NO126860B - - Google Patents

Description

Process for the preparation of acylaminoalkyl-benzenesulfonylureas.

The object of the invention is a process for the production of acylaminoalkyl-benzenesulfonylureas.

The method is characterized by reacting acylaminoalkyl-benzenesulfinic acids, their alkali salts or their halides with hydroxyurea and that during the reaction of the sulfinic acids or their alkali salts with hydroxyurea, a condensing agent is added.

The reaction is conveniently carried out in an indifferent solvent or suspending agent at an elevated temperature.

Examples of suitable diluents are: aliphatic or aromatic hydrocarbons, petroleum ether, cyclohexane, decahydronaphthalene, benzene, toluene, xylol, chlorinated hydrocarbons such as trichloroethylene, trichloroethane, chlorobenzene or dichlorobenzene or organic ethers such as dioxane, further carboxylic acids such as glacial acetic acid or formic acid. Particularly suitable are such indifferent solvents which dissolve the urea substances well and also have a high dissolving power for the condensation agent used.

Instead of the sulfinic acids, their salts, especially the alkali altenes, can also be used.

When polyphosphoric acid is used as a condensation agent, the reaction is conveniently carried out with an excess of this acid at room temperature or at a slightly elevated temperature, stirring the reaction components together until a syrup is formed which is conveniently set aside for a few hours, e.g. overnight.

It often pays to stir vigorously during the reaction.

For processing, when polyphosphoric acid is used as a condensation agent, it can be mixed with water, for example. When using water-miscible diluents, the precipitate is then suctioned off and by dissolving in highly diluted ammonia and acidifying the filtrate, the desired product is isolated in its crude state.

Otherwise, for the preparation of the reaction mixture after completion of the reaction, it can be treated with highly diluted aqueous ammonia, as the benzenesulfonylureas formed go into aqueous solution and after separation of the organic solvent, they can be precipitated by acidification.

The benzenesulfinic acids used as starting material can be formed by reduction of corresponding benzenesulfochlorides according to methods known per se, for example by reduction with sodium sulphite. They are poorly soluble in water, but can be transferred relatively easily, for example by treatment with thionyl chlorides, into the corresponding sulfinic acid chlorides.

The method can be used for the production of such known acylaminoalkyl-benzenesulfonylureas which are characterized by formula I

and which can consequently be prepared from benzenesulfinic acids of the general formula or their alkali salts or benzenesulfinic acid halides of formula III and hydroxyureas of formula IV

In the formula means

X (a) a phenyl radical, which may be substituted by fluorine, chlorine, bromine,

low molecular weight alkyl, alkoxy, alkenoxy, 'alkoxyalkoxy, phen-alkoxy or phenoxy, low molecular weight acyl, benzoyl, trifluoromethyl, low molecular weight acyloxy, -CN or -NC^ and, if desired, can also have fluorine, chlorine, bromine, low molecular weight alkyl as a further substituent , alkyloxy, or alkoxyalkyloxy, (b) a naphthyl residue, which may optionally be substituted once or twice with chlorine, bromine, - low molecular weight alkyl or alkoxy,

(c) a tetrahydronaphthyl or indanyl residue,

(d) a thiophenyl radical which may optionally be substituted once or twice with low molecular weight alkyl, alkoxy, alkoxy alkoxy, allyloxy, benzyloxy, chlorine or bromine,

(e) a tetramethylenephenyl residue.

The meaning of X mentioned under point (a) is preferred.

Of the disubstituted phenyl residues standing for X, these are preferred

which have the substituents in the 2- and 5-position to the carbonamide group. Y means a hydrocarbon chain with 2-3 carbon atoms, preferably

the grouping -CI^-CH^-,

R"*" (a) alkyl with 3-6 carbon atoms,

(b) cycloalkyl of 5-8 carbon atoms,

(c) cyclohexenyl,

(d) cyclohexyl substituted with chlorine, methoxy or one to two methyl groups, the methyl groups preferably being in the ^I position on the cyclohexyl residue,

(e) cyclohexylmethyl, cyclohexenylmethyl,

(f) endomethylene-cyclohexyl, endomethylene-cyclohexenyl, endomethylene-cyclohexylmethyl, endomethylene-cyclohexenylmethyl,

(g) nortricyclyl, adamantyl.

In the above and following definitions, low molecular weight alkyl always means one with 1-2 carbon atoms in a straight or branched chain. Low molecular weight acyl means an acyl residue (organic acid residue) with up to H carbon atoms, preferably a straight or branched alkanoyl residue of corresponding chain length.

As examples for the bridge link Y can be mentioned

-CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2~

-C<H>2<->CH(CH3)-, with -CH2~CH2- being preferred.

A production method for hydroxyureas of formula IV is described in German patent no. 1,131,655.

Other methods are already known for the production of the process products. The condensation of acylaminoalkyl-benzenesulfinic acids with hydroxyureas has not previously been proposed, however.

Attempts to condense correspondingly substituted benzenesulfonic acids with ureas to acylaminoalkylbenzenesulfonylureas have previously been unsuccessful. It was therefore surprising that the reaction of the benzolsulfinic acids with oxyurea gives the desired products in good yield. In particular, it was not to be expected that the molecule of the acylaminoalkyl-benzenesulfinic acid is available for the reaction without thereby drawing in the acylamino group.

The process products are used as pharmaceutical products for lowering blood sugar level.

Example 1. N-/^4-(3-<2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfony_17-N1-(4-meth.thy.lcyclohexyl.)-urea..

7.1 g of 4-(3-'<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfinic acid, prepared by reduction of the corresponding sulfochloride with Na2SO3 (m.p. 106-108°C) and 3, 5 g of N-(4-methylcyclohexyl)-N'-hydroxyurea are suspended in 60 ml of dioxane. A solution of 2 ml of thionyl chloride in 20 ml of dioxane is slowly added dropwise. The clear solution formed is heated for 2 hours at 60°C. When mixed with water, a precipitate appears which is extracted with 0.5% ammonia. After acidification of this ammoniacal solution and recrystallization from methanol, N-/_ 4-(3-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulphonyl-N^CM-methylcyclohexyD-urea with m.p. l89-190°C.

Example 2.

N-/_ 4-(3-<2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-butylurea.

10.6 g of 4-($-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfinic acid and 5.3 g of N-butyl-N'-hydroxyurea are suspended in 80 ml of petroleum ether. During 15 minutes, a solution of 4.7 g of thionyl chloride in 30 ml of petroleum ether is added dropwise and then heated for 2 hours until boiling. After cooling, the petroleum ether is poured off and the residue is extracted with 0.5% ammonia. After acidification of the ammoniacal solution and recrystallization from methanol, N-[(4-(6-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N-butylurea is obtained m.p. l48-l49°C.

Example 3. N-/_ 4-(3-1Senzamido-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urihstof f. -

3.78 g of benzamido-ethyl-benzenesulfinic acid (prepared by reduction of the corresponding sulfochloride with Na2S0^, melting point 121-123°C from methanol) and 3.2 g of N-cyclohexyl-N'-hydroxyurea f. are finely triturated. 50 ml of dioxane and 100 g of polyphosphoric acid are then added and everything is extracted into a viscous syrup. After standing overnight, mix with water, extract and aspirate. The formed • product is treated with highly diluted ammonia. After extraction from undissolved, a precipitate is obtained by acidifying the filtrate, which is washed with water and recrystallized from dilute methanol... The thus formed N-/_ 4-(3-benzamido-ethyl)-benzenesulfonyl_1/-N'- cyclohexyl urea melts at 198-200°C.

Example 4.

N-/_ 4 - (8-<2-Methoxy-5_chlorobenzamido>-ethyl 1)-benzolsulfony_1/-N' -

cyclohexylurea.

3.53 g of 4-(g<-<>2-methoxy-5-chlorobenzamido>-ethyl)-benzene-' sulfinic acid (prepared by reduction of the corresponding sulfochloride with Na2S0j, m.p. 106-108°C) is triturated with 1 .6 g of N-cyclohexy1-N'-hydroxyurea, 50 ml of glacial acetic acid and 60 g of polyphosphoric acid in a grating bowl to a syrup. After standing for 3 hours at room temperature, it is mixed with ice water, the formed precipitate is sucked off and treated with slightly diluted ammonia. After extraction, the filtrate is acidified and the semi-solid precipitate formed is dissolved again in dilute ammonia and precipitated again. After recrystallization from methanol, N-/_ 4-(3-<2-methoxy-5_chlorobenzamido>-ethyl )-benzene-sulfonyl/-

N'-cyclohexylurea with m.p. 169-170°C. The experiment is equally successful using only 30 g of polyphosphoric acid.

Example 5.

N-/_ 4-(8-<2-Methoxy-5-chlorobenzamido>-ethyl 1)-benzenesulfony 17-N' -

butylurea.

8.8 g of 4-(g-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfinic acid and 3.3 g of N-butyl-N'-hydroxyurea are triturated in a grater with 50 ml of dioxane. After adding 100 g of polyphosphoric acid, a homogeneous mass is formed. After 3 hours, it is mixed with ice water and the precipitate is extracted with 0.5% ammonia. After acidification of the ammoniacal solution and recrystallization from methanol, N-[<_> 4-(6-<2-methoxy-5-chlorobenzamido>-ethyl 1)-benzenesulfonyl7-N'-butyl urea is obtained with m.p. 148-149°C

Example 6. N-(4-(8-<2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea.

7.1 g of 4-(8-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfinic acid' and 3.5 g of N-(4-methylcyclohexyl)-N'-hydroxyurea are triturated in the grater with 100 ml of glacial acetic acid . After adding 100 g of polyphosphoric acid, a homogeneous mass is formed which is left for 3 hours at room temperature. When reacting with water, a precipitate falls out which is extracted with 0.5% ammonia. After acidification of the ammoniacal solution and recrystallization from methanol, N- /_ 4 - (8-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfony 17-N1 -

(4-methylcyclohexyl)-urea with m.p. l89-190°C.

Example 7.

7.1 g of 4-(8-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfinic acid are introduced into 8 ml of thionyl chloride and allowed to cool. During gas evolution, dissolution occurs. Excess thionyl chloride is removed after 30 minutes in a vacuum and added with stirring to the crude 4-(8-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfinic acid chloride formed as a residue. (m.p. 104-106°C), 60 ml dry dioxane and then 3.5 g N-/_ 4-methyl-cyclohexyl/-N'-hydroxyurea f.

It is heated for 2 hours with stirring at 60°C and mixed with water after cooling. The formed precipitate is treated with approx. 0.5% aqueous ammonia. After filtration, the aqueous ammoniacal solution is acidified.

You get a precipitate of

N-_/—4- (£3-<2-Methoxy-5-chloro-benzamido>-ethyl)-benzenesulfony 17-N' - (4-methylcyclohexyl)-urea. Recrystallized from methanol, the substance melts at 189-190°C.

Claims (1)

Process for the production of acylaminoalkyl-benzenesulfonylureas, characterized in that one reacts acylaminoalkyl-benzenesulfinic acids, their alkali salts or their halides with hydroxyureas and that during the reaction of the sulfinic acids or their alkali salts with hydroxyurea, a condensation agent is added.