the precipitated crystal was filtered off with suction and washed with toluene. It is unreacted 2-methyl-4 (5) -nitroimidazole 70-80% and inorganic salts.

The nitrobenzene layer was separated and extracted with 2 times HCl: ice -1: 1. The extracts were combined and washed with 2 times toluene. Chloroform is added to the acid extract and neutralized with aqueous ammonia at a temperature up to 20 ° C to pH 7.5. The chloroform layer was then separated and the aqueous solution was extracted once more with chloroform.

The chloroform is dried and concentrated to dryness in vacuo. An equal amount of ethyl acetate was added to the residue and 1- (3'-chloro-2-hydroxypropyl) -2-methyl-5-nitroiraidazole crystallized with stirring and cooling, which was filtered off with suction and dried. This gives 13.4 g, i.e. 64.2 of the product, m.p. 86-89 ° C.

Claims (5)

OBJECT OF THE INVENTION 1. A process for the preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole of the formula I CHo-CH-CHo ² II ² OH Cl by reaction of 2-methyl-4/5 / -nitroiraidazolu with epichlorohydrin ^comprising: in that the reaction is carried out in anhydrous nitrobenzene in the presence of a Lewis acid at -10 to + 70 ° C for 0.1 to 1.0 hours with 0 1 to 3 moles of Lewis acid and 1 to 6 moles of epichlorohydrin per mole of 2-methyl-4 (5) -nitroimidazole. 2. The process of claim 1 wherein the Lewis acid is anhydrous aluminum chloride. 3. A method according to claim 1, wherein 0.9 to 1 mol of Lewis acid is used per mole of 2-methyl-4 (5) -nitroimidazole. 4. The process of claims 1, 2 and 3, wherein 1 to 3 moles of epichlorohydrin are used per mole of 2-methyl-4 (5) -nitroiraidazole. 5. The process of claims 1, 2, 3 and 4 wherein the reaction is carried out at a temperature of 0 to 20 ° C.