CA1069910A - 1-methyl-2-(phenyl-oxymethyl)-5-nitroimidazoles and process for their manufacture - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of the formula I

Description

:

9~
, The present invention relates to 1-methyl-2-(phenyl-oxy~
methyl)-5-nitro-imidazoles and to a process for their manufacture. :~
1-(2-hydroxyethyl)-2-methyl-5-nitro-imidazole ~Metronidazol) is being used for the treatment of protozoal diseases, such as trichomoniasis and'amoebiasis. .
Object of this invention are 1-methyl-2-~phenyl oxymethyl)- . .
5-nitro-imidazo].es of the formula I .
.
. . . .......... .

CH2 - { ~ A-R (I)

2 ~ H3 ~ R2 - . . .
-- . . . . ....... .. . . .. . . .

in which A stands for a sulfur atom or a sulfoxide (-SO-) group, ':
h vd ro en., . ' R1 stands for methyl or ethyl, and.R2 fo~ met Iyl or halogen. .-.:
Further object of this invention is a process for the ~
.
manufacture of 1-methyl-2-(phenyl-oxymethyl)-5-ni.tro-imidazoles of the formula I, which comprises ~ ' :, ' - . .
-~ .. a) reacting a ni~ro-'imidazole of the formula II ........... . '-~
., . :
N
CH2 - X ' (II) .:.
2 ~ ~
CH~ .
in which X stands for a halogen atom, such as fluorine, chlorine, bromine or iodine atom, or for an acyloxy group, . ' such as an acetoxy, propionyloxy, butyryloxy, benzoyloxy, :
,:;: .
- toloyloxy, nitrobenzoyloxy group, or for an arylsulfonyloxy : :
group, such as a benzene-sulfonyloxy, toluenesulfonyloxy, or :~
nitrobenzene-su].'fonyloxy group, with a phenol or an alkali ' -~
metal or ammonium salt thereof, which corresponds to the - 2 ~

`~

. . .

9~0 ~'' ~~ ~~ '. :~ .
~ ' formula IIl Y-0 ~ A-R~
~2 ~ ' .. . ..... . . . . . . . . . ~ ~
~ in which Y stands for a hydrogen atom, an alkali metal ion, ;~
- : espec.ially a sodium or potassium ion, or ammonium, and A, ~ ;
and R2 are defined as above, or~ : ~
.. ., ,, , .- . .
.- b) alkylatlng a niero-imidazole of the formu1a IV - ~
.

~ ~ - C}lz - C ~ S~Y ~ (LV) ~ ~:

'' ' `,~-''`' , in which Y and R2 are defined as above, and optionally o-xi- ~.
dizing the so-obtained sulfide compound of formula I to yield . : ;~
a sulfoxide.
As starting compounds of formula II, there may be used,for :; . :. ..
;~ example, 1-methyl-2-chloro-methyl-5-nitro-imidazole, 1-methyl-2-bromo-methyl-5-nitro-lmidazole, 1-methyl-2-iodo-methyl-5-nitro-. ~.
imidazole, 1-methyl-2-acetyloxy-methyl-5-nitro-imidazole, 1- . '~
methyl.-2-benzoyloxy-methyl-5-nitro-imidazole,.1-methyl-2-(4~
nitrobenzoyloxy)-methyl-5-nitro-imidazole or 1-methyl-2-(toluene~ `
sulfonyloxy)-methyl-5-nitro-imldazole.: - .:~
,::.
These starting compounds of formula I~I may be prepared ac- .:~
cording to German Offenlegungsschrift No. 1,595,929 by reacting ~ ::
1-methyl-2-hydroxymethyl-5-nitro-imidazole (cf. German Offen~
legungsschrift No. 1j470,102) with a thionyl halide, or by re- .
acting it with an acetyl, benzoyl, 4-nitrobenzoyl.or 4-toluene-~ 3 ~

~'.'`~';~, r-~

,, -~ HOE 75/F 183 K
~69911~

sulfonyl halide or anhydride.
As starting compounds of formula III, there may be used, for example, 4-methyl-mercapto-phenol, 4-ethyl-mercapto-phen~ , 4-methyl-sulfinyl-phenol, 4-ethyl-sulfinyl-phenol, 3-methyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-iodo-4-methyl-, -~-ethyl-mercapto-phenol, 3-methyl-, 3-fluoro-, 3-chloro-, 3-bromo-/ 3-iodo-4 methyl- or -4-ethyl-sulfinyl phenol.
Instead of the free phenols, the alkali metal or ammoni-um salts thereof may also be used.
The starting compounds of ~ormula III may be prepared by reacting 4~mercapto-phenol corresponding substituted in 3-position with one molar equivalent ofadialkyl sulfate in the presence of one molar equivalent of an alkaline substance, a dialkyl sulfate used being dimethyl or diethyl sulfate.
The alkyl-sulfinyI-phenols are prepared by reacting an alkyl-mercapto-phenol with a molar e~uivalent of an oxidizing agent, for example hydrogen peroxide or a peroxo acid, for example peracetic acid, perbenzalc acid, or m-chloroperbenzoic acid, as well as nitric acid or chromic acid.
As starting material of formula IV, t~ere are mentioned , l-methyl-2-(4-mercaptophenyl-oxymethyl(-5-nitro-imidazole, 1-methyl-2-(3-methyl-4-mercaptophenyl-oxymethyl)-5-nitro-imidazole, l-methyl-2-(3-fluoro-4-mercaptophenyl oxymethyl)-5-nitro-imi-dazole, l-methyl-2-(3-chloro-4-mercaptophenyl-oxymethyl)-5-nitro-imidazole, l-methyi-2-(3-bromo-4-mercaptophenyl-oxymethyl)-5-nitro-imidazole,1-methyl-2-(3-iodo-4-mercaptophenyl-oxymethyl)-5-nitro-imidazole, or an alkali metal salt thereof. Since the mercapto compounds easily oxidize in the air to yield disulfides, their -i isolation is avoided and, instead, the mercapto compound in . ,.., . : , .: . .. ., ,.:: :,:". : ,: : , , . ,::
. : .. ::, ... : : :: ,, . , ::, .. , .,, .. , :. :., . " . .:.. :.,.:.:. , , ' . " ,.. . .:: :.:

69~

- question is alkylated in stat;u nascendi to yield the end product of formula I.
This compound is obtained by hydrolysis of the correspond-ing 'I-methyl-2-(4-thiocyanatophenyl-oxymethyl)-5-nitro-imidazole' -with.concentrated sulfuric acid at room tempera-ture under a nitrogen atmosphere in the presence of an alkylating agent, ~or example dimethyl sulfate. 1-Methyl-2-(4-thiocyanatophenyl-oxy-methyl)-5-nitro-lmidaæole (m.p. 140C~ and the R2-substi'tuted - produts thereof are obtained by reacting a compound of formula II with 4-thiocyanato-phenol. - ' Methods a) and b) of the process of the inventlon are-advantageously carried out using equimolar amounts of the start-ing compounds used, advantageously in a solvent or dispersing agent in the case of a).
Method b) of this process may also be carried out in the --,.
absence of such a solvent or dispersing agent. In this case, the alkylating agent used as a reaction component in excess ~erves as the reaction medium. -' ' For ~he reactions accordiny to method a), polar solvents 2G are preferably used, for example alcohols, such as methanol, ethanol, propanol,'isopropanol, butanol, 2-methoxy-ethànol, 2~
ethoxy-ethanol; ketones, such as acetone, diethyl-ketone, methyl-'' ~; ;
- . .~-.
- ethyl-ketone, methyl-isobutyl-ketone; amides, such as dimethyl-.
~ formàmide, dimethylacetamide, N-methyl-pyrrolidone, tetramethyl-urea, hexamethyl phosphoric acid triamide, dimethyl-sulfoxide; -' heterocyclic bases, such as pyridine, picoline or quinoline.
When the free phenols of formula III are used, it is ad-vantageous to use an acid scavenger, for example a base , such ';;~
~9 as triethylamine or pyridine, and alkali metal or alkaline earth -- 5 - ;

L~

69~

metal carbonat:es and bicarbonates, hydroxides and alkoxides, or example methoxide, ethoxide or butoxide.
- The reaction temperature suitable for method a) ranges from .
0 to 80C, but advantageously it is room temperature~ The re-, action time ranges from a few minutes to several hours.
The alkylation reaction temperature for method b) ranges from 20 to 80C, preferably from 20 to 60C. The reaction time ranges from four to eighteen hours.
As alkalyting agents, there are used,- for example, methyl 1Q or ethyl halides, especially the iodides; dimethyl or diethyl si1lfate; and arylsulfonic acld esters, especially 4-toluene~
~ . . ..
sulonic acid methyl or ethyl ester. ---- The sulfides of formula I (A = -S-), obtained according to the said methods a) and b), may be converted by oxidation into the corresponding sulfoxides (A= -So-~, The oxidation reaction is suitably carried out using one molar equivalent of an oxidiz-ing agent, for example hydrogen peroxide or a peroxo acid l such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, as ~ -well as nitric acid or chromic acid. The oxidation temperature generally ranges from 0 to 30C.
- :, The products of t~e invention are isolated accordin~ to ;~
the-usual methods by distillation of the solvent used or dilution -~
of the reaction solution with water, optionally foll~wed by a purification by recrystallization from a suitable solvent or mixture of solvents.
The new 1-methyl-2-(phenyl-oxymethyl)-5-nitro-imidazoles of formula I according to the invention are suitable for the treatment of protozoal diseases in humans and animals as caused, 29 for example by infections with Trichomonas vaginalis and Enta-:

.. .' ;:

`

moeba hist*lytica. Moreover, they are effectlve against bacteria and fungi~
The new compounds of the invention may be administered by `
- the oral or local route. The oral administration is generally - 5 made-in the form of tablets or capsules containing, per daily dosage unit, from about 10 to 750 mg of the active ingredient, in admixture with a conventional diluent and/or ~xipient. De- ~`
pending on the case, the individual dosage unit ranges from 2 to 100 mg of active substance per kg of body weight of the 1Q patient. For local administration, gels, creams, ointments or suppositories may be used.
The following Examples illustrate the invention.
E X A M P L E 1: (Method a) ': ` ' : -~ Methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole ~ 13.8 Grams (0.1 mol) of a potassium carbonate powder are added to a solution of 14.0 g (0.1 mol) of 4-methylmer-capto-phenol in 30 ml of dimethylformamide; then a solution of 17.6 g (0.1 mol~ of 1-methyl-2-chloromethyl 5-nitro-imi-dazole in 40 ml of dimethylformamide is added dropwise while 2a stirring at 25~C. The weakly exothermic reaction is kept -;
at a maximum temperature of 35C by cooling with ice water.
Stirring o the mixture is continued for 1 hour at 25C, ;;
the reaction mlxture is poured onto ice/water, the-precipi-- tate is suction-filtered, washed with water and recrystalliz-` 25 ed from methanol with an addition of charcoal.
In thls manner, 19.5 g (70 ~ of the theoretical yield) of 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imida-zole are obtained as light-yellow crystals, melting point:
29 116C.

-- F-~

, :

~6~9~

According to the process described above, the following compounds are prepared:
1.2: From l-methyl-2-chloromethyl-5-nitro-imidazole (MCNI) and 4-ethyl-mercapto-phenol, the 1-methyl-2-(4-ethylthio-phenyl-oxymethyl)-5-nitro-imidazole, m.p. 90C.
1.3: 1-Methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-, imidazole To a solution of 15.4 g (0.1 mol of 3-methyl-4-methyl-mercaptophenal in 30 ml of dimethylformamide, 13.8 g (0.1 mol) of ;' potassium carbonate powder are added, and then a solution of~l7.6 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 40 ml of dimethylformamide is added dropwise while stirring at 25C. The temperature of the faintly exothermaL reaction is adjusted to at most 35C by cooling with ice water. ~he mixture is then stirred lS for another hour at 25C, poured onto ice/water, the precipitate is suction-filtered, washed with water and recrystallized from methanol with an additlon of charcoal to yield 21.7 g (74 ~ of ~the theoretical yield) of l-methyl-2-(3-methyl-4-methylthlophenyl-~oxymethyl)-5-nitro-imidazole in the form of yellow crystals, m.p.
:::
~108C.
According to this method, the following compounds are prepared:
1.4: From l-methyl-2-chloromethyl-S-nitro-imidazole (MCNI) and

3-methyl-4-ethylmercaptophenol, the 1-methyl-2-(3-methyl-

4-ethylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 80C;
1.5: from MCNI and 3-chloro-4-methylmercaptophenol, the l-methyl-2-(3-chloro-4-methylthiophenyl-oxymethyl)-5-nitro-`-'28 imidazole, m.p. 114C, and ~ 8 -99~ _ E 75/F 183 K
~'' 1.6: from MCNI and 3-chloro-4-ethylmercaptophenol, the 1-methyl-2-(3 chloro-4-ethylthiophenyl-oxymethyl)-5-nitro imidazole m.p. 86C. -E X A M P L E 2: ~oxidation) 2 1: 1-Methy ~ - ;
.
:, :
imidazole ::
27.9 Grams (0.1 mol) of 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and the solution is added dropwise while stir-~
~0 ring at 25C to a solution of ~7.25 g (0.1 mol) of m~chloro~
- ,~
perbenzoic acid in 70 ml of chloroform~ The reaction mix-ture is stirred for 1 hour at 25C, the solution is shaken -~
with dilu-te sodium carbonate solution, the chloroform phase ,~. ,.~, is separated, dried over sodium sulfate and~evaporated.
The residue is recrystallized from ethanol with the addi-tion of charcoal.
Thus, 21.5 g (73 % of the theoretical yield) of 1-methy1-2-(4-methyl-sulfinylphenyl-oxymethyl~-5-nitro-imi-.:,:
dazole are obtained as yellowish crystals, m.p. 130C.
According to the method described above, the followirlg compound is prepa~ed:
2.2: Erom 1-methyl-2-(4-ethylthiophenyl-oxymethyll-5-nitro-imi-.
dazole, the 1-methyl-2-(4-ethylsulfinylphenyl-oxymethyl)~

5-nitro~imidazole, m.p. 103C. ;
2.3: 1-M~ -2-(3-methyl-4-methylsulfinylphenyl-oxyme hyl)-5-nitro-imidazole 29.3 g (0.1 mol) of i-methyl-2-(3-methyl-4-methylthio-phenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml 29 of chloroform, and the solution is added dropwise while

6 9 ~ -r -- 106~91~
stirring at 25C to a solution of 17.25 g (0.1 mol) of 3 - chloroperbenzoic acid in 70 ml of chloroform. The reaction mixture is stirred for 1 hour at 25C, shaken with dilute sodium carbonate solution, the chloroform phase is separated, dried o~r sodium sulfate and con-centrated by evaporation. The residue i5 recrystallized from ethanol with an addition of charcoal, to yield 21.0 g (68 % of the theoretical yield) of 1-methyl-2-(3-methyl-4-methylsulfinylphenyl-oxymethyl)-5-nitro-imida-zole in the form of yellow crystals, m.p. 121C.
According to this method, the following compounds are prepared:
2.4: From l-methyl-2-~3-methyl-4-ethylthiophenyl-oxymethyl)-5-nitro-imidazole, the l-methyl-2-(3-methyl-4-ethylsul-finylphenyl-oxymethyl)-5-nitro-imidazole;
2.5: from 1-methyl-2-(3-chloro-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, the l-methyl-2-(3-chloro-4-methylsul-finylphenyl-oxymethyl)-S-nitro-imidazole, and ~2.6: from 1-methyl-2-(3-chloro-4-ethylthiophenyl-oxymethyl)-5-~ ~ nitro-imidazole, the 1-methyl-2-(3-chloro-4-ethylsul-finylphenyl-oxymethyl)-5-nitro-imidazole.
~E X;A M P L E 3: (Method b) 3.1: 1-Methyl-2-~4-methylthiophenyl-oxymethyl)-5-nitro~imidazole 5.8 g tQ.02mols) of 1-methyl-2-(4-thiocyanatophenyl-oxymethyl)=5-nitro-imidazole are introduced portionwise while stirring, under a nitrogen atmosphere~ at room temperature, into a mixture o~ 26.5 ml of concentrated sulfuric acid and 5.0 g ~0.04 mol) of dimethylsulfate and allowed to stand overnight at room temperature.
3D The solution is then heated to 60C for 30 minutes, cooled and poured , , : ,: . . , .. : . ,: ',:. . :'::. ::: ~,: ' .. :-.: :

~ HOE 75/F 183 K
~L~369~
.

onto ice/water. The precipitate is suction-filtered and -~
washed with water. In addition to bis-4,4'-(1-methyl-5-nitro-imidazolyl-2-methoxy)-diphenyl disulfide (m.p. 160C), column chromatographical purification on silica gel yields the 1-methyl-2-(4-methylthlophenyl-oxymethyl)-5-nitro-imidazole, m.p. 116C.

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Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a 1-methyl-2-(phenyl-oxy-methyl)-5-nitro-imidazole of the formula I

wherein A represents a sulfur atom or a sulfoxide group, R1 represents methyl or ethyl, and R2 represents hydrogen, methyl or halogen, in which (a) a nitro-imidazole of the formula II

wherein X represents a halogen atom, an acyloxy group or an aryl-sulfonyloxy group, is reacted with a phenol or an alkali metal or ammonium salt thereof of the formula III

wherein Y represents a hydrogen atom, an alkali metal ion or ammonium, and A, R1 and R2 are defined as above, or (b) a nitro-imidazole of the formula IV

wherein Y and R2 are defined as above, is alkylated, and the resulting sulfide compound of the formula I may be oxi-dized to yield a sulfoxide.

2. A process as claimed in claim 1 in which the preparation is carried out according to reaction (a) in the presence of a sol-vent at a temperature of from 0 - 80°C and the reactants of the formulae II and III are used in equimolar amounts.

3. A process as claimed in claim 1 in which the preparation is carried out according to reaction (b) at a temperature of from 20 - 80°C and the compound of the formula IV is alkylated using an alkylating agent selected from the group consisting of methyl halides, ethyl halides, dimethyl sulfate, diethyl sulfate and arylsulfonic acid esters.

4. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim l for the preparation of 1-methyl 2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole in which 4-methylmercapto-phenol is reacted with 1-methyl-2-chloro-methyl-5-nitro-imidazole in a solvent in the presence of potas-sium carbonate and the resultant product is subsequently isolated.

6. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole in which 1- methyl-2-(4-thiocyanatophenyl-oxymethyl)-5-nitro-imidazole is alkylated with dimethylsulfate in the presence of sulphuric acid and a solvent and the product 1-methyl-2-(4-methylthiophenyl-oxy-methyl)-5-nitro-imidazole is subsequently isolated.

7. 1-Methyl -2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, whenever obtained according to a process as claimed in claim 5 or claim 6 or by an obvious chemical equivalent thereof.

8. A process as claimed in claim 1 for the preparation of 1-methyl-2-(4-methylsulfinyl-phenyl-oxymethyl)-5-nitro-imidazole in which 4-methylmercapto-phenol is reacted with 1-methyl-2-chloro-methyl-5-nitro-imidazole in a solvent in the presence of potassium carbonate, the resultant 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole is dissolved in a solvent and oxidized with m-chloroperbenzoic acid and the product is subsequently isolated.

9. 1-Methyl-2-(4-methylsulfinyl-phenyl-oxymethyl)-5-nitro-imida-zole, whenever obtained according a process as claimed in claim 8 or by an obvious chemical equivalent thereof.

10. A process as claimed in claim 1 for the preparation of 1-methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5- nitro-imidazole in which 3-methyl-4-methylmercapto-phenol is reacted with 1-methyl-2-chloromethyl-5-nitro-imidazole in a solvent in the presence of potassium carbonate and the product is subsequently isolated.

11. 1-Methyl-2-(3-methyl-4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, whenever obtained according to a process as claimed in claim 10 or by an obvious chemical equivalent thereof.