CS245808B1 - Preparation method of 1-(3-chlorine-2-hydroxypropyl)-2-methyl-5-nitroimidazole - Google Patents

Abstract

The invention relates to a novel process of preparation 1- (3-chloro-2-hydroxypropyl) -2-methyl-5- -nitroimidazolu. This is done by reacting 2-methyl-4- (5) -nitroimidazole sulfate with epichlorohydrin in anhydrous reaction medium containing homogeneous sulfuric acid and saturated an oxygenated organic substance with at least one an oxygen atom, wherein the epichlorohydrin and sulfuric acid is metered into the reaction blends in portions and alternately.

Description

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

The present invention relates to a novel process for the preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole. This is accomplished by reacting 2-methyl-4- (S) -nitroimidazole sulfate with epichlorohydrin in an anhydrous reaction medium containing, in a homogeneous phase, sulfuric acid and a saturated oxygenated organic substance with at least one oxygen atom, wherein epichlorohydrin and sulfuric acid are metered in into the reaction mixture in portions and alternately.

The invention relates to a novel process for the preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole which is used against various protozoal infections, such as e.g. trichomonas.

The title compound has so far been prepared by reacting 2-methyl-4- (5-nitroimidazole with epichlorohydrin in 85% formic acid) (Hoffer M., Grundberg E .:

J. Med. Chem. 17, 1079 (1974), or by alkylation of 2-methyl-4- (5-nitroimidazole with bis- (3-chloro-2-hydroxypropyl) sulfate in a 25% yield (U.S. Pat. 3,519,637). Nitrobenzene, however, is highly toxic and was therefore replaced by acetone or nitromethane or ethyl acetate also by catalysis with Lewis acid (243,559). are up to 40%.

The present invention provides a process for preparing 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-initroimidazole from epichlorohydrin and 2-methyl-4 (S) -nitroimidazole by reacting 2-methyl-4 ( 5) -nitroimldazole with epichlorohydrin in an anhydrous reaction medium containing sulfuric acid in a homogeneous phase and a saturated oxygenated organic substance with at least one oxygen atom, wherein epichlorohydrin and sulfuric acid are metered into the reaction mixture in portions and alternately.

The sulfuric acid salt of 2-methyl-4 (S) -nitroimidazole, i.e. the corresponding sulfate, is obtained by adding 2-methyl-4 (S) -nitroimidazole to a mixture of sulfuric acid and a saturated mixed organic solvent as defined above. Sulfuric acid need not be present in stoichiometric amounts, it can only be added during the reaction when the remaining 2-methyl-4 (S) -nitroimidazole is then converted to the corresponding sulfate.

The mixed solvent may consist, for example, of monohydric or polyhydric alcohols (methanol, glycol, glycerin), ketones with a maximum of 6 carbon atoms, carboxylic acids (monochloroacetic acid, formic acid, acetic acid) or their anhydrides. Of the heterocyclic compounds, e.g. dioxane or tetrahydrofuran. The corresponding substances may also be in the solid state so long as they form a homogenous mixture with sulfuric acid.

The absence of water is important for this reaction. If moisture is present, a larger excess of sulfuric acid should be added. It is not absolutely necessary that all 2-methyl-4- (5'-nitroimidazole is dissolved in the mixture at the start of the reaction. It is gradually converted into a homogeneous mixture by successive dosing of sulfuric acid and epichlorohydrin.

The reaction is carried out at 10 to 50 ° C, preferably 45 to 50 ° C.

After completion of the reaction, the mixture was poured into ice water and allowed to stratify. The lower organic layer was mixed with chloroform and neutralized with ammonia solution to pH = 7 to 7.5 with stirring and cooling (if the reaction mixture did not decompose after pouring water, it was neutralized completely without separation). Upon neutralization, unreacted 2-methyl-4- (5'-nitroimidazole is precipitated, which is filtered off, washed with water and subjected to regeneration. The filtrate is allowed to stratify, the aqueous layer is extracted with chloroform which is added to the chloroform layer of the filtrate. The aqueous acidic layer was neutralized with aqueous ammonia solution to pH = 7 to 7.5 in the presence of pure chloroform, the lower chloroform layer was separated and the acidic (aqueous) was back extracted with chloroform. The chloroform layers are freed from chloroform in a vacuum evaporator, the distillation residue (oily liquid) is mixed with an equal amount of ethyl acetate, the mixture is allowed to crystallize under cooling and stirring, and the precipitated product is filtered off, the mother liquors are concentrated in a vacuum evaporator (max. ), an equal mass of ethyl acetate was added and the previous procedure was repeated product yields are 40-45%, using regenerated 2-methyl-4 (S) -nitroimidazole 60-65 percent. This is regenerated by dissolving hot in ethanol, mixing with activated charcoal (carboraffin j, which is hot filtered and the solution is allowed to crystallize. After filtration and drying, 2-methyl-4- (5'-nitroimidazole) is useful for synthesis.

Further details of the method of the present invention, as well as advantages, are apparent from the examples without limiting it.

Example 1

To 14 ml of acetone and 2.3 ml of ethylene glycol was slowly added 15.8 g (0.16 mol) of conc. H2SO4 at a mixture temperature of up to 40 ° C. Then, 20.0 g (0.157 mol) of 2-methyl-4 (S) -nitroimidazole is slowly added to the solution with stirring. In addition, epichlorohydrin and sulfuric acid are alternatively metered in over the course of 90 to 10 minutes with stirring and cooling in the following order:

1. 17.4 g (0.19 mol) epichlorohydrin

2. 2.3 g H2SO4

3. 15.5 g (0.17 mol) epichlorohydrin

4. 2.3 g H2SO4

5. 13.5 g (0.145 mol) epichlorohydrin

6. 2.0 g H2SO4

7. 15.5 g (0.17 mol) epichlorohydrin

The temperature is maintained between 45 and 50 ° C.

After completion of the dosing, the reaction mixture is poured into 100 ml of cold water. Two layers are formed - upper water and lower orga245808 niche. To the organic layer was added 200 mL of chloroform, and with stirring and cooling (18-20 ° C) the mixture was neutralized with about 9 mL of aqueous ammonia solution to pH = 7 to 7.5. Upon neutralization, unreacted 2-methyl-4- (5'-nitroimidazole in an amount of 4 to 6 g) precipitated, which was filtered off with suction, washed with water and recovered. The combined chloroform layers are extracted 3 times with 20 ml of 9 N H2SO4, the aqueous (acidic) layer is separated, 200 ml of chloroform are added thereto, and neutralized with about 35 ml of an aqueous solution of 25% NH4 OH. to pH = 7 to 7.5 The chloroform layer is separated and the aqueous layer is extracted 2 times with 20 ml of chloroform, the chloroform layers are combined and the solvent is distilled off in a vacuum evaporator at a maximum temperature of 40 ° C. 5 g) of an equal mass of ethyl acetate was added and the crude product crystallized under stirring and cooling, and the filtrate was concentrated by evaporation and the process repeated to give 15.6 g (45%) of 1- (3-chloro-2-hydr). oxypropyl) -2-methyl-5-nitroimidazole, m.p. 84-87 ^° C.

Example 2

17.6 g of monochloroacetic acid and 20.0 g (0.157 mol) of 2-methyl-4 (S) -nitroimidazole are dissolved in 11.7 g of concentrated sulfuric acid at a temperature of up to 50 ° C. Epichlorohydrin and sulfuric acid were added to the reaction mixture at 45-50 ° C with stirring and cooling for 90-110 minutes in the following amounts:

1. 25.1 g (0.27 mol) of epichlorohydrin

2. 2.3 g H2SO4

3. 17.7 g (0.19 mol) epichlorohydrin

4. 2.3 g H2SO4

5. 22.3 g (0.24 mol of epichlorohydrin)

The isolation procedure described in Example 1 gives 6.1 g of unreacted starting material and 13.8 g (40% of theory) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, m.p. 84.5 to

87.5 ° C.

Example 3

To 7.6 g of 85% formic acid at 40 ° C was added under stirring and cooling

9.5 g acetic anhydride and 9.5 g conc. sulfuric acid. 20 g (0.157 mol) of 2-methyl-4 (S) -nitroimidazole are then added to this suspension at 45-50 ° C for 80-110 minutes with stirring and cooling, epichlorohydrin and sulfuric acid are added in the following amounts:

1. 10.2 g (0.11 mol) of epichlorohydrin

2. 6.4 g (H2SO4

3. 12.1 g (0.13 mol of epichlorohydrin)

4. 2.3 g H2SO4

5. 12.1 g (0.13 mol of epichlorohydrin)

6. 2.3 g H2SO4

7. 17.7 g (0.19 mol) epichlorohydrin

The reaction mixture was worked up by the isolation procedure described in Example 1. It was obtained

14.5 g (42% of theory) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, m.p. 84.5-87.5 ° C.

Example 4

To a mixture of 12.0 mL dioxane, 2.0 mL tetrahydrofuran, 4.0 mL acetone and 12 mL butanol was added 15.9 g conc. sulfuric acid at a temperature of up to 45 ° C and then 20 g (0.157 mole of 2-2methyl-4- (5'-nitroimidazole) are added. At 45-50 ° C, epichlorohydrin and sulfuric acid are metered in with the following amounts while cooling and stirring:

1. 25.1 g (0.27 mol of epichlorohydrin)

2. 2.0 g H2SO4

3. 19.0 g (0.20 mol of epichlorohydrin)

4. 2.0 g H2SO4

5. 19.0 g (0.20 mol of epichlorohydrin)

The reaction mixture is worked up according to the isolation procedure described in Example 1. 13.8 g (40% of theory) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, m.p. Low: 14 ° C.

Claims (4)

245808 nicka. 200 ml of chloroform are added to the organic layer and the mixture is neutralized with about 9 ml of aqueous ammonia solution to pH = 7 to 7.5 with stirring and cooling (18 to 20 ° C). Proteutralization yields unreacted 2-methyl-4 (5] -nitroimidazole in 4-6 g. This is suctioned off, washed with water and subjected to regeneration. The filtrate is layered, the aqueous layer is extracted twice with 20 ml of chloroform. The combined chloroform layers are extracted 3 times with 20 mL of 9 N 2 SO 4, the aqueous (acidic) layer is separated, 200 mL of chloroform is added and neutralized with about 35 mL. The pH of the aqueous layer was 25% NH 4 OH to pH = 7.5 to 7. The chloroform layer was separated and the aqueous layer was extracted with 2 x 20 mL chloroform, and the chloroform layers were combined and the solvent was distilled off under vacuum. evaporation at a maximum temperature of 40 DEG C. The same amount of ethyl acetate is added to the distillation residue (16.5 g) and the crude product is crystallized with stirring and the filtrate is concentrated by evaporation and the process is repeated. 6 g (45%) of 1 - (3-chloro-2-h of hydroxypropyl) -2-methyl-5-nitro-imidazole, m.p. EXAMPLE 2 17.6 g of monochloroacetic acid and 20.0 g (0.157 mol) of 2-methyl-4 (5) -nitroimidazole are dissolved in 11.7 g of concentrated sulfuric acid at a temperature of up to 50 ° C. Epichlorohydrin and sulfuric acid are added to the reactor at 45-50 ° C for 90-110 minutes in the following amounts: 1. 25.1 g (0.27 mol) of epichlorohydrin 2. 2.3 g H2SO4 3. 17.7 g (0.19 mol) epichlorohydrin 4. 2.3 g H2SO4 5. 22.3 g (0.24 mol) epichlorohydrin The isolation procedure described in Example 1 gives 6, 1 g of unreacted starting material and 13.8 g (40% of theory) of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, m.p. High: 5 ° C. Example To 7.6 g of 85% formic acid at 40 DEG C., 9.5 g of acetic anhydride and 9.5 g of conc. sulfuric acid. Then 20 g (0.157 mol) of 2-methyl-4 (5) -nitroimidazole are added. To this suspension, epi-chlorohydrin and sulfuric acid are metered in at 80 DEG-110 DEG C. for 80 to 110 minutes in the following amounts: 1. 10.2 g (0.11 mol) of epichlorohydrin 2. 6 , 4 g (H2SO4 3. 12.1 g (0.13 mol) epichlorohydrin 4. 2.3 g H2SO4 5. 12.1 g (0.13 mol) epichlorohydrin 6. 2.3 g H2SO4 7. 17.7 g (0.19 mol) epichlorohydrin The reaction mixture was worked up as described in Example 1. 14.5 g (42% of theory) of 1- (3-chloro-2-hydroxy-propyl) -2-methyl-5 was obtained. -nitroimidazole, m.p. 84.5-87.5 ° C 15.9 g of conc. Are added to a mixture of 12.0 ml of dioxane, 2.0 ml of tetrahydrofuran, 4.0 ml of acetone and 12 ml of butanol. sulfuric acid at 45 ° C and 20 g (0.157 mmol) of 2-methyl-4 (5) -nitroimidazole are then added. Then, at 45 to 50 ° C, while cooling and stirring, epichlorohydrin and acid kinase are dosed in the following amounts: 1. 25.1 g (0.27 mol) epichlorohydrin 2. 2.0 g H2SO 4 3. 19.0 g (0.20 mol) epichlorohydrin 4. 2.0 g H 2 SO 4 5. 19.0 g (0.20 mole) epichlorohydrin The reaction mixture is worked up according to the isolation procedure described in Example 1. 13.8 g (40% of theory) is obtained. 3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, m.p. 84-87.5 ° C. ARTICLE Preparation of 1- (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole from epichlorohydrin and 2-methyl-4 (5) -nitroimidazole, which reacts with sulfate 2 -methyl-4 (5) -nitroimidazole with epichlorohydrin in an anhydrous reaction medium containing sulfuric acid and saturated oxygenate with at least one oxygen atom in the homogeneous phase, wherein epichlorohydrin and sulfuric acid are metered into the reaction medium mixed blends and alternately.