SE409705B - CERTAIN STATED NITRILE COMPOUNDS FOR USE AS INTERMEDIATES FOR THE PREPARATION OF 2,4-DIAMINO-5-BENZYLPYRIMIDINES WITH ACTIVITY AGAINST MALARIA AND BACTERIA - Google Patents

Description

7k06661-4-2 (2) an alkoxy or alkylthio group containing 1-4 carbon atoms, or (b) X represents a hydrogen atom, when Y and Z each represent an alkoxy group containing 1-4 carbon atoms or taken together represents an alkylenedioxy group containing 1-4 carbon atoms.

The alkyl groups having 2-4 carbon atoms are ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl groups, so R 1 and R 3 may be selected from any of these groups, although ethyl is preferred. It is also preferred that the R1 and R3 substituents be identical, for example 3,5-diethyl derivatives are particularly preferred. The group R2 preferably has 1-8 carbon atoms, most preferably 1-4 carbon atoms. It is especially preferred that R 2 is a methoxy, ethoxy, ethyl, propyl or butyl group. Alternatively, R 1 may be a methyl group.

When Y or Z represents an alkoxy group, this is preferably a methoxy group. When X represents a hydrogen atom, the moiety -CHYZ represents a dialkyl or an alkylene acetal group, preferably a dimethylacetal group. The dialkyl acetal group has an acyclic structure, while the alkylene acetal group has a cyclic structure.

The 2,4-diamino-5-benzylpyrimidines which can be prepared from the nitrile compounds according to the invention are those having the general Ûcnz-š) w »m2 (I) and R 3 is as defined above. For the preparation of these 2,4-diamino-5-benzylpyrimidines from the nitrile compounds of the invention, a guanidine is reacted with one of the nitrile compounds of the invention.

The reaction with guanidine may conveniently be carried out in a solvent in the form of a lower alkanol, for example methanol, ethanol or isopropanol, at elevated temperatures.

It is especially preferred that the reaction be carried out at the reflux temperature of the reaction mixture, but suitable reaction rates have been achieved at temperatures down to room temperature. It has been found that the reaction between guanidine and compounds of formula (II), where X and Y together represent an additional bond and Z represents an anilino group, can also be carried out if the guanidine is in the form of the carbonate in a polar aprotic solvent. eg dimethyl sulfoxide or hexamethylphosphoramide. However, the guanidine is normally used in the form of the salt of a strong acid, such as the hydrochloride, in the presence of at least one equivalent of a base sufficient to release the guanidine.

Various procedures can be used for the preparation of the new nitrile compounds according to the invention.

When both X and Y represent an additional bond and Z represents an alkoxy or alkylthio group, the compound of formula (II) may be prepared, for example, by reacting the appropriate benzaldehyde with the appropriately B-substituted propionitrile. A mixture of benzene and desired benzyl isomers is formed. When Z represents an anilino group, the compound of formula (II) (II) can be prepared by reacting the appropriate benzaldehyde with a β-amino-propionitrile.

When X is a hydrogen atom and Y and Z represent alkoxy groups or an alkylenedioxy group, the compound of formula (II) can be prepared by reacting the appropriate benzaldehyde with a β-alkoxy substituted propionitrile in the presence of alkanol and an alkali metal alkoxide or by reducing the appropriate α-benzylidene-B, β-dialkoxypropionitrile.

The appropriate benzaldehyde can be obtained from known reactions described in the literature. The 4-alkoxybenzaldehydes with alkyl substituents in 3,5-positions can be prepared by reacting suitable alkylated phenols with dimethylformamide and phosphorus oxychloride (Vilsmeier-Haach Reaction) or with hexamethylenetetramine 74066614 »740666144 (Organic Synthesis, Collective Vol. IV, p. 866 or Chemical Abstracts 56, 1447lb and 57, 149811 and 57, 16459i), followed by alkylation of the phenolic group with such alkylating agents as alkyl halide or dialkyl sulfate.

When 3,4,5-trialkyl-substituted compounds of formula (II) are desired, they may conveniently be prepared from the corresponding benzoate by the process described in Dutch patent 70.07108. In this process, the benzoate is reacted with dimethyl sulfone or sulfoxide, after which the carbonyl group in the reaction product is reduced to an alcohol group. The (B-hydroxy-B-phenylethyl) methyl sulfone thus prepared can then be reacted with a β-aminopropionitrile to form a compound of formula (II). A preferred method of preparing the above benzoates, wherein R 1 and R 3 are identical alkyl groups, involves (1) alkylation of a suitably para-substituted acetophenone, for example para-ethyl-substituted acetophenone, at 3- and 5-positions in the benzene ring during use of the Friedel-Crafts reaction with an alkyl halide containing 2-4 carbon atoms; (2) oxidizing the alkylated acetophenone thus obtained to the corresponding benzoic acid; and then (3) esterification of the benzoic acid.

The Friedel-Crafts alkylation proceeds unexpectedly well with 4-alkylated acetophenones. If it is desired to prepare benzoate in which R1 and R1 are identical, a monoalkylated parasubstituted acetophenone can be prepared by a mild Friedel-Crafts reaction, for example, and subjected to further Friedel-Crafts alkylation using another alkyl halide. If it is desired to form a 3,4-dialkyl-5-ethyl compound, the 3,4-dialkyl groups being other than ethyl, it is possible, for example, to alkylate the para-alkyl acetophenone with an alkyl halide using the Friedel-Crafts reaction for 3 non to obtain 3,4-dialkylacetophenone. The product is isolated from other by-products by known methods, for example fractional distillation, after which it is further alkylated with ethyl bromide to give the 3,4-dialkyl-5-ethyl acetophenone, which can subsequently be converted to a corresponding benzoate, as described above. 741166614: The oxidation of the substituted acetophenones to the benzoic acids is preferably carried out using hypochlorite or hypobromite salts. The use of hypochlorites, eg sodium hypochlorite, is suitable because of their cheapness and also the reaction is better.

The Friedel-Crafts alkylation can also be carried out on the unsubstituted acetophenone, but it has been found that the alkylation for the production of 3,4,5-trialkylated acetophenones proceeds unexpectedly well with the 4-alkyl-substituted acetophenones and especially well in connection with The ethylation of 4-ethylacetophenonl The substituted benzoic acid formed after step (2) in the above method can be converted to the corresponding aldehyde by reaction with thionyl chloride, followed by Rosenmund reduction.

The trisubstituted benzylpyrimidines of formula (I) are generally useful in the treatment of bacterial and protozoan infections in mammals by administering an effective antiprotozoal or antibacterial amount of such a compound or a pharmaceutically acceptable salt thereof or a composition containing the compound or salt.

The following examples illustrate both the preparation of the novel nitrile compounds of the invention and the use thereof as intermediates for the preparation of benzylpyrimidines of formula (I).

EXAMPLE 1 3,4,5-Triethylbenzoic acid was esterified to the methyl derivative in methanol under reflux, containing hydrogen chloride. A 67% by weight suspension (1 g) of sodium hydride in mineral oil, dimethyl sulfone (3.8 g) and dimethyl sulfoxide (18 ml) was heated at 55 ° C for 1 hour with stirring. After the reaction mixture was cooled to 50 ° C, methyl 3,4,5-triethylbenzoate (4.6 g) was added, and the mixture was heated at 0 ° C for 1.5 hours. The mixture was poured over ice and acidified to give crude methyl acetate. 3,4,5-triethylbenzoylmethylsulfone (5.5 g), mp 125-126 ° C after recrystallization from ethanol.

A slurry of crude methyl 3,4,5-triethylbenzoylmethylsulfone (4.5 g) in ethanol (3 ml) and water (10 ml) was stirred at room temperature while sodium borohydride (0.2 g) in water (4 ml) ) was added over about 15 min. The reaction mixture was stirred for an additional 1.5 hours, cooled to 2 ° C, filtered and the combined solids washed with ice water to give crude methyl B-hydroxy-B * - (3,4,5 -triethylphenyl) ethyl sulfone (3.7 g). This melted at 101-102 ° C after recrystallization from ethyl acetate. A mixture of methyl β-hydroxy-β- (3,4,5-triethylphenyl) ethyl sulfone (2.83 g), β-anilinopropionitrile (1.65 g), dimethyl sulfoxide (4 ml) and potassium tert Butoxide (1.3 g) in tert-butanol (8.3 ml) was heated at 48 ° C for 1.5 hours and then poured into ice water to give α- (3,4,5-tri ethylbenzyl) -B-anilinoacrylonitrile (3.7 g), mp 154-165 ° C after recrystallization from ethanol.

A mixture of α- (3,4,5-triethylbenzyl) -B-anilinoacrylonitrile (3.2 g), guanidine hydrochloride (2.9 g) and sodium methylate (2.2 g) in ethanol (40 ml) was heated under reflux for 25 hours. About 1/3 of the solvent was boiled off, and the remaining reaction mixture was cooled. The resulting solid was removed by filtration and recrystallized from acetone; This gave 2,4-diamino-5- - (3,4,5-triethylbenzyl) pyrimidine (1.1 g), mp 175-175 ° C.

EXAMPLE 2 3,4,5-Triethylbenzoic acid was treated with an excess of thionyl chloride and then reduced to 3,4,5-triethylbenzaldehyde under Rosenmund conditions. The aldehyde was condensed with B-methoxy-propionitrile in methanol, containing an excess of sodium methoxide, to give α- (3,4,5-triethylbenzyl) -B, B-dimethoxypropionitrile. This was then heated under reflux with guanidine hydrochloride in methanolic sodium methylate to give 2,4-diamino--5- (3,4,5-triethylbenzyl) pyrimidine.

EXAMPLE 3 g of 3,4,5-triethylbenzaldehyde were condensed with β-anilinopropionitrile in dimethyl sulfoxide, containing potassium tert-butoxide in tert-butanol, at about 5500 for about 2 hours to give u- (3,4,5- triethylbenzyl) -B-anilinoacrylonitrile, which was converted to 2,4-diamino-5- (3,4,5-triethylbenzyl) pyrimidine as in Example 1.

EXAMPLE 4 β-Methylacetophenone was alkylated with ethyl bromide in a Friedel -Crafts reaction to give 4-methyl-3,5-diethylacetophenone. This was oxidized to 4-methyl-3,5-diethylbenzoic acid by sodium hypochlorite. The acid was esterified under Fischer conditions.

The ester was converted to 5- (4-methyl-3,5-diethylbenzyl) -2,4-diaminopyrimidine according to the procedures of Example 1.

Claims (1)

7406661-4 CLAIMS Nitrile compounds for use as intermediates for the preparation of 2,4-diamino-5-benzylpyrimidines of the general formula 'm2 2 NR 0:12 »m2 (I, in which R1 and R3 each have 2 -4 carbon atoms, R 2 represents an alkyl or represents the same or different alkyl groups, of alkoxy group having 1-2 carbon atoms, characterized in that they have the general formula CN / 2 / c \ c (II) XHR-Y in wherein R 1, R 2 and R 3 are as defined above, and either (a) X and Y taken together represent an additional bond, when Z represents (1) an anilino group, or (2) an alkoxy or alkylthio group containing 1-4 carbon atoms, or (b) X represents a hydrogen atom, when Y and Z each represent an alkoxy group containing 1-4 carbon atoms or taken together denote an alkylenedioxy group containing 1-4 carbon atoms. PROMISED PUBLICATIONS: Sweden 408 551 (C07C 121/70), 409 030 (CUYC 121/70), 409 031 (C07C 121/70) France 1 497 933