GB2087378A

GB2087378A - Sulphur-containing substituted aldehydes

Info

Publication number: GB2087378A
Application number: GB8114951A
Authority: GB
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1977-11-10
Filing date: 1978-11-09
Publication date: 1982-05-26
Also published as: AR228423A1; NL7811170A; GB2007669B; JPS5476586A; BR7807425A; EP0035624B1; FI783368A; MC1222A1; EP0032395B1; EP0035624A2; EP0003212B1; SE7811593L; ES481038A1; IT1100210B; EP0032395A1; FR2422404B1; AT359070B; PH15918A; FR2422632B1; GR71725B

Abstract

Novel aromatic aldehydes of the formula <IMAGE> wherein R<1> denotes hydrogen or C1-6-alkyl; R<2> denotes hydrogen; R<3> denotes mercapto, C1-6-alkylthio, carboxy C1-6-alkylthio C1-6-alkoxy- C1-6-alkylthio, dimethyl-carbamoylthio, -S(O)R' or -SO2R' and R<4> denotes C1-6-alkylthio, -S(O)R' or SO2R', or R min denotes hydrogen; R<2> and R<4> denote C1-6-alkylthio, -S(O)R' or -SO2R', and R<3> denotes C1-6alkoxy, mercapto, C1-6-alkylthio, carboxy-C1-6-alkylthio, dimethylcarbamoylthio, -S(O)R', -SO2R' or NR''R''', or R' denotes hydrogen; R<2> denotes C1-6-alkoxy; R<3> denotes mercapto, C1-6-alkylthio. carboxy- C1-6-alkylthio, C1-6-alkoxy C1-6- alkylthio, dimethylcarbarmoylthio, -S(O)R' or -SO2R', and R4 denotes C1-6-alkylthio, S(O)R' or -SO2R', or R<1> denotes hydrogen; R<2> denotes halogen; R<3> denotes C1-6-alkylthio, -S(O)R' or -SO2R', and R4 denotes C1-6-alkylthio, S(O)R' or -SO2R', or R<1> denotes hydrogen; R<2> denotes halogen or C1-6-alkoxy; R<3> denotes mercapto, C1-6-alkylthio, carboxy- C1-6-alkylthio, carbalkoxy-C1-6-alkylthio, cyano-C1-6-alkylthio, C1-6-alkoxy- C1-6-alkylthio, C1-6-alkoxy-C1-6- alkoxy, C1-6-alkylthio, dimethylcarbamoylthio, -S(O)R' or -SO2R', and R<4> denotes halogen or C1-6-alkoxy; R' denotes C1-6-alkyl; R'' and R''' independently of one another denote hydrogen or C1-6-alkyl or together denote C2-6-alkylene (possibly with 1-3 double bonds), with the exception of 3,4-bis(methylthio)- benzaldehyde.

Description

SPECIFICATION 2,4-diamino-5-benzylpyrimidines and a process for their preparation The present invention relates to new 2,4-diamino-5-benzylpyrimidines of the general formula

wherein R1 denotes hydrogen or C,_6-alkyl; R denotes hydrogen; R denotes mercapto, C1-6-

physiologically compatible salts, a process for their preparation, as well as pharmaceutical preparations based on these compounds and the production of said pharmaceutical preparations. The general formula I comprises the groups of compounds of the formulae 1-1 to 1-5:

In the formulae 1-1 to I-5: R1a denotes hydrogen or C1-6-alkyl;

R2b denotes C1-6-alkoxy; R2c denotes halogen; R2d denotes halogen or C1-6-alkoxy;

thio, -S(O)R', -SO2R' or -NR"R"';

R4b denotes halogen or C1-6- alkoxy. The substituents R', R" and R'" have the meanings already specified above. Examples of C,_6-alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl, tert.-butyl, pentyl and hexyl, methyl and ethyl being preferred. Examples of C2-6-alkylene radicals are ethylene, trimethylene, tetramethylene and pentamethylene. Examples of radicals derived therefrom having 1-3 double bonds are vinylene, propylene, 2-butenylene, 1,3-butadienylene, 1,4-pentadienylene or 1,3,5-hexatrienylene. Halogen substituents are in particular chlorine, bromine and iodine, chlorine and bromine being preferred. The process for the preparation of the compounds according to the invention is characterised in that (a) a compound of the formula

wherein R', R , R and R4 have the afore-mentioned meaning, Z denotes a -C(CH) = CH-Y or -CH(CN)CH(OR5)2' group, Y denotes a leaving group, and R5 denotes C1-6-alkyl, 2-C1-6 alkoxyethyl, 2-phenoxyethyl or 2-benzyloxyethyl, or both R5 radicals together denote C1-6alkylene, is condensed with guanidine or a guanidine salt, or (b) in a compound of the formula

wherein X denotes halogen and R , R , R and R4 have the afore-mentioned meanings, the substituent X is reductively eliminated, or (c) to prepare a compound of the formula 1-1, a substituted benzylpyrimidine of the formula

wherein R6 denotes C1-6-alkoxy (preferably methoxy), benzyloxy, hydroxy or halogen,is reacted with a compound of the formula

wherein R a, R a and R4a have the afore-mentioned meanings, or (d) a compound of the formula I is modified at the substituents R , R and/or R4 by generally known methods, and the compound obtained is converted if desired into a physiologically compatible salt. According to variant (a) of the process according to the invention, a compound II is reacted with guanidine or a guanidine salt. The reaction can be carried out in a manner known per se, e.g. in an organic solvent such as an alkanol (methanol, ethanol), in dimethylformamide, dimethylsulphoxide or N-methylpyrazolone, at a temperature between 25 and 200[deg], preferably between 50 and 170[deg]. The carbonate and hydrochloride may for example be used as guanidine salts.Typical examples of leaving groups represented by the symbol Y in the formula II are for

such as 2-methoxyethoxy and 2-ethoxyethoxy, 2-phenoxyethoxy, 2-benzyloxyethoxy, alkylthio groups, the amino group and amino groups substituted by aliphatic, aromatic or heterocyclic groups, such as alkylamino, benzylamino, arylamino (e.g. optionally substituted anilino or naphthylamino), dialkylamino, 1-imidazolyl, pyrrolidino, piperidino, piperazino or morpholino. Particularly preferred as a leaving group is the anilino radical, whose phenyl ring may be mono or poly-substituted by halogen, alkyl or alkoxy. The starting compounds II may, as shown in the reaction scheme I, be prepared from compounds of the formula VIII, and the individual reaction steps can be carried out in analogy to known conversions.

of the formula NC-CH2-CH2-OR5 to form a compound of the formula VI, and may be reacted in the presence of an alkali metal alkoxide such as sodium methoxide or potassium tert.-butylate and an alcohol such as methanol, ethanol or propanol, to form a compound of the formula II-a.

compound II-e, which can be converted with guanidine to form a compound I. If an aldehyde of the formula VIII is firstly reacted with malodinitrile under the conditions of a Knoevenage, condensation (optionally in the presence of a basic catalyst), then a dinitrile of the formula VII is obtained that can be converted by selective hydrogenation, e.g. with half a mole of sodium borohydride, into the compound II-b. An aldehyde of the formula VIII can be converted by condensation with -morpholinoprophionitrile into a compound of formula 11-c, which can either be used directly as a starting material for the conversion according to the invention or, and in fact preferably, first of all converted, by replacing the morpholino group by the aniline group, into a compound of the formula II-d.

though the morpholino-anilino variant represents the most expedient way for preparing the benzylpyrimidines I since in this way better yields may be achieved under milder conditions. The methods for preparing the sulphur-containing benzylpyrimidines of the invention from aldehydes of the formula I are in principle analogous to the known methods for preparing the corresponding, sulphur-free benzylpyrimidines. The aldehydes of the formula VIII are, with the exception of 3,4-bis-(methylthio)-benzaldehyde (i.e. compound VIII-1 with R'a = hydrogen and R3a = R4a = methylthio), new compounds and are likewise the subject of the present invention. By analogy with the subdivision of the compounds I, the aldehydes VIII may be divided in the following sub-groups VIII-1 to VIII-5:

In the formulae VIII-1 to VIII-5, the substituents have the meanings already defined above. The aldehydes of the formula VIII may be prepared from known compounds according to methods known per se, e.g. such as described in detail in Examples 9-18 and as diagrammatically illustrated in the following reaction summaries II-V, or in an analogous manner. A reaction for which there is up to now no parallel in the literature and which is therefore new is the thermolysis of a compound XXIII to form compound VIII-5d (cf. reaction scheme V). The reaction is preferably carried out in dimethylformamide at a temperature of approximately 50[deg]C up to the reflux temperature of the reaction mixture. The reaction is catalysed by traces of alkali metal xanthogenates, for example potassium xanthogenate. The reductive elimination of the halogen atom X, which is preferably a chlorine or bromine atom, in a compound of the formula III according to process variant (b) can be carried out in a manner known per se by treating a compound III with suitable reducing agents such as zinc in glacial acetic acid, amalgamated zinc in caustic soda, or by catalytic hydrogenation, for example in the presence of a noble metal catalyst such as palladium, and in an inert solvent such as ethanol. The compounds of the formula III are new and are likewise the object of the present invention. They can be prepared by methods similar to the known methods, which are summarised in the following reaction scheme VI. Reaction scheme II

Reaction scheme III

Reaction scheme IV

Reaction sphere V

Reaction scheme VI

The conversion of a compound IV with a compound V according to process variant (c) can be carried out in the presence of an inorganic acid, for example orthophosphoric acid, polyphosphoric acid, a hydrohalic acid such as hydrochloric acid or hydrobromic acid, or an organic acid, for example a trihalogenated acetic acid such as trifluoroacetic acid. The reaction is preferably carried out in a temperature range from about 50 to about 100[deg]C. In general, the inorganic or organic acid used for the reaction may serve as solvent, but if desired an inert organic solvent may also be used. The acid addition salt of a compound of the formula 1-1 thus obtained is separated in the usual way at the end of the reaction and is then purified by conventional purification methods, such as crystallisation or filtration. The free base can be obtained by neutralising the acid addition salt, for example with an alkali metal hydroxide. Whereas the starting compounds of the formula IV are known, some of the compounds of the formula V are new compounds. The new compounds can be prepared in a manner known per se from known compounds, e.g. 1,2-dimercaptobenzene, 2-methylmercaptobenzene, 3,4-dimercaptotoluene or 3,4-bis-(methylthio)-toluene, or by analogy to the preparation of these known compounds, for example by alkylating a mercapto group and/or oxidising an alkylthio group to an alkylsulphinyl or alkylsulphonyl group. A carboxyalkylthio compound may be prepared by for example reacting a mercapto compound with an w-halogenated carboxylic acid derivative, such as an ester or amide, followed, by hydrolysis. Specific compounds of the formula I according to the invention can also be modified within the framework of generally known methods at the substitutents R , R and/or R4, i.e. can be converted into one another (process variant d). Thus, for example, a mercapto group in a compound I can be converted with an alkylating agent into an alkylthio group, an alkoxyalkylthio group or a carboxyalkylthio group. Alkylthio groups can be oxidised to alkylsulphinyl and/or alkylsulphonyl groups, or these can be reduced in a method known per se to alkylthio groups. The dimethylcarbamoylthio group can be converted by hydrolysis into the mercapto group. Salts of the compounds of formula I include salts with acids (so-called acid addition salts), and also, depending on the substituent on the benzyl radical, salts with bases. For the preparation of acid addition salts, in particular of salts that can be used in pharmaceutical preparations, i.e. that are physiologically compatible, there may be used the inorganic and organic salts conventionally employed for this purpose, such as hydrochloric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, succinic acid, fumaric acid, levulinic acid, salicylic acid, citric acid, isocitric acid, adipic acid, lactic acid, a-ketoglutaric acid, malic acid, malonic acid, glyceric acid, mevalonic acid, glucuronic acid, neuraminic acid, glutaric acid, glucaric acid, aspartic acid, gluconic acid, mandelic acid, ascorbic acid, lactobionic acid, glucoheptonic acid, glutamic acid, nicotinic acid, pantothenic acid, folic acid, adenylic acid, geranylic acid, cytidilic acid, inosinic acid and methanesulphonic acid. Examples of salts with bases are the sodium and potassium salt. The compounds of the formula I and their salts have an antibacterial action. They inhibit bacterial dihydrofolic acid reductase (DHFR) and moreover potentiate the action of sulphonamides and other dihydrofolic acid synthetase inhibitors. Examples of sulphonamides that are potentiated by the compounds according to the invention are members of the pyrimidine, isoxazole, oxazole, and pyrazine series such as sulphadiazine, sulphadimethoxine, sulphadoxine, sulphamerazine, sulphameter, sulphamethazine, 6-methoxy-4sulphanilamidopyrimidine, sulphamethoxyazole, sulphisoxazole, 3-sulphanilamido-4,5-dimethylisoxazole, sulphamoxole and sulphalene. The compounds according to the invention are quantitatively differentiated from known compounds by lower 50% inhibition concentrations of bacterial DHFR, for example in the case of E. coli, and by basically higher Q-values (50% inhibition of DHFR in rats/50% inhibition of DHFR in E. coli), which represents a measure of the selectivity of inhibition of bacterial DHFR, as well as by a lower toxicity. Data illustrating the antibacterial action of some typical compounds according to the invetion are summarised in Table 1. Table 1

The benzylpyrimidines according to the invention can thus be used as pharmaceutical preparations with a direct or delayed release of the active substance, in admixture with an organic or inorganic inert carrier material suitable for oral, rectal or parenteral application, e.g. water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycols, Vaseline, etc. The pharmaceuticl preparations may be formulated in solid form, e.g. as tablets, pills, suppositories or capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or emulsions. They may optionally be sterilised and/or contain further adjuvants such as preservatives, stabilisers, wetting agents or emulsifying agents, taste improvement agents, salts for altering the osmotic pressure, or buffer substances.The pharmaceutical preparations may be formulated in a manner generally known to those in the art. In preparations in which the compounds according to the invention are applied in combination with sulphonamides, the weight ratio of the two components with respect to one another may vary within wide limits. The ratio may be between 1:40 and 10:1, and is preferably 1:5 to 5:1. A tablet may for example contain 80 to 400 mg of a compound I and 400-80 mg of a sulphonamide. In preparations containing a compound I as the single active component, 100-1000 mg serves as a guideline for an individual dose which, depending on requirements, can be administered one or more times per day.

Example 1 A solution of 36 g of 3,5-dimethoxy-4-methylthiobenzaldehyde and 28 g of -morpholinopropionitrile in 300 ml of dimethylsulphoxide was heated to 60[deg]C and 3.9 g of solid sodium methylate was added thereto. A slightly exothermic reaction was observed and the solution immediately became dark. The solution was stirred for one hour in an oil bath (60[deg]C), cooled, and poured into iced water. The product was then extracted with ethyl acetate, washed with sodium chloride solution, and dried over sodium sulphate. After removing the solvent, 56 g

obtained in the form of a bright yellow oil (M.P. 1 10-1 13[deg]C, in ethyl acetate/pentane), which was processed further in this form. 56 g of 3,5-dimethoxy-a-(morpholinomethylene)-4-(methylthio)-hydrocinnamic acid nitrile dissolved in 250 ml of isopropanol were added to a mixture of 18.6 g of aniline and 11.5 g of acetic acid prepared while cooling with ice. The mixture was heated for 2 hours under reflux, 100 ml of isopropanol were distilled off towards the end of the reaction, the reaction mixture was then cooled to 0[deg]C, 300 ml of water were added, and the product was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. 50 g of crude a-anilinomethylene-3,5-dimethoxy-4(methylthio)-hydrocinnamic acid nitrile crystallised from the residue. Recrystallisation from ethyl acetate/pentane provided 40 g (72%) of the compound having a melting point of 206-210[deg]C.A solution of 10.2 g of a-anilinomethylene-3,5-dimethoxy-4-(methylthio)-hydrocinnamic acid nitrile and 16.6 g of guanidine carbonate in 200 ml of ethanol, containing 2.15 g of sodium, was heated for 20 hours under reflux. The solvent was removed, the residue was suspended in iced water, and the crystals were suction filtered, exhaustively washed with iced water, and recrystallised from hot ethanol. 7.1 g (77.5%) of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)benzyl]-pyrimidine, having a melting point of 231-232[deg]C, were obtained.

Example 2 By analogy to the method described in Example 1, further aldehydes of the formula VIII were converted via compound II-c and II-d into compounds of the formula I. The results are given in Table 1.

Example 3

A solution of 1.4 g of 3-bromo-4,5-bis-(methylthio)-benzaldehyde, 0.85 g of -methoxypropionitrile and 0.14 g of sodium methylate in 15 ml of absolute methanol was heated for 18 hours under reflux. The solvent was removed, the residue was taken up in 10 ml of methylene chloride, and the solution was washed with water, dried, and concentrated by evaporation. The crude 3-bromo-4,5-bis-(methylthio)-a-(methoxymethylene)-hydrocinnamic acid nitrile (1.5 g) obtained was heated for 18 hours under reflux with 0.6 g of guanidine hydrochloride and 0.35 g of sodium methylate in 5 ml of ethanol.After distilling off the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate/methanol (3:1, v/v) as eluting agent, and recrystallised from methanol. 2,4-diamino-5-[3-bromo-4,5-bis-(methylthio)-benzyl]pyrimidine was obtained, having a M.P. of 240-243[deg]C.

Example 4 A mixture of 10.6 g of 3,5-dimethoxy-4-methylthio-benzaldehyde, 6.2 g of ethyl cyanoacetate and 2 drops of piperidine was heated in an open flask for 90 minutes at 120[deg]C while stirring, and was then cooled and recrystallised from ether/n-heptane. The yield of ethyl a-cyano-3,5dimethoxy-4-methylthiocinnamate, M.P. 98-100[deg]C (from ethanol), was 12.0 g (80%). 0.23 g of sodium borohydride was added while stirring to a suspension of 6.0 g of ethyl acyano-3,5-dimethoxy-4-methylthiocinnamate in 130 ml of ethanol and 2 drops of 1 N caustic soda, a solution thereupon being formed. After 30 minutes, the ethanol was evaporated off at 40.C under a water jet vacuum, the residue was taken up in ether, and the solution was washed with water and filtered through silica gel. 5.0 g (79.1 %) of ethyl a-cyano-3,5-dimethoxy-4methylthiohydrocinnamate was obtained as a colourless oil. In another experiment a solution of 3 g of ethyl a-cyano-3,5-dimethoxy-4-methylthiocinnamate in 250 ml of methanol and 500 mg of 5% Pd/C was hydrogenated for 24 hours under normal pressure and at room temperature. After conventional working up, 3.0 g (~100%) of ethyl acyano-3,5-dimethoxy-4-methylthiohydrocinnamate were isolated. 2.7 g of guanidine hydrochloride were added to a solution of 0.7 g of sodium in 60 ml of absolute ethanol. After 30 minutes the suspension was filtered and 4.5 g of ethyl a-cyano-3,5dimethoxy-4-methylthiohydrocinnamate were added to the filtrate. The reaction mixture was boiled under reflux for 18 hours, evaporated to dryness, and the residue was suspended in water and extracted three times with 200 ml of ethyl acetate. The extract was concentrated by evaporation and the residue was crystallised from methanol. 1.8 g (38.5%) of 2,6-diamino-5(3,5-dimethoxy-4-methylthiobenzyl)-4-pyrimidinol having a M.P. of 213-215[deg]C was obtained. 0.73 g of dimethylaniline as added dropwise while stirring to a suspension of 0.96 g of 2,6diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-4-pyrimidinol in 7.6 g of phosphorus oxychloride. The mixture was boiled for 4 hours while stirring and approximately half the excess phosphorus oxychloride was distilled off under reduced pressure. Approximately 10 g of ice was added to the remainder. The suspension was then allowed to stand for 36 hours at room temperature and adjusted to a pH of 10 with concentrated ammonia solution. The suspension formed was freed from dimethylaniline by steam distillation. After cooling the aqueous suspension, the solid crude product was suction filtered, dissolved in benzene/methanol (4:1, v/v), and filtered through silica gel.After evaporating off the solvent, the 2,6-diamino-4-chloro5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine was recrystallised from methanol; M.P. 218-221 [deg]C. 150 mg of zinc powder was added to a solution of 167.7 mg of 2,6-diamino-4-chloro-5-(3,5dimethoxy-4-methylthiobenzyl)-pyrimidine in 1.6 ml of glacial acetic acid and 10 mg of mercuric chloride in 0.2 ml of water. The mixture was boiled under reflux overnight while stirring. The solution obtained was filtered hot, and unreacted zinc was washed out with 0.5 ml of glacial acetic acid. The filtrate was diluted with 2 ml of water and made alkaline with concentrated ammonia solution while cooling. The suspension was extracted three times with 5 ml of ethyl acetate, the extract was dried and concentrated by evaporation, and the residue was recrystallised from methanol. 148 mg of 2,4-diamino-5-(3,5-dimethoxy-4-methylthiobenzyl)-pyrimidine having a M.P. of 231-232[deg]C were obtained.

Example 5 A mixture of 3.03 g of 3,4-bis-(methylthio)-toluene, 2.8 g of 2,4-diamino-5-methoxymethylpyrimidine and 15 ml of orthophosphoric acid was stirred for 6 hours at 100[deg]. After cooling and diluting with 5 ml of water, 45 ml of a 50% potassium hydroxide solution ws dripped in at 0[deg]. The solid product was suction filtered, stirred twice with water, dissolved in methanol, and the solvent was then evaporated. The residue (2.5 g) was purified by column chromatography on silica gel using ethyl acetate/methanol (3:1, v/v) as eluting agent. The 2,4-diamino-5-[2methyl-4,5-bis(methylthio)-benzyl]-pyrimidine isolated was recrystallised from methanol; M.P. 217-222'C.

Example 6 3.9 g of 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine were dissolved in 90 ml of acetic acid, 1.3 g of 30% hydrogen peroxide was added, and the mixture was stirred for 3 hours at room temperature. The solution was then poured onto iced water and made alkaline with concentrated ammonia solution. The crystalline precipitate was suction filtered and recrystallised from methanol/methylene chloride. 2.8 g (70%) of 2,4-diamino-5-[3,5-dimethoxy4-(methylsulphinyl)-benzyl]-pyrimidine was obtained in the form of bright yellow crystals having a M.P. of 288-289[deg]C.

Example 7 610 mg of 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulphinyl)-benzyl]-pyrimidine, dissolved in 15 ml of glacial acetic acid and 1 ml of 30% hydrogen peroxide, were stirred for 24 hours at room temperature. The mixture was then poured into ice, made alkaline with concentrated ammonia solution, and the crystalline precipitate was suction filtered, washed well with water and dried; yield: 580 mg (85%) of 2,4-diamino-5-[3,5-dimethoxy-4-(methylsulphonyl)-benzyl]pyrimidine, M.P. 297-298[deg]C (with decomposition).

Example 8 9 g of 2,4-diamino-5-(3,5-dimethoxy-4-mercaptobenzyl)-pyrimidine-hydrochloride, 4.1 g of potassium carbonate and 2.5 g of dimethylsulphate were heated in 80 ml of acetone for 16 hours under reflux. The reaction solution was filtered, the solvent was removed, and the residue was taken up in ethyl acetate and washed with water. On concentrating the dried solution by evaporation, 2.7 g (88%) of colourless 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]pyrimidine having a M.P. of 230-232[deg]C crystallised out.

Example 9 A solution of 23 g of sodium nitrite in 60 ml of water was added dropwise to a suspension, kept at 0-5[deg]C, of 63.3 g of methyl 4-amino-3,5-dimethoxybenzoate in 300 ml of water and 75 ml of concentrated hydrochloric acid. The now clear, orange-coloured solution was dripped into an ice-cold, vigorously stirred solution of 80 g of potassium methyl xanthogenate in 300 ml of water, whereupon a vigorous evolution of gas was observed. After stirring for 4 hours at room temperature the product was extracted with ethyl acetate, and the extract was washed with sodium chloride solution and dried over sodium sulphate. 54 g (60%) of crude S-[4(methoxycarbonyl)-2,6-dimethoxy-phenyl]-0-methyldithiocarbonate, having a M.P. of 1 1 3 1 1 5[deg]C, were obtained from the residue remaining after evaporation. A mixture of 29 g of S-[4-(methoxycarbonyl)-2,6-dimethoxyphenyl]-0-methyldithiocarbonate and 2 g of potassium methyl xanthogenate was stirred in 450 ml of dimethylformamide for one hour at 100[deg]C. The solvent was then removed under reduced pressure and the residue was taken up in ethyl acetate. After washing with water and saturated sodium chloride solution, the residue was dried over sodium sulphate and the solvent was removed. The residue provided, after recrystallisation from cyclohexane, 18.8 g (81 %) of methyl 3,5-dimethoxy-4-(methylthio)benzoate in the form of colourless crystals having a M.P. of 86-88[deg]C. 50 g of morpholine in 200 ml of toluene was added dropwise to a solution, cooled to 0[deg]C, of 1 50 g of sodium dimethoxyethoxy alanate (70% in toluene) in 150 ml of toluene. The clear solution was then stirred at 0[deg]C and added dropwise while stirring to a solution, cooled to - 20[deg]C, of 30 g of methyl 3,5-dimethoxy-4-(methylthio)-benzoate in 700 ml of toluene. The mixture was stirred for a further 5 hours and then 100 ml of water was slowly added dropwise, 100 ml of 3N hydrochloric acid was added, and finally the phases were separated in a separating funnel. The aqueous phase was extracted twice with ethyl acetate while the organic phases were washed with sodium chloride solution and dried over sodium sulphate.Concentration of the solution resulted in 26 g of a yellow oil that crystallised completely and, after recrystallisation from ethyl acetate/pentane, yielded 21 g (78%) of 3,5-dimethyoxy-4-(methylthio)-benzaldehyde having a M.P. of 54-56[deg]C.

Example 10 In a manner analogous to that described in Example 9, 21 .1 g of methyl 4-amino-3,5dimethoxybenzoate were converted into 19 g (68%) of S-[4-methoxycarbonyl)-2,6-dimethoxyphenyl]-0-ethyldithio carbonate having a M. P. of 84-86 [deg]C, and the latter was further converted in 90% yield into methyl 3,5-dimethoxy-4-ethylthiobenzoate having a M.P. of 50-52[deg]C. 120 ml of a 20% diisobutyl aluminium hydride solution in hexane were added dropwise within 10 minutes to a solution of 10.8 g of methyl 3,5-dimethoxy-4-(ethylthio)-benzoate in 100 ml of absolute ether stirred at 0[deg]C. The resulting mixture was stirred for a further 2 hours at 0-5[deg]C, 100 ml of water was slowly added dropwise followed by 150 ml of 3N hydrochloric acid, and the product was taken up in ether and washed till neutral. The solution was dried over sodium sulphate, the solvent was removed, and the remaining yellow oil (1 1.2 g) was taken up in 100 ml of methylene chloride and the solution was stirred at room temperature in the presence of 15 g of manganese dioxide. After 3 hours a further 15 g of manganese dioxide was added.The resulting mixture was then stirred for 3 hours, filtered through a filter aid based on diatomaceous earths, and the filtrate was then concentrated by evaporation. The residue, when crystallised from ether/pentane, yielded 9.2 g (96.5%) of 3,5-dimethoxy-4-(ethylthio)-benzaldehyde in the form of colourless crystals having a M.P. of 38-39[deg]C.

Example 11 In a manner similar to that described in Example 9, 21 .1 g of methyl 4-amino-3,5dimethoxybenzoate were converted into 23 g (66%) of S-[4-(methoxycarbonyl)-2,6-dimethoxy-

a 42% yield into methyl 3,5-dimethoxy-4-(2-methoxyethylthio)-benzoate of M.P. 56-58[deg]C, and finally reduced to 3,5-dimethoxy-4-(2-methoxyethylthio)-benzaldehyde (yield 88%).

Example 12 48 g of ethyl 3,5-dibromo-4-nitrobenzoate were added in portions at 15-30[deg]C under a nitrogen atmosphere and while stirring and cooling with iced water, to a suspension of sodium mercaptide prepared from 35.5 g of a 55% sodium hydride dispersion in mineral oil and 270 ml of dimethylformamide and 39.6 g of methyl mercaptan in 190 ml of dimethylformamide. The mixture was stirred for 4 hours at room temperature, poured into 4 I of water, the precipitated crystals were combined with the ether extracts from the filtrate, and the solvent was removed. Recrystallisation of the residue from ether/petroleum ether yielded 10.2 g of ethyl 3,4,5-tris-(methylthio)-benzoate. The aqueous filtrate obtained during the working up was cooled and adjusted to pH 2 with concentrated hydrochloric acid, and the solid material was suction filtered and dried.After esterification with ethanol/HCI, 28 g of a mixture of ethyl 3-bromo-4,5bis-(methylthio)-benzoate and ethyl 3,4,5-tris-(methylthio)-benzoate (weight ratio approx. 1:1) was obtained, which was separated by column chromatography on silica gel using methylene chloride as eluting agent. 13.8 g (32%) of ethyl 3-bromo-4,5-bis-(methylthio)-benzoate of M.P. 69-71[deg]C and 12.8 g (in all 23 g, i.e. 60%) of ethyl 3,4,5-tris-(methylthio)-benzoate of M.P. 89-93'C were obtained. On esterifying the mixture with methanol/HCI and working up in an analogous manner, methyl 3-bromo-4,5-bis-(methylthio)-benzoate of M.P. 105-106[deg]C and methyl 3,4,5-tris-(methylthio)-benzoate of M.P. 122-124[deg]C were obtained. In a manner similar to that described in Example 10, 35.9 g of methyl 3-bromo-4,5-bis(methylthio)-benzoate were then reduced in 62% yield to 3-bromo-4,5-bis-(methylthio)-benzaldehyde, and 24.1 g of methyl 3,4,5-tris-(methylthio)-benzoate were reduced in 58% yield to 3,4,5-tris-(methylthio)-benzaldehyde of M.P. 160-161 [deg]C. In another embodiment methyl 3-bromo-4,5-bis-(methylthio)-benzoate and methyl 3,4,5-tris(methylthio)-benzoate were prepared as follows: (a) 1.76 g of ethyl 4-nitro-3,5-dibromobenzoate was added in portions at 15-25[deg]C under a nitrogen atmosphere and while stirring and cooling with iced water, to a suspension of sodium mercaptide prepared from 0.55 g of 55% sodium hydride dispersion (in mineral oil) in 10 ml of dimethylformamide and 1 ml of methyl mercaptan in 6 ml of dimethylformamide.The reaction mixture was then stirred for 20 minutes at room temperature, evaporated to dryness under a high vacuum at 45[deg]C, 30 ml of water was added to the residue, and the latter was then extracted with ether. The ether extract was dried, filtered, and concentrated by evaporation. 1.5 g (94%) of ethyl 3-bromo-4,5-bis-(methylthio)-benzoate of M.P. 72-73[deg]C were obtained from the residue after recrystallisation from hot n-heptane. (b) 28 g of ethyl 4-nitro-3,5-dibromobenzoate was added in portions at 15-25[deg]C under a nitrogen atmosphere and while stirring and cooling with iced water to a suspension of sodium mercaptide prepared from 20.7 g of 55% sodium hydride dispersion (in mineral oil) in 160 ml of dimethylformamide and 27 ml of methyl mercaptan in 110 ml of dimethylformamide.The reaction mixture was then stirred for 4 hours at room temperature, evaporated to dryness under a high vacuum at 45[deg]C, 750 ml of water was added to the residue, and the latter was extracted 5 times with ether, each time with 150 ml of ether. The ether extrct was dried, filtered, and concentrated by evaporation. 16.5 g (75%) of ethyl 3,4,5-tris-(methylthio)-benzoate of M.P. 90-92'C were obtained from the residue after recrystallisation from hot n-heptane.

Example 13 20 ml of methyl mercaptan was added to a suspension, cooled to 0[deg]C, of 10.8 g of sodium methylate in 150 ml of methanol. The mixture was stirred for 30 minutes at 0[deg]C and 13.6 g of ethyl 3,5-dibromo-4-nitrobenzoate were added, resulting in a thick suspension. After 5 minutes the reaction mixture was concentrated by evaporation, the residue was extracted with ether, and the extract was washed with water. After recrystallisation from methanol, 13 g (92%) of methyl 3,5-dibromo-4-(methylthio)-benzoate of M.P. 101-102[deg]C were obtained. In a manner analogous to that described in Example 10, 14.7 g of methyl 3,5-dibromo-4- (methylthio)-benzoate were reduced in 83% yield to 3,5-dibromo-4-(methylthio)-benzaldehyde of M.P. 87-89[deg]C.

Example 14 A mixture of 22 g of ethyl 4-amino-3,5-dibromobenzoate, 100 ml of acetic acid, and 14.4 g of 2,5-diethoxytetrahydrofuran was kept for one hour at 100[deg]C and then concentrated by evaporation under reduced pressure. The dark residue was taken up in ethyl acetate, the solution was first washed with sodium bicarbonate solution and then with sodium chloride solution, and was finally dried over sodium sulphate and evaporated to dryness. 20 g (60%) of ethyl 3,5-dibromo-4-pyrrolo-benzoate of M.P. 106-107[deg]C were obtained from ether/petroleum ether. 18.5 g of this compound in 40 ml of warm dimethylformamide was added dropwise to a solution, stirred at room temperature, of methyl mercaptide (prepared from 6 g of sodium hydride and approx. 15 g of methyl mercaptan in dimethylformamide) in 100 ml of dimethylformamide.The resulting solution was stirred for a further 16 hours at room temperature, concentrated by evaporation, taken up in ethyl acetate, adjusted to pH of 2 with hydrochloric acid, washed with saturated sodium chloride solution, dried over sodium sulphate, and reconcentrated by evaporation. The residue was esterified in ethanol/HCI and the solution was then concentrated by evaporation. 8.8 g (57%) of crystalline ethyl 3,5-bis-(methylthio)-4-pyrrolobenzoate of M.P. 108-109[deg]C were obtained from the residue dissolved in ether, after addition of hexane. In a manner similar to that described in Example 10, 21 g of ethyl 3,5-bis-(methylthio)-4pyrrolo-benzoate were then reduced in 67% yield to 3,5-bis-(methylthio)-4-pyrrolo-benzaldehyde of M.P. 146-148[deg]C.

Example 15 6.2 ml (5.0 g) of methyl mercaptan was added dropwise to a suspension, stirred at 0[deg]C, of 4.7 g of sodium hydride (50%), freed from oil by washing twice with pentane, in 100 ml of dimethylformamide. After 15 minutes, 12.25 g of 3,5-dimethoxy-4-bromobenzaldehyde in 50 ml of dimethyl-formamide was added dropwise. The brown solution, which became lighter in colour, was stirred for half an hour at room temperature, poured onto iced water, and the mixture was then extracted with ethyl acetate. The extract was washed with water, cold 1 N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, and the yellow oil remaining after removal of the solvent was crystallised from methanol. Yield 8.9 g (84%) of 3,5-dimethoxy-4-(methylthio)-benzaldehyde of M.P. 55-56[deg]C.

Example 16 A solution of 18 g of methyl mercaptan in 70 ml of dimethylformamide was added dropwise while stirring and at 0-5[deg]C under a nitrogen atmosphere to a suspension of 16.5 g of sodium hydride (55%) in 200 ml of dimethylformamide. After 30 minutes' stirring at room temperature, 1 .5 g of cuprous chloride followed by 21 g of 3,5-dibromo-4-hydroxybenzaldehyde were added. The reaction mixture was stirred for 68 hours at 120[deg]C, a further 1.5 g of cuprous chloride was added, and the reaction mixture was then stirred a further 20 hours at 150[deg]C. The mixture was then concentrated by evaporation in a high vacuum, the residue was taken up in 10% NaCI solution, and the solution was then filtered through diatomaceous earth. The aqueous phase was extracted with ether, acidified with concentrated hydrochloric acid, while cooling, and extracted with ethyl acetate.The ethyl acetate extracts washed with water were dried and concentrated by evaporation, 9 g of the mixture obtained (in all 14 g) were dissolved in 90 ml of acetone, and 10.7 g of potassium carbonate were added. 7.5 ml of dimethyl sulphate were added to the resultant suspension. The reaction mixture was stirred for 18 hours at 50[deg]C and then suction filtered, and the inorganic salts were washed with acetone and the filtrate was concentrated by evaporation. The evaporation residue was dissolved in ethyl acetate, washed in succession with concentrated ammonia and water, and separated using heptane/acetone (7:1, v/v). 3-bromo-5methylthio-anisaldehyde of M.P. 54-56[deg]C, yield 3.5 g, was first eluted, followed by 3,5-bis(methylthio)-anisaldehyde of M.P. 84-86[deg]C (from n-heptane), yield 2.6 g.

Example 17 27.3 g of 1-methyl-3,4-dithiophenol (prepared from 4-methylanthranilic acid according to Synthesis 1976, 471) in 110 ml of ethanol were added dropwise within 20 minutes to a solution of 23 g of 85% potassium hydroxide in 190 ml of ethanol. 49.6 g of methyl iodide in 70 ml of ethanol was added after 45 minutes to the solution, the KI that had precipitated out after 30 minutes' stirring was filtered off, the ethanol was evaporated off, and the 3,4-bis(methylthio)-toluene obtained was distilled at 95-98[deg]C/1 mm Hg. Yield 30.0g (93%), M.P. 38-39[deg]C (heptane). 21 .6 g of phosphorus oxychloride was added dropwise at 15-20[deg]C to a solution of 27 g of 3,4-bis-(methylthio)-toluene in 20 g of N-methylformanilide, and the solution was stirred for 24 hours at 55[deg]C. A suspension of 9.6 g of N-methylformanilide and 10.8 g of phosphorus oxychloride was then added to the reaction solution, which was stirred for a further 24 hours at 55.C. Water was added to the cooled mixture, the latter was extracted with ether, the combined extracts were dried and evaporated to dryness, and the residue was chromatographed on silica gel using benzene. 14.7 g of 3,4-bis-(methylthio)-6-methylbenzaldehyde of M.P. 51-52[deg]C (heptane) were obtained. In an analogous manner, 1,2-bis-(methylthio)-benzene was obtained in an 83% yield from 1,2-dithiophenol, and was converted in 39% yield into 3,4-bis-(methylthio)-benzaldehyde of M.P. 50[deg]C.

Example 18 18 g of syringaldehyde followed by 15 g of dimethylthiocarbamoyl chloride were added in portions to a suspension, stirred at 0[deg]C, of 2.64 g of sodium hydride in 150 ml of dimethylformamide in such a way that the internal temperature did not exceed 10[deg]C. The reaction mixture was then stirred for 4 hours at room temperature, taken up in ethyl acetate, washed in succession with cold 3N hydrochloric acid, 1 N caustic soda and saturated sodium chloride solution, and dried. 16.2 g (60%) of 0-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethylthiocarbamate of M.P. 173-176[deg]C crystallised, after addition of hexane, from the solution concentrated by evaporation. 14.5 g of 0-(4-formyl-2,6-dimethoxyphenyl)-N,N-dimethyl-thiocarbamate were heated for 2 hours at 220[deg]C, cooled, and crystallised from ethyl acetate/hexane. 12.1 g (83%) of S-(4formyl-2,6-dimethoxyphenyl)-N,N-dimethylthiocarbamate of M.P. 183-186[deg]C were obtained. This compound was converted by basic hydrolysis into 3,5-dimethoxy-4-mercapto-benzaldenhyde. 0-(4-formyl-2-methoxyphenyl)-N,N-dimethyl-thiocarbamate of M.P. 114-115[deg]C was prepared in 78.5% yield in a similar manner from vanillin, and was then converted in 83% yield into S(4-formyl-2-methoxyphenyl)-N,N-dimethyl-thiocarbamate of M.P. 109-1 10[deg]C and finally hydrolysed to 4-mercapto-3-methoxybenzaldehyde.

Example 19 A suspension of 1.6 g of 2,4-diamino-5-[4-(N,N-dimethyl-carbamoylthio)-3,5-dimethoxybenzyl]-pyrimidine in 25 ml of methanol and 25 ml of 3N caustic soda was heated for 16 hours under reflux and under an argon atmosphere, whereupon a clear solution was formed. The crystalline precipitate that separated out on cooling was suction filtered and dissolved in 20 ml of water and 10 ml of methanol. 500 mg of sodium borohydride was added to the solution, the latter was allowed to stand for one hour and then acidified to pH 3 with 3N hydrochloric acid, and the crystals formed were suction filtered and dried under a high vacuum. 0.8 g (62%) of 2,4-diamino-5-(4-mercapto-3,5-dimethoxybenzyl)-pyrimidine-hydrochloride of M.P. 275-277 [deg]C was obtained..

Example 20 86 g of guanidine hydrochloride were added to a solution of 20.7 g of sodium in 250 ml of methanol. After filtration, the solution was added dropwise at 95[deg]C within 30 minutes to a solution of 98 g of freshly prepared 3,5-dimethoxy-4-(methylthio)-a-(2-methoxyethoxymethytene)-hydrocinnamic acid nitrile in 250 ml of ethylene glycol monomethyl ether, the methanol being continuously distilled off. The temperature was raised for one hour to 120[deg]C and during this time 200 ml of solvent were distilled off under reduced pressure. The reaction mixture was then cooled to 0[deg]C and 400 ml of water were added. The crystalline precipitate was suction filtered and then washed in succession with water, ethanol and ether. Yield: 59 g of colourless 2,4-diamino-5-[3,5-dimethoxy-4-(methylthio)-benzyl]-pyrimidine of M.P. 219-223[deg]C. The starting material was prepared as follows:

500 ml of anhydrous ethylene glycol monomethyl ether. The solution was heated to 90[deg]C and 106 g of 3,5-dimethoxy-4-(methylthio)-benzaldehyde was added in portions while stirring. The reaction mixture was heated to 125[deg]C, 50 ml of solvent distilling off. Residual solvent was removed under reduced pressure at 65[deg]C and the residue was taken up in ethylene chloride and washed 3 times, each time with 300 ml of water. The aqueous phases were extracted twice with 300 ml of ethylene chloride, and the combined organic phases were dried over sodium sulphate and evaporated to dryness. The dark oil (155 g) obtained was distilled under a high vacuum at 200[deg]C and yielded 98 g (60%) of 3,5-dimethoxy-4-(methylthio)-a-(2-methoxyethoxymethylene)-hydrocinnamic acid nitrile in the form of a viscous yellow oil, which was immediately processed further.

Example 21 1.35 g of sodium methylate was added to a solution of 5.3 g of 3,5-dimethoxy-4- (methylthio)-benzaldehyde and 3.1 g of -imidazolyl propionitrile in 50 ml of ethanol, and then heated for 5 hours under reflux. To the brown solution was added a suspension of 4.8 g of guanidine hydrochloride and 2.7 g of sodium methylate in 50 ml of ethanol. The ethanol was distilled off and the residue was then stirred for 90 minutes at 100[deg]C. The reaction mixture was suspended in water and filtered, and the filtrate was concentrated by evaporation and the residue was recrystallised from ethanol/ether. 3.6 g (48%) of 2,4-diamino-5-[3,5-dimethoxy-4(methylthio)-benzyl]-pyrimidine of M.P. 224-227[deg]C were obtained in the form of bright yellow crystals.

Example 22 0.6 g of hydrogen peroxide (30%) was added to a solution of 1.6 g of 2,4-diamino-5-[4(ethylthio)-3,5-dimethoxybenzyl]-pyrimidine in 30 ml of acetic acid and the mixture was stirred for 4 hours at room temperature. The mixture was then poured onto ice, adjusted to a pH of 10 with concentrated ammonia solution, and the precipitated crystals were suction filtered. After recrystallisation from methanol/ether, 1.45 g (86%) of 2,4-diamino-5-[4-ethylsulphinyl)-3,5dimethoxybenzyl]-pyrimidine were obtained in the form of colourless needles, M.P. 256-258 [deg]C (with decomposition).

Example 23 2.1 ml of 30% hydrogen peroxide was added to a solution of 5.82 g of 2,4-diamino-5-[3,5dimethoxy-4-(methylthio)-benzyl]-pyrimidine in 130 ml of glacial acetic acid. The mixture was stirred for 7 hours at room temperature. 70 ml of this solution were poured onto approx. 70 g of ice, the mixture was made alkaline with concentrated ammonia while cooling, suction filtered, the residue was suspended in a small amount of concentrated ammonia and then, after decanting, triturated with ethyl acetate, suction filtered and dried. 1.25 g of crude 2,4-diamino-5-[4-methoxy-3-methylsulphinyl-5methylthiobenzyl]-pyrimidine was obtained, while 0.4 g of pure product of M.P. 215-217[deg]C was obtained from the ammoniacal filtrate by extraction with ethyl acetate and evaporation to dryness. A further 0.6 ml of 30% hydrogen peroxide was added to the other part of the reaction mixture, and stirred overnight at room temperature. After working up in a similar manner and recrystallisation from ethanol, 300 mg of 2,4-diamino-5-[4-methoxy-3,5-bis-(methylsulphinyl)benzyl]-pyrimidine of M.P. 1 78-1 80[deg]C was obtained.

Example 24 36 g of 2,4-diamino-5-[3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine was added at room temperature under a nitrogen atmosphere to a suspension of sodium mercaptide prepared from 10 g of 55% sodium hydride dispersion (in mineral oil) in 200 ml of dimethyl formamide and 11 g of methyl mercaptan in 50 ml of dimethylformamide. The mixture was stirred for 3 hours at 55[deg]C, ethyl bromoacetate (24.5 ml) was then added dropwise at 1 5-25[deg]C, and the mixture was stirred for a further hour at room temperature. The solution was concentrated by evaporation in a high vacuum, the residue was taken up in 1 N HCI, the solution was washed with ether, adjusted to pH 8 by adding 1 N NaOH while cooling with ice, was then suction filtered, and the residue was washed well with water and dried.Yield: 32 g (84.6%) of 2,4-diamino-5-[4-(carbethoxymethylthio)-3,5-dimethoxybenzyl]-pyrimidine of M.P. 156-161 [deg]C.

Example 25 A mixture of 9.5 g of 2,4-diamino-5-[4-carbethoxy-methylthio)-3,5-dimethoxybenzyl]-pyrimidine, 75 ml of ethanol, 50 ml of water and 27.5 ml of 1 N NaOH was stirred for 2 hours. After filtration, the ethanol was removed under reduced pressure, and the residue was neutralised by adding 27.5 ml of 1 N HCI, suction filtered, washed with water and dried. 7 g of 2,4-diamino-5[4-(carboxymethylthio)-3,5-dimethoxybenzyl]-pyrimidine of M.P. 280[deg]C (with decomposition) was obtained.

Example 26 3.6 g of 2,4-diamino-5-[3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine was added at room temperature and under a nitrogen atmosphere to a solution of sodium mercaptide prepared from 1 g of 55% sodium hydride dispersion (in mineral oil) in 20 ml of dimethylformamide and 1.1 g of methyl mercaptan in 5 ml of dimethylformamide. The mixture was stirred for 2 hours at 55[deg]C and 5-bromovaleronitrile (2.5 ml) was then added dropwise at 15-25[deg]C and the mixture was stirred for a further hour at room temperature. The solution was concentrated by evaporation in a high vacuum, and the residue was triturated with ether, suction filtered, suspended in water, and again suction filtered. 1.9 g of 2,4-diamino-5-[4-(4cyanobutylthio)-3,5-dimethoxybenzyl]-pyrimidine of M.P. 186-188[deg]C was obtained after double recrystallisation from methanol.

Example 27 5.45 g of 2,4-diamino-5-[3,5-dimethoxy-4-(dimethylcarbamoylthio)-benzyl]-pyrimidine was added to a suspension of sodium mercaptan prepared from 1.44 g of 55% sodium hydride dispersion (in mineral oil) in 30 ml of dimethylformamide and 1.94 ml (1.58 g) of methyl mercaptan in 7.5 ml of dimethylformamide. The mixture was stirred for one hour at 55[deg]C and then 4.57 g of 1-(2-chlorethoxy)-2-methoxyethane was then added at 20[deg]C. After 10 minutes at room temperature, the reaction mixture was worked up in the usual manner and, after recrystallisation from methanol, 2,4-diamino-5-[3,5-dimethoxy-4-[2-(2-methoxyethoxy)-ethylthio]benzyl]-pyrimidine of M.P. 161-162[deg]C was obtained, which was shown by thin layer chromatography to be of uniform composition.

Example 28 A mixture of 3.6 g of 2-(2-chlorethoxy)-2'-methoxydiethyl ether, 3.1 g of sodium-4-[(2,4diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxyphenyl thiolate and 30 ml of dimethylformamide was stirred for 2 hours at 80[deg]C, suction filtered, and the filtrate was evaporated to dryness. The residue was triturated with ether, suction filtered, washed with water and dried. The crude product obtained (3.5 g) was purified by column chromatography on silica gel using methanol/ propanol/NH4OH (5:5:0.5; v/v/v) and yielded 1.8 g of pure 2,4-diamino-5-{3,5-dimethoxy-4[2-[2-(2-methoxyethoxy)-ethoxy]-ethylthio]-benzyl}-pyrimidine of M.P. 130-131 [deg]C.

Example 29 Tablets of the following composition were prepared:

The mixture was granulated wet with addition of water and pressed into tablets.

Claims

1. Aldehydes of the general formula

of 3,4-bis-(methylthio)-benzaldehyde.

2. Aldehydes of the general formula

alkylthio, -S(O)R' or -SOzR', or R1 denotes hydrogen; R2 denotes halogen; R denotes C1-6

the exception of 3,4-bis-(methylthio)-benzaldehyde.

3. Aldehydes of the general formula

C1-6-alkylthio, -S(O)R' or -SO2R', with the exception of 3,4-bis-(methylthio)-benzaldehyde.

4. Aldehydes of the general formula

denotes C1-6 alkylthio, -S(O)R' or -SO,R'.

5. Aldehydes of the general formula

alkylthio, -S(O)R' or -SO2R'.

6. Aldehydes of the general formula

C1-6-alkylthio, S(O)R' or -SO2R'.

7. Aldehydes of the general formula

thio, dimethylcarbamoylthio, -S(O)R' or -SOzR', and R4b denotes halogen or C1-6-alkoxy.

8. Aldehydes of the general formula

halogen or C1-6- alkoxy.