DE2051871A1 - Beta-amino-alpha-aryloxymethylacrylonitrile - and 2,4-diamino-5-benzylpyrimidine derivs. useful as antibacterial agents - Google Patents

Abstract

Cpds. of the formula: Ar-CH2-C(CN)=CH-NR5R6 (I) (where Ar is phenyl (opt. subst.) and NR5R6 is an aliph., heterocyclic or aromatic amino group in which one of R5 and R6 can be H) substantially free of contamination by the isomeric beta-amino-alpha-benzylidene-propionitriles are claimed; processes for their manufacture are also claimed. 2,4-Diamino-5-benzyl-pyrimidines (e.g. trimethoprim) having antimalarial and antibacterial activity are prepd. by reacting (I) with guanidine. Hydrolysis of (I) with aqs. acid gives new (and claimed) cpds. Ar-C(CN)=CH-OH, alkylation of which gives corr. beta-(lower alkoxy)-alpha-benzyl-acrylonitriles.

Description

Intermediates for the preparation of benzylpyrimidines The present The invention relates to intermediates for the preparation of 2,4-diamino-5-benzylpyrimidines.

2,4-diamino-5- (3'.4'.5t-trimethoxybenzyl) -pyrimidine of the formula (I) also known as Trivethopris, is a valuable known compound with antibacterial properties see (US Patents 2,909,522 and 3,049,543).

Trimethoprim is particularly useful for treating surface infections and especially effective against bacilli-induced dysentery caused by the Shigella dysenteriae bacterium and it continues to be effective against the bacterium Eschericia coli.

Trimethoprim can preferably be taken orally as tablets, capsules and sos reiter or it can be administered in solutions or suspensions. The preferred one Dosage of this compound (I) is 5 to 10 mg / kg of body weight in mammals, if it is given two to three times a day. If it is used as salt, it must in the case of the anion, an inherent toxicity will be absent. Salts of the following Acids are preferred: hydrochloric acid, phosphoric acid, Succinic acid, Lactic acid, acetic acid, pyruvic acid, oxaloacetic acid, fumaric acid and citric acid.

If the drug is given together with sulfonamides, will a strongly potentiated effect as a result of the subsequent blockade of the biochemical The process that leads to the de novo synthesis of coenzymes F is observed can be used both in vitro and in experimental infections in mice with Staphyloccoccus and Proteus species can be demonstrated5 for example trimethoprim can be advantageous can be combined with sulfamethoxazole for certain respiratory infections.

Other compounds of this type also have antibacterial activity or potentiating effects.

The maximum antibacterial effectiveness was found in the derivatives which carry electron-donating substituents in benzene nuclei and in the 6-position of the pyrimidine part are not substituted. Diaveridin - (2,4-diamino-5- (3 ', 4'-dimethoxybenzyl) pyrimidine) or ormetoprim- (2,4-diamino-5- (2'-methyl-4 ', 5'-dimethoxybenzyl) pyrimidine) known for exhibiting coccidiostatic properties when taken together be used with sulfachinoxaline or sulfadimethoxine.

All of the known commercially viable manufacturing processes for trimethoprim or for its homologues run through the appropriate benzaldehyde away. This is how the route developed a few years ago, in which one (1) the benzaldehyde with β-substituted propionitrile in the presence of both an alcohol and one Solvent and a strong base condensed and (2) the X-substituted-a; benzyl acrylonitrile reacted with guanidine (see US Pat. No. 3,049,544 and Stenbuck, Baltzly and Hood, J. org. Chem. 1983 (1963) not changed in the main features up to now, although Considerable progress will be made on certain of the points indicated could. The benzaldehyde, however, is a material that is not readily available stands, so its cost is a substantial part in the manufacture of trimethoprim turn off. Nonetheless, despite significant efforts regarding the synthesis or at least to obtain the benzaldehyde at a reasonable cost, no progress on this point has been made to the present invention.

However, it has now been found that trimethoprim is very easily reduced receive numerous special benefits can be if you can the process sequence shown in the accompanying drawings is used, in which the compound (II) is the readily available gallic acid, stages (I) and (2) Are methylations, stage (3) involves the reaction with dimethyl sulfone, step (4) is a reduction, step (5) is a reaction with a β-substituted one Propionitrile, where Z is an alkoxy, thioalkyl or amino group, is the compound (VI) is a β-Z-substituted βOt-benzyl acrylonitrile and step (6) is the reaction with guanidine is.

It is of particular importance that this sequence is not necessary makes using expensive 3,4,5-trimethoxybenzaldehyde. In addition, each level can the process flow very easily, either in the laboratory or in the commercial Scope to be carried out.

In addition, the yields of the desired product are in each stage satisfactory.

The dimethyl sulfone Ch3.SO2.CH3, which is used in step (3), can by dimethyl sulfoxide CH3. SO. CH3 must be replaced, although it has been determined that dimethyl sulfone is more advantageous; so is dimethyl sulfone in the stage. (3) more effective and the aldol product (V) gives a higher yield in step (5).

It has also been found that the reactions given above are generally applicable. Alkoxy-substituted benzoic acid esters react easily with dimethyl sulfone or dimethyl sulfoxide after reaction (a) where in the formulas R is an alkyl group with preferably 1 to ii carbon atoms, R1 one or more alkoxy groups, preferably with 1 to 11 carbon atoms (for example a thoxy, xthoxy, n-propoxy, t-butoxy group), R2 A substituent of your choice, such as a halogen atom, especially chlorine, bromine or iodine, an alkyl group, preferably with 1 to 4 carbon atoms (for example a methyl, ethyl, propyl or buty group), an amido or an amino group and n = is 1 or 2; the compound of the formula (VII) is dimethyl sulfone if n = 2 and dimethyl sulfoxide if n = 1.

Furthermore, the compounds of the formula (IX) are easily reduced after the following reaction (b) where in the formula the radicals Rl, R2 and n have the meanings given above. The compounds of the formula (X) react easily with β-Z-substituted propionitriles after reaction (c).

in which the radicals R1, R2 and Z have the meaning given above.

In the reactions described above, it will preferred, that the phenyl group with an alkoxy group, especially methoxy group, in para- or meta position and most advantageously in both or all such positions is substituted, to the alkyl or alkoxy groups defined in the above formulas include normal, iso- or tertiary-branched forms.

The compounds of the formulas (X) or (IX) are new and can be used with Advantage as an intermediate product in the above-mentioned process route for production of trimethoprim or its analogs can be used.

The present invention therefore has a compound of the formula (XII) as an object, wherein the radicals Rl, R2 and n have the meaning defined above and the radicals R3 and R4 are hydrogen atoms or together represent an additional bond between the carbon atoms and oxygen atoms. Such compounds advantageously have an alkoxy substituent in the para position to the phenyl group and they preferably have such substitutions in both or in all para and meta positions. The alkoxy group is preferably a methoxy group and the intermediates of the formulas (IV) and (V) or their sulfoxide analogs are 3,4,5-trimethoxy-substituted, and they are particularly suitable for the preparation of trimethoprim.

Compounds of the formula (XII) can advantageously be processed further be to intermediates of the formula (XI) or in particular of the formula (VI) with to obtain high yield and purity.

If the substituent Z is an amino group, the product is in obtained a form that is practically free from contamination by the corresponding Isomeric ß-substituted oC-benzylidene propionitrile. It has been found that such Intermediate products particularly suitable for further processing into 5-benzylpyrimidines are what affect the stability and homogeneity of the intermediate products according to the invention can be traced back.

The reaction of a benzoic acid ester with the compound the Formula (VII) as exemplified by the stages (3) in the course of the reaction of the accompanying drawings and in reaction (a) above, is given in Presence of a base causes along with to get best results Dimethyl sulfoxide is used as a solvent for the compound of formula (VII) will. Desirably these two are mixed prior to addition to the benzoic acid ester mixed. Any base that is sufficiently strong is the methylsulfinyl or methylsulfonyl carbanion Forming in an appropriate amount is suitable for this reaction. Preferably the reaction is carried out in a solvent, the base being the sodium amide or hydride is supplied, from the ammonia or hydrogen in the case of the perfect Conversion to the anions mentioned above are given.

The reduction, which is exemplified by ite stage (4) and the reaction (b) is demonstrated can suitably be effected by a reducing agent is used which is in solution, for example in a homogeneous System reacts. Suitably complex hydrides such as those of boron or Aluminum made with alcoholic or aqueous solution average are compatible, for example in the form of a suitable alkali metal, for example Sodium or lithium, salt can be used. Other types of reducing agents, such as aluminum isopropoxide in isopropanol, can also be used for this purpose will.

The reducing agent should preferably contain the sulfone or sulfoxide group do not reduce in the compounds of the form (IV) and (IX).

The reaction with a ß-Z-substituted propionitrile, as it is in Step (5) and shown in reaction (c), for example, will be most advantageous carried out in the presence of both a base and a solvent. The base as such must be strong enough to cause a significant amount of the to convert provided compounds of the formulas (V) and (X) into the corresponding anions to convict. The base is desirably a hydroxide or alkoxide, preferably a methoxide or a tertiary butoxide ion or the methylsulfinylcarbanion in a dimethyl sulfoxide medium and is suitably in the form of an alkali metal (for example sodium or potassium) or quaternary (for example NBenzyl-N, N, -N-trimethyl) - Ammonium hydroxide or alkoxide supplied. The solvent is a polar non-aqueous solvent, that is compatible with the two editorial partners and solves them. It can be an alkanol, such as methanol5 ethanol or isopropanol, but in particular will be a polar one non-protonic solvent such as dimethyl sulfoxide, hexamethyl phosphoramide or N, N-dimethylacetamide used. The propionitrile can be one of the compounds of defined type as described in US Patent 3,049,544, or, more preferably, of the kind specified in the co-pending British Patent application ll9o9 / 69 are described or in particular of the primary anilino type, as specifically described in copending British patent application 11908/69 (both German patent application P 2010166.6) are described.

Accordingly, the defined group Z can be an amino group NR5R6, which is an aliphatic, heterocyclic or aromatic amino group and these can only have one hydrogen atom as R5 and R6. In general it can be noted that as a free amine, HNR5R6 is preferred, which has a pKa value, which is no less than 0, and in particular no greater than about 6.

In particular, it is particularly preferred that the NR5-R6 group is a primary anilino group. The phenyl ring of this group can optionally with one or more substituents such as halogen atoms and alkyl and alkoxy groups may be substituted, however, the unsubstituted anilino group is preferred. The halogen atom can be fluorine, bromine or iodine or, suitably, chlorine and the alkyl or alkoxide groups preferably have from 1 to 4 carbon atoms, as already with regard to the substituents in the compounds of the formula (XII) has been defined.

Substituted anilines of this type are, for example, o- and p-toluidine, p-anisidine, p-chloro-aniline, -2,5-dichloroaniline and -3,4-dichloroaniline.

The NR5R6 group can in addition to the previously identified primary anilino group also a primary amino group, such as a monoalkylamino, benzylamino or naphthylamino, preferably a ß-naphthylamino group or it can be a secondary amino group, such as a dialkylamino, pyrrolidino, piperidino, N-methylanilino or piperazino group, for example N methylpiperazino or preferably the morpholino group.

The present invention therefore also has a method for Preparation of a compound of the formula (X) or in particular a compound of the formula (V) or its sulfoxide analog, as explained here, the subject matter, for which purpose a compound of the formula (IX) is reduced.

The invention has a method of making a compound of Formula (IX) or a particular compound of the formula (IV) or its sulfoxide analog, As previously defined for the subject matter, a benzoic acid derivative of the formula (VIII), or in particular of the formula (III), as defined above, with dimethyl sulfone or dimethyl sulfoxide in the presence of a base that is sufficiently strong to produce the to form suitable carbanion in an appropriate amount for the reaction. Preferably the reaction is carried out in a solvent with sodium amide or sodium hydride carried out as a base.

The compounds of formula (X) can be used to form the suitable i-substituted β-benzylacrylonitriles of the formula (XI) can be used. For the Preparation of a compound of formula (XI), especially when the substituent Z is a Amino group, preferably a primary one Anilino group as above is defined, is a compound of formula (X) with the corresponding β-substituted Propionitrile brought to implementation. The reaction is advantageous in the presence a base and a solvent carried out. To find the appropriate starting material to obtain trimethoprim, a compound of the formula (V) is reacted so that a compound of formula (VI) is obtained.

For the manufacture of trimethoprim or its analogues, a Compound of the formula (VI) and its sulfide analogs or, in general, a compound of formula (XI) is used. In particular, the present invention has use of the intermediate compound of the formula (V) or in general of the formula (x) in the Manufacture of trimethoprim or its analogues is the subject.

A compound of the formula (VI) or of the formula (XI) is made with guanidine reacted to form the corresponding 5-benzylpyrimidine.

To obtain such compounds are the appropriate ones β-anilino derivatives particularly useful. Advantageously, such an amine is mixed with guanidine, suitably in a lower alcohol solvent such as methanol, ethanol or isopropanol, implemented at elevated temperatures. It is particularly preferred that the reaction is carried out at the reflux temperature of the reaction mixture, but it was found that useful speeds as well at lower temperatures down to can be reached at room temperature. In particular, it was found that the reaction takes place very quickly at reflux temperatures, taking hours instead of weeks for their expiry.

Although the reactivity with guanidine of the ß-amino-α-enzylacrylonitrile of formula (VI) or (XI), other than those with a ß-primary anilino group, how the morpholino derivatives, especially in alkanols is lower, has been found that it can be increased and the yield significantly improved if the guanidine in the form of the carbonate in a polar, non-protonic solvent, as above described in relation to other methods, for example particularly with dimethyl sulfoxide or hexamethyl phosphoramide is used0 The reaction is running decreases slowly below 1400C, but rapidly at around 160 ° d or above. Best results were used in these particular cases with dimethyl sulfoxide at or near reflux temperatures obtained and if the previous reaction step also in the same medium was performed, the ß-amino-α-benzyl acrylonitrile intermediate does not have to isolated, although isolation is usually preferred> because on in this way a purer benzylpyrimidine is obtained.

All of the end products made by the above procedures have either antibacterial effectiveness or potentiating properties, although the degree this effectiveness and the potentiating effect is itself with the substitution and the purpose for which the connections are used. Furthermore can use the products themselves as starting materials for the manufacture of other derivatives and their analogs are used by further reactions with functional groups will.

The pyrimidine products were found to be both satisfactory high yield as well as without contamination with polymers and colored impurities can be obtained. As indicated above, this object of the invention is more critical Significance because the currently applicable regulations regarding the purity of the pharmaceutical products are very strict and the products are very pure Shape and, of course, must be manufactured at a reasonable cost. These two Requirements are now as a result of the present invention for benzylpyrimidines easy to reach.

The following examples illustrate the invention.

Example 1 Trimethyl Gallic Acid A solution of sodium hydroxide (904 g) and water (5642 g) and ice, so that the final temperature of o0a was reached, was produced in a 12 1 three-barrel round bottom flask, which is equipped with a stirrer, Temperature tester, fork tube (Y-tube) and dip tube (dip tube) was understood. That Reaction vessel was continuous with a stream of nitrogen flowing through the Solution was beaded, purified. Gallic acid (564 g) was added, whereby the Warming the solution caused the temperature to rise to about 10 ° C. Dimethyl sulfate (575.9 ml) was added, the temperature was allowed to rise to 20 to 250C and then with Using an ice bath controlled for 20 minutes (whereby you can increase the temperature gradually let) 0 Two successive portions of dimethyl sulfate of the same size were added and the temperature is kept at 30 to 350C for 20 minutes and at 40 to 450C for 10 minutes The fork tube was removed and replaced with a reflux condenser. The mixture was refluxed over a mantle for 2 hours, then in an ice bath 500C quenched and the pH value to 3 to 4 with cold hydrochloric acid (approx. 260 ml) set. Cooling was continued to 1000 and the product collected. That Product was washed with ice water (1000 ml) and under vacuum at 60 ° C. overnight dried. The yield was 565 g of crude trimethyl gallic acid (contaminated with a small amount of ester) with a melting point of 139 to 154 ° C; (89 yield).

Example 2 trimethyl gallic acid (565 g) and methanol (2300 ml) became mixed and then heated to 550C for 5 hours.

At this time anhydrous hydrogen chloride (46 g) was added to the mixture directed. The reaction mixture was dissolved in an Eio9-water mixture (8 l), the iON sodium hydroxide solution (290 ml) was poured with stirring.

The solid slurries were filtered, washed with ice water and dried under vacuum at 50 ° C., giving 3,4,5-trimethoxymethylbenzoate, 523 g, melting point 87 to 88 ° Cl. received 0 sodium amide (27 g, 0.69 minor), dimethyl sulfoxide (225 ml) and dimethyl sulfone (56.5 g, 0.6 mol) were taken together for one hour at 55 ° C heated and cooled to 50 ° C. 0 3,4,5-trimethoxymethyl benzoate (65.4 g, 0.29 mol) added and the mixture heated at 600C for one hour to allow the reaction to proceed bring to.

The mixture was poured into ice (1100 g) with dilute (1: 1) hydrochloric acid (180 ml) acidified and chilled in an ice bath. The crystalline product was filtered, washed with ice water (2 1 150 ml) and ice-cold ethanol (2 1 100 ml). After this if it was air-dried overnight, methyl-α - (3,4,5-trimethoxyacetophenone) sulfone was obtained, Yield: 74 g, melting point 147 to 14800.

Methyl α- (3,4,5-trimethoxyacetophenone) sulfone (38.1 g), desalted Water (100 ml) and ethanol (30 ml) were mixed and cooled to 1500, a pre-cooled one Solution of sodium borohydride (2 g) in deionized water (40 ml) was gradually increased The cooling tape was then removed and the reaction mixture was added for an hour touched. The slurry was cooled to 200, the solids filtered, with ice water washed and dried under vacuum at 500C, whereby 34.2 g of the corresponding ß-Hydroxy-ß-3,4,5-trimethoxyphenethylsulfone, melting point 153 to 154 ° C, was obtained.

a) The above sulfone (29 g), ß-anilinopropionitrile (16.5 g) and dimethyl sulfoxide (40 ml) were heated together at 4000 and a solution of potassium t-butoxide in t-butanol (13.6; 83 ml) was carefully added. The temperature was kept at 45 ° C for one hour. The alcohol was then removed from the reaction mixture removed by evaporation in vacuo and the residue poured into ice water (200 ml). The crystalline crude product was collected and recrystallized from ethanol under Formation of ß-anilino- «-3,4,5-trimethoxybenzyl acrylonitrile, yield = 26 g (according to Washing with ethanol and hexane).

Under the conditions described under a) above, the following Sulphones with B-anilinopropionitrile with formation of the corresponding ß-anilino-α-halobenzyl acrylonitrile condensed: b) ß-Hydroxy-ß- (3,4-dichlorophenethyl) -methylsulfon lis- -fert ß-anilino-α-3,4-dichlorobenzyl acrylonitrile, c) ß-Hydroxy-ß- (2-iodophenethyl) -methylsulfon gives B-anilino- «-2-iodobenzyl acrylonitrile, d) ß-Hydroxy-ß- (3-iodophenethyl) -methylsulfon gives ß-anilino- o4-3-iodobenzyl acrylonitrile, e) ß-Hydroxy-ß- (4-iodophenethyl) -methylsulfon gives ß-anilino-α-4-iodobenzyl acrylonitrile, f) ß-Hydroxy-ß- (2-bromophenethyl) methyl sulfone gives ß-anilino-α-2-bromobenzyl acrylonitrile.

Example 3 A three-necked flask equipped with a condenser, RWhr means and thermometer was washed with hexane-washed sodium amide (4.0 g) and distilled and dried Dimethylsulfolide (75 ml) charged. The mixture was slowly warmed to 45 ° C. in an outdoor water bath and the reaction initiated. The temperature was gradually increased to 600C and one hour to finish the Maintain reaction.

The mixture was cooled to + 15 ° C and a solution of 3,4,5-trimethoxymethyl benzoate (12 g) in dimethyl sulfoxide (25 ml) was added dropwise. The temperature was raised kept between 20 and 250C by external cooling. The mixture became a half Stirred for hour at room temperature and quenched in ice water (300 ml). It was then carefully acidified to pH 5 to 6 with cold dilute hydrochloric acid (1: 1).

It was extracted into chloroform (3 x 100 ml), the organic layer washed with water (4 i 50 ml), dried over sodium sulfate, filtered and the All solvent evaporated quickly. The heavy oil weighed 15 g and crystallized slowly when standing.

The cleaning was effected by making the thick one oil dissolved in ethyl acetate (75 ml), charcoal added and the filtrate in an ice-acetone bath chilled. The white @ - (methyl-sulfinyl) -3,4,5-trimethoxyacetophenone was filtered and then dried. Yield = 10 g; Melting point 113 to 11500.

After recrystallization from acetone, the melting point was 115 to 116 ° C and the analytical results were: calculated found C 53.05 52.69 H 5.92 5.84 Example 4 X - (methylsulfinyl) -3,4,5-trimethoiyacetophenone (14 g), deionized water (50 ml) and methanol (35 ml) were combined and cooled to + 150 ° C. Under magnetic stirring, a solution of sodium borohydride (0.5 g) in water (10 ml) was added. The reaction was exothermic, but could be achieved by external cooling 15 to 200C.

The mixture was stirred for 2 hours at room temperature and the methanol stripped under vacuum at 45 to 500C. The aqueous solution was made with chloroform (3 x 75 ml) extracted, the organic layer washed with water (1 x 75 ml), then dried over anhydrous magnesium sulfate, filtered and given a clear thick Oil evaporates. A few drops of ethyl acetate caused complete crystallization of β-hydroxy-B-3,4,5-trimethoxyphenethylmethylsulfoYido Yield = 14 g. The product could be used in the subsequent stage without further purification.

The melting point was 150 to 155 ° C (isomers). After recrystallization the following analytical results were obtained from ethyl acetate: calculated found C 5294 52.37 H 6.61 6.70 EXAMPLE 5 β-Hydroxh-β-3,4,5-trimethoxyphenethylmethyl sulfoxide (5.4 g), β-inilinopropionitrile (3 g), dimethyl sulfoxide (25 ml) and sodium methylate (2.0 g) were combined in a flask at room temperature and slowly heated with stirring on a steam bath up to 90 to 950C. The mixture became very dark and the reaction was over after 20 minutes at 950C.

The mixture was quenched in ice water and the dark oily precipitate washed by decantation. It was dissolved in ethanol (15 ml) and cooled. the heavy yellow crystalline precipitate was filtered with cold ethanol and hexane washed and dried.

Yield = 2 g. The product was identical to a sample made from 5,4,5-trimethoxybenzaldehyde and β-anilinopropionitrile was produced.

Hexamethylphosphoramide was used in place of dimethyl sulfoxide and potassium hydroxide in methanol used instead of sodium methylate, with the same results were obtained in all cases.

Example 6 A guanidine solution was prepared from guanidine hydrochloride (15 g), sodium methoxide (10 g) and ethanol (100 ml).

It was cooled, filtered free of salt and treated with - (3,4,5-trimethoxybenzyl) -ß-anilinoacrylonitrile (16 g) combined. The mixture was then refluxed on the steam bath overnight held and the hot solution treated with charcoal Darco G-60 (2.0 g) and on 1/4 volume evaporates. It was cooled and filtered for complete crystallization and with cold methanol, acetone and Ether washed and dried. Yield = 13 g (91% of the theoretical amount); Melting point 198 to 200 ° C.

Example 7 The procedure of Example 2 was repeated except that Hexamethylphosphoramide (40 ml) used in place of dimethyl sulfoxide and after Working up gave ß-anilino-α-3,4,5-trimethoxybenzyl acrylonitrile. yield = 26 g; Melting point 126 to 12800.

Example 8 A mixture of (3.3 g; 0.0115 mol) methyl- «- (3,4,5-trimethoxyacetophenone) sulfone, Isopropanol (distilled from aluminum isopropoxide) (75 ml) and from aluminum isopropoxide (2.7 g; 0.0132 mol) was refluxed. Periodically, a few drops of the Run the distillate over a 15 inch Vigreaux column and verify its presence tested by acetone with 2,4-dinitrophenylhydrazone reagent. Reflux after two days and removing the distillate, the acetone test was negative. During the reflux time was additional dry isopropyl alcohol (50 ml) necessary to replace this, what was removed by checking, The reaction mixture was evaporated to dryness and mixed with 2N hydrochloric acid (230 ml). The mixture was washed four times with chloroform. The combined chloroform wash liquors were dried over magnesium sulfate and evaporated to give a solid; 3.3 g (97 *); Melting point 151 to 153 ° C. After recrystallization from chloroformbenzene β-hydroxy-β-3,4,5-trimethoxyphenethylmethylsulfone was obtained; Yield 3.1 g (92 70); Melting point 153.5 to 155.50C. The recrystallized product showed a Stains on a silica gel thin layer after developing with chloroform-acetone (9: 1) and visualization with iodine vapors.

Example 9 ß-Hydroxy-ß-3,4,5-trimethoxyphenethylmethylsulfone (5 g) B-anilinopropionitrile (3), dimethyl sulfolide (20 ml) and a solution of potassium hydroxide in methanol (20%; 2 ml) were reacted together at 90 to 950C for 20 minutes.

After working up, β-anilino-α-3,4,5-trimethoxybenzyl acrylonitrile was obtained (3 g); Melting point 126 to 12900 (recrystallized from ethanol).

Example 10 The procedure of Example 9 was repeated except that Hexamethylphosphoramide (20 ml) used in place of dimethyl sulfoxide and after Working up gave β-anilino-o (-3,4,5-trimethoxybenzyl acrylonitrile (2 g); Melting point 125 to 12700 (recrystallized from ethanol).

Example 11 The procedure of Example 9 was repeated, including Sodium methoxide (0.5 g) used instead of potassium hydroxide in methanol and after Working up gave ß-anillno-α-3,4,5-trlmethoiybenzyiaoryinitril.

Yield = 3 g; Melting point 128 to 13,000.

Example 12 ß-Hydroxy-ß-3,4,5-trimethoxyphenethylmethylæulSon (10 g), β-anilinopropionitrile (5.1 g), hexamethylphosphoramide (20 ml) and sodium methoxide (1 g) were reacted at 60 ° C. for 30 minutes and, after working up, β-anilino-α-3,4,5-trimsthoxybenzyl acrylonitrile was obtained. Expansion = 6 g, melting point 127 to 129 ° C.

Example 13 The procedure of Example 11 was repeated, wherein man N, N-dimethylacetamide (25 ml) used instead of dimethyl sulfoxide and after work-up obtained ß-anilino-α -3,4,5-trimethoiybenzylacrylnitril. Yield = 2.5 G; Melting point 125 to 12800.

Example 14 ß-Hydroxy-ß-D4,5-trimethoxyphenethylmethylsulfoxide (5.4 g), ß-anilinopropionitrile (3 g), dimethyl sulfoxide (25 ml) and sodium methylate (0.5 g) were reacted together at 90 to 950C for 1 hour. The mixture was then in Poured ice-water, collected the solid and recrystallized from denatured ethanol with formation of ß-anilino-α-3,4,5-trimethoxybenzyl acrylonitrile. yield = 2 g (30%); Melting point 125 to 12700.

Example 15 The procedure of Example 14 was repeated, wherein potassium hydroxide (2g) in methanol (5ml) was used in place of sodium methoxide and after work-up, U-amilino-α-3,4,5-trimethoxybenzyl acrylonitrile was obtained. Yield = 2 g; Melting point 125 to 12800.

Example 16 The procedure of Example 14 was repeated, wherein man Used hexamethyl phosphoramide in place of dimethyl sulfoxide and sodium methoxide (2 g) and after working up, ß-anilino-α-3,4,5-trimethoxybenzyl acrylonitrile was obtained. Yield = 2 g; Melting point 125 to 1290C.

Example 17 The procedure of Example 14 was repeated, wherein potassium t-butoxide in t-butanol (13.6%; 15 ml) was used in place of sodium methoxide and after working up, ß-anilino-α-3,4,5-trimethorybenzyl acrylonitrile was obtained Yield = 1 g; Melting point 128 to 1300C.

Example 18 The procedure of Example 17 was repeated, wherein hexamethylphosphoramide (25 ml) was used in place of dimethyl sulfoxide and After working up, ß-anilino-α-3,4,5-trimetboxybenzylaerylnitrile was obtained.

Yield = 1 g; Melting point 123 to 12600.

Example 19 β-Morpholinopropionitrile (3.0 g), β-Hydroxy-β-3,4,5 trimethoxyphenethylmethylsulfone (2.9 g), sodium methoxide (0.3 g) and hexamethylphosphoramide (6 ml) were combined at 60 to 650C for 40 minutes and then poured into ice-water (50 ml). The raw one Solid was collected by decantation and recrystallized from ethanol (10 ml) with formation of B-morpholino- «-3,4,5-trimethoxybenzyl acrylonitrile. Yield = 2 g.

Example 20 The procedure of Example 18 was repeated, wherein one used benzyltrimethylammonium hydroxide instead of sodium methoxide and After working up, β-morpholino-o <-3,4,5-trimethoxybenzyl acrylonitrile was obtained with 50% yield.

Example 21 ß-Anilino-α-3,4,5-trimethuzybenzylaorylnitril (32 g) and a solution of guanidine hydrochloride (19 g) and sodium methoxide (13 g) in denatured ethanol (100 ml) was refluxed for 2 1/2 hours, the solvent (31 ml) removed by boiling and the mixture cooled. The resulting crystals of 2,4-diemino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine were collected and used with denatured ethanol and acetone washed. Yield = 27 g (94%); Melting point 198 to 200 ° c.

If methanol is used instead of denatured ethanol, so obtained 2,4-diamino-5- (3 ', 4', 5 'trimethoxybenzyl) pyrimidine is followed in 86% yield 6 hours reflux; with isopropanol, the reaction and the yield proceeded for 2 hours was 78 5.

Example 22 The products of Examples 2 (b) to (f) were prepared according to the Process of Example 21 converted to a) 2,4-diamino-5- (3 ', 4'-dichlorobenzyl) pyrimidine ; Melting point 237 to 2390, b) 2,4-diamino-5- (2'-iodobenzyl) pyrimidine; Melting point 265-2670, c) 2,4-diamino-5- (3'-iodobenzyl) pyrimidine.

Melting point 220.5 to 2220, d) 2,4-diamino-5-94'-iodobenzyl) pyrimidine, Melting point 246 to 2480, e) and 2,4-diamino-5- (2'-bromobenzyl) -pyrimidine, melting point 248 to 2500.

Example 23 β-Morpholino-α-3,4,5-trimethoxybenzyl ayl nitrile (32 g), guanidine carbonate (34 g) and dimethyl sulfoxide (50 ml) were added together for 1 hour at 1600C with thorough stirring.

The reaction mixture was cooled and poured into ice-water (200 ml) and provided 2,4-diamino-5- (3 ', 4 ", 5'-trimethoxybenzyl) pyrimidine, which collected and washed with water and acetone. Yield = 23.6 g (80%); Melting point 196 to 19800.

Reaction sequence

Claims (21)

1. Compound of the general formula wherein the radical R1 is one or more alkoxy groups, preferably with 1 to 4 carbon atoms, R2 is a substituent of your choice such as a halogen atom, especially chlorine, bromine or iodine, an alkyl group, preferably with 1 to 4 carbon atoms, an anido or an amino group, n is either 1 or 2 and the radicals R3 and R4 are hydrogen atoms or together form an additional bond between the carbon and oxygen atoms. 2. Compound according to claim 1, characterized in that the phenyl group is an alkoxy substituent in para-formation. 3. Compound according to claim 2, characterized in that the phenyl group is an alkoxy substituent in both or in all para and meta positions. 4. A compound according to any one of claims 1 to 3, d a d u r c h g e it should be noted that the alkoxy group is a methoxy group. 5. A compound according to claim 4, characterized in that the phenyl group 3,4,5-trimethoxy-substituted. 6. Methyl α- (3,4,5-trimethoxyacetophenone) sulfone. 7. # - (Methylsulfinyl) -3,4,5-trimethoxyacetophenone. 8. β-Hydroxy-β-3,4,5-trimethoxyphenethylmethyl sulfone. 9. β-Hydroxy-β-3,4,5-trimethoxyphenethyl methyl sulfoxide. 10. Process for the preparation of a compound of the general formula (IX) characterized in that a benzoic acid derivative of the formula (VIII) in which the radicals R1 and R2 have the meaning given above and R is an alkyl group, preferably having 1 to 4 carbon atoms, with a compound of the formula (VII) CH3.Sn.CH3 (VII) in which n is either 1 or 2, in the presence a base which is sufficiently strong to provide the appropriate carbanion in an amount sufficient for the reaction to react. 11. The method according to claim 10, d a d u r c h ge k e n n z e i c hnet, that the reaction takes place in a solvent with the added base, such as sodium anide or sodium hydride is carried out. 12. The method according to any one of claims 10 and 11, characterized in that that the solvent used is dinethyl sulfoxide. 13. The method according to one of the aspects 10-12, characterized in that that R is an alkyl group having 1 to 4 carbon atoms. 14. The method according to claim 13, characterized in that the used Benzoic acid derivative is 3.4.5-trimethoxy-substituted. 15. Process for the preparation of a compound of the general formula (x) wherein R1, R2 and n have the meaning given above, characterized in that a compound of the formula (IX) in which R1, R2 and n have the meaning given above, reduced. 16. The method according to claim 15, characterized in that n = 2 is. 17. The method according to claim 16, characterized in that a complex Hydride, such as that of boron or aluminum, with alcoholic or aqueous solvents is compatible, is used as a reducing agent. 18. The method according to claim 17, characterized in that there. complex Hydride in the form of a salt with a likali metal such as .B. Sodium or lithium is used. 19. The method according to claim 15, characterized in that aluminum isoproporide is used in isopropanol as a reducing agent. 20. The method according to any one of claims 15-19, characterized in that that one methyl-α- (3,4,5 -trimethoxyacetophenone) sulfone or # - (methylauflinyl) 3.4.5-trimethoxyacetophenone with formation of B-hydroxy-ß-3.4.5-trimethoxyphanethylmethyl-suflon or sulfoxide reduced. 21. Use of the compounds according to one of claims 1-9 for the preparation of a substituted 2,4-diamino-5-benzylpyrimidine, characterized in that a compound of the general formula (IX) in which R1, R2 and n have the meaning given above, reduced, the reduction product of the general formula (X) with ß-Z-substituted propionitrile of the formula wherein Z is an amino, alkoxy or thioalkyl group, brings about the reaction and the resulting ß-amino-α-benzyl acrylonitrile of the general formula (XI) with guanidine to implement.