CH624942A5 - Process for the preparation of 1-methyl-2-(alkylsulphonylphenoxymethyl)-5-nitroimidazoles - Google Patents

Description

624 942

2nd

PATENT CLAIM Process for the preparation of l-methyl-2-phenoxy-methyl) -5-nitro-imidazoles of the formula I.

—Ch2-o- / JV- r2

CH2-0- / ^

-R £

R-

(I)

o2n

II1

M 3 CI) '

R ^

wherein R1 is methyl and R2 is methylsulfonyl or ethylsulfonyl and R3 is hydrogen, methyl or halogen, characterized in that l-methyl-2- (phenoxymethyl) -5-ni-tro-imidazole of the formula II

found,

wherein R1 is methyl, R2 is methylsulfonyl or ethylsulfonyl and io R3 is hydrogen, methyl or halogen such as fluorine, chlorine, bromine or iodine, which is characterized in that l-methyl-2- (phenoxymethyl) -5-nitro-imidazole of the formula II

A - R

wherein A is a sulfur atom or a sulfoxide group (—SO—), R is methyl or ethyl, R1 is methyl and R3 is hydrogen, methyl or halogen.

CH-PS 616 926 relates to l-alkyl-2- (phen-oxymethyl) -5-nitro-imidazoles of the formula

R

ch2-o

R-

wherein R1 is methyl or ethyl, R2 trifluoromethyl, trichloromethyl, nitro, cyano, methylsulfonyl or ethylsulfonyl and R3 is hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, tri-chloromethyl, nitro or cyano, process for the preparation of these compounds, them containing pharmaceutical compositions and their use.

Furthermore, l-methyl-2- (phenoxymethyl) -5-nitro-imidazoles of the formula

OoN

ch2-o wherein R1 is nitro, cyano, methylsulfonyl or ethylsulfonyl and R2 is methyl or halogen, processes for the preparation of these compounds, pharmaceutical compositions containing them and their use have already been proposed.

It has now become a process for the preparation of 1-methyl-2- (phenoxymethyl) -5-nitro-imidazoles of the formula I.

(II)

wherein A is a sulfur atom or a sulfoxide group (-SO-), R is methyl or ethyl, R1 is methyl and R3 is hydrogen, methyl or halogen such as fluorine, chlorine, bromine or iodine.

25 The l-methyl-2- (phen-oxymethyl) -5-nitro-imidazoles of the formula II used as starting materials are described in CH-PS 605 813. You can from l-methyl-2-chloromethyl-5-nitro-imidazole (available according to DE-OS 1 595 929 and DE-OS 1 470 102) and optionally substituted alkyl-30 mercaptophenols or alkylsulfinylphenols (available from the corresponding mercaptophenols and dialkyl sulfate and, if appropriate, subsequent oxidation with perbenzoic acid) in dimethylformamide and in the presence of potassium carbonate.

35 Examples of possible starting materials of the formula II are:

l-methyl-2- (4-methylthio-phenoxymethyl) -5-nitro-imidazole l-methyl-2- (4-ethylthio-phenoxymethyl) -5-nitro-40 imidazole l-methyl-2- (3-methyl- 4-methylthio-phenoxymethyl) -5-nitro-imidazole

1-Methyl -2- (3-methyl-4-ethylthio-phenoxymethyl) -5-nitro-imidazole

45 l-methyl-2- (3-fluoro-, -chloro-, -bromo-, -iodo-4-methylthio-phenoxymethyl) -5-nitro-imidazole l-methyl-2- (3-fluoro-, -chlor -, -bromo-, -iodine-4-ethythio-

phenoxymethyl) -5-nitro-imidazole l-methyl-2- (4-methylsulfinyl-phenoxymethyl) -5-nitro ~ so imidazole l-methyl-2- (4-ethylsulfinyl-phenoxymethyl) -5-nitro-imidazole l-methyl -2- (3-methyl-4-methylsulfinyl-phenoxymethyl) -5-nitro-imidazole 55 l-methyl-2- (3-methyl-4-ethylsulfinyl-phenoxymethyl) -5-nitro-imidazole l-methyl-2- (3-fluorine, chlorine, bromine, iodine-4-methyl

sulfinyl-phenoxymethyl) -5-nitro-imidazole 1-methyl-2- (3-fluoro-, -chloro-, -bromo-, -iodo-4-ethyl-60 sulfinyl-phenoxymethyl) -5-nitro-imidazole

Single or double molar amounts of an oxidizing agent are expediently used for the oxidation. An excess of the oxidizing agent can often be used advantageously. If the corresponding 65 sulfides (A = —S— in formula II) are used as starting materials, at least two molar equivalents of oxidizing agent are required. If the corresponding sulfoxides (A = -SO- in formula II) are used as the starting material, a molar equivalent of oxidizing agent is required.

624 942

tel. Possible oxidizing agents are, for example, hydrogen peroxide or peracids, e.g. Peracetic acid, pertrifluoroacetic acid, chloroperbenzoic acids, in particular 3-chloroperbenzoic acid, nitric acid, chromic acid and its salts, chromic anhydride, permanganates, hypochlorites, chlorates, perchlorates, periodates and nitrogen oxides, especially nitrous oxide.

The oxidation reactions are advantageously carried out in a solvent or distribution medium. Solvents which are not attacked by the oxidizing agent, such as e.g. Acetic acid, tri-fluoroacetic acid. When using perbenzoic acid, methylene chloride and chloroform are also suitable as solvents. The oxidation reactions are generally carried out at temperatures between 0 and 100 ° C, in particular at 40-60 ° C. Depending on the reaction conditions, the reaction times range from a few minutes to a few hours.

The process products are isolated by diluting the reaction solution with water with simultaneous precipitation, or by evaporating the organic solvent in vacuo. If necessary, cleaning can be carried out by recrystallization from a suitable solvent or solvent mixture.

example 1

l-methyl-2- (4-methylsulfonylphenoxymethyl) -5-nitro-imidazole

27.9 g (0.1 mol) of l-methyl-2- (4-methylthio-phenoxy-methyl) -5-nitro-imidazole (mp. 116 ° C.) are dissolved in 250 ml of glacial acetic acid and, with stirring at room temperature, 24 , 3 g (0.25 mol) of 35% hydrogen peroxide were added dropwise. The exothermic reaction causes the temperature to rise to approx. 45 ° C. The mixture is then heated to 60 ° C. for 1 hour with stirring. After cooling to room temperature, the batch is poured onto 800 ml of an ice / water mixture, the precipitate is filtered off with suction, washed with water and recrystallized from isopropanol with the addition of activated carbon. This gives 29 g = 93% of theory l-methyl-2- (4-methyl-sulfonylphenoxymethyl) -5-nitro-imidazole in the form of yellowish crystals with a melting point of 157 ° C. Instead of the starting material l-methyl-2- (4-methylthiosphenoxymethyl) -5-nitro-imidazole, the corresponding sulfoxide,

l-methyl-2- (4-methylsulfinyl-phenoxymethyl) -5-nitro-imidazole

(Mp 130 ° C) can be used. It is then sufficient to use half the amount of hydrogen superoxide. The following can be prepared in the same way: l-methyl-2- (4-ethylsulfonylphenoxymethyl) -5-nitro-imidazole, mp. 132 ° C. by oxidation of l-methyl-2- (4-ethylthio-phenoxymethyl) -5- nitro-imidazole (mp. 90 ° C) or 15 l-methyl-2- (4-ethylsulfinyl-phenoxymethyl) -5-nitro-imidazole (mp. 103 ° C).

1-methyl-2- (3-methyl-4-methylsulfonyl-phenoxymethyl) -5-nitro-imidazole (mp. 141 ° C.) by oxidation of l-methyl-2- (3-methyl-4-methylthio-phenoxymethyl) -5-nitro-20 imidazole (mp. 108 ° C) or l-methyl-2- (3-methyl-4-methyl-sulfinyl-phenoxymethyl) -5-nitro-imidazole (mp. 121 ° C).

l-methyl-2- (3-methyl-4-ethylsulfonyl-phenoxymethyl) -5-nitro-imidazole (mp. 115 ° C.) by oxidation of l-methyl-2- (3-methyl-4-ethylthio-phenoxymethyl) -5-nitro-25 imidazole (mp. 80 ° C) or l-methyl-2- (3-methyl-4-ethylsulfinyl-phenoxymethyl) -5-nitro-imidazole (mp. 95 ° C).

l-methyl-2- (3-chloro-4-methylsulfonyl-phenoxymethyl) -5-nitro-imidazole by oxidation of 30 l-methyl-2- (3-chloro-4-methylthio-phenoxymethyl) -5-nitro-imidazole or l-methyl-2- (3-chloro-4-methylsulfinyl-phenoxymethyl) -5-nitro-imidazole.

1-methyl-2- (3-chloro-4-ethylsulfonyl-phenoxymethyl) -5-nitro-imidazole by oxidation of 35 l-methyl-2- (3-chloro-4-ethylthio-phenoxymethyl) -nitro-imidazole or l -Methyl-2- (3-chloro-4-ethylsulfinyl-phenoxy-methyl) -5-nitro-imidazole.