NO123851B - - Google Patents

Description

Pyrimidine compounds with fungicidal action.

The present invention relates to pyrimidine compounds with fungicidal action which are characterized by having the formula:

as well as non-phytotoxic acid addition salts thereof, where R is alkyl with 1-13 carbon atoms, cycloalkyl with 3-8 carbon atoms or phenyl,

R''" is benzyl, phenyl, thienyl, furyl, alkyl with 1 to 13 carbon atoms or

v cycloalkyl with 3-8 carbon atoms, X is hydrogen, hydroxyl, lower

acyloxy, halogen, amino, (lower acyl)amino, alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, 2-imidazolylthio, anilino or hydroxylamino, the substituents R, R" and X can also be substituted with one or several of chlorine, fluorine, nitro, methyl, methoxy and trifluoromethyl, except 5-isopropylpyrimidine and 5-isoheptylpyrimidine.

These pyrimidine compounds can be prepared as follows:

(A) when X is a hydroxyl group, by reacting a 5-halopyrimidine with a ketone of the formula R-C:O-R"^, where R and R^" have the meaning given above, and an alkyl-alkali metal under cooling in the presence of a low-melting polar organic solvent or in a mixture of solvents, (B) when X is a hydrogen atom, in that (1) a substituent'!: maleonic acid ester of the formula: where R and R"'' have the meaning given above, and R'* and R,<M> are lower alkyl radicals, is reacted with urea or a suitably substituted derivative of urea, the barbituric acid derivative thus produced is reacted with phosphorus oxyhalide, and the resulting trihalo-pyr:aidin derivative is hydrogenated, or ( 2) an alcohol prepared according to step (A) is reacted with a reducing agent to replace the hydroxy group mr-d with a hydrogen atom, (C) when X is a halogen atom, by reacting an alcohol prepared according to step (A) with a halogenating agent to replace the hydroxyl group in the alcohol with a corresponding halo gene atom, (D) when X is an alkoxy group with 1-3 carbon atoms, by reacting a 5-oc-halopyrimidine prepared according to step (C) with the corresponding alkali metal alkoxide in alkanol solution with a saturated solution of liquid ammonia in the corresponding dry alkanol, (E) when X is an amino group, in that a 5-α-halogenpyrimidine prepared according to step (C) is reacted with liquid ammonia at elevated temperature and pressure, (F) when X is a hydroxylamino group, in that a 5 -lx--nal°gen Pyri-ruidine prepared according to step (C) is reacted with hydroxylfnine in the presence of an alkali metal alkoxide and an alkanol, (G) when T is an anilino group, in that a 5-a-halogenypyrimidine prepared according to step (C) is reacted with aniline in the presence of an inert ;solvent at an elevated temperature,' ;(H) when X is a 2-imidazolylthio group, by reacting the corresponding mercaptan with a 5-a-halopyrimidine prepared according to step ;( G) in the presence of a base and an inert solvent, ;(i) when X is not" a lower acyloxy is a lower acylamino group, by respectively reacting an alcohol produced according to step (A) or an amine produced according to step (E) with the corresponding lower alkanoic acid or its reactive derivative, and, if desired, reacting the product obtained with a acid to form a non-phytotoxic salt thereof. Such non-phytotoxic acid addition salts of the above-mentioned bases can be prepared by using acids of sufficient acidity to form acid addition salts with the weakly basic pyrimidine group or with an amine substituent attached thereto. One can e.g. use hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, oxalic acid, methanesulfonic acid, hydrochloric acid, hydroiodic acid, benzenesulfonic acid, p-toluenesulfonic acid, maleic acid and the like. Previously, Margot et al, US Patent No. 2,839,446 described new pyrimidines that were claimed to have fungicidal activity. These compounds are characterized in that they contain at least one trichloromethane sulfenyl capto group, preferably attached in the 2-position of the pyrimidine ring. ;Furthermore, Ballard et al, US patent no. 2,658,895 has described 2-alkylphenyl-3,4,5j6-tetrahydropyrimidines which are stated to have fungicidal and cleaning properties in addition to being able to be used as asphalt additives. ; Brederick et al., Chem. Ber., 93, 230-35 (1960), describes the preparation of 5-isopropylpyrimidine bg 5-isoheptylpyrimidine. Any applicability of these compounds is not indicated. Lowin et al., Arch. Biochem. and Biophysics, 101, 197-203, (1963), describes how 5-hydroxymethylpyrimidine can be used as a substrate in studies of in vivo inhibition of thiamine synthesis. The new pyrimidines according to the present invention have been shown to be useful for combating fungi which attack foodstuffs, crops and soil. The new compounds have proven useful in combating both airborne and soil-borne fungi that attack plants. Relatively unexpectedly and surprisingly, it has been shown that the new pyrimidine compounds according to the present invention, in contrast to closely related pyridine compounds, are systemically active as fungicides. This means that the pyrimidine compounds are absorbed by the plant and transported around it via the plant's vascular system. Furthermore, it has been shown that these new pyrimidines have the ability to cause certain plants to produce, in a hitherto unknown and not understood way, fungicidal compounds of unknown structure. These compounds can be extracted from the plant tissue by known methods, and it can be demonstrated that they have fungicidal activity in standard fungicide samples. The systemic fungicidal effect of the new pyriinidins has been shown, among other things, by the following remarkable experiment: cucumber<p>ro can, e.g. Vo,ues in a short period of e.g. 10 minutes, in an ethanol-light iscparaffinic oil solution of a 5-substituted pyrimidine. The seeds are taken out of the solution, dried and planted and they will germinate into plants which will be free from powdery mildew and which will be protected against this fungal attack. Among other things, the new compounds have been shown to be suitable in vitro and in vivo tests for the regulation and control of fungi such as Erysiphe polygoni, the organism that produces bean powdery mildew, Colle-totrichum lagenarium, the organism that produces cucumber anthracnose, Uromyces phaseoli, the organism that produces bean rust, Piricularis oryzae, the organism that produces rice blight, and Rhizoctonia solani, the organism that produces fermentation in cotton. Furthermore, it has been shown that certain fungi that attack ornamental shrubs, such as e.g. the fungus Sphaerotheca pannosa var rosae, i.e. the one that produces powdery mildew on roses, as well as Erysiphe graminis, the organism that produces powdery mildew on grass, can be combated by the new pyrimidines. The new compounds according to the invention are also active against certain grass pathogens which every year cause great damage to grass lawns. These pathogens include Helminthosporium sativum, the organism that produces Leaf Spot, Rhizoctonia solani, the organism that produces Brown Patch, Sclerotinia homoeocarpa , the organism that causes Dollar Spot, Fusarium roseum, the organism that causes Root Rot, and Pythium sp., the organism that causes Pythium blight. The new compounds according to the invention are used as fungicides by applying them to the infected plants or the infected soils. This can be suitably carried out by spraying, dipping, spreading or soaking. The new compounds according to the invention are supplied to the plants in effective quantities and these quantities can vary according to the organism to be attacked, the strength of the infection, and other factors such as e.g. the environment in which the treatment is to be carried out. Generally, it has been found that an aqueous shower containing from Z to ([ 00 ppm. of the active substance is satisfactory when the treatment is carried out in a greenhouse.-; It is obvious that a somewhat higher concentration of the active substance is desirable compound when the treatment is to be carried out on open land. In such a case, one usually uses from about 15 to about 1000 ppm of the 5-substituted-pyrimidine. ;If one wishes to combat the above-mentioned grass pathogens, effective control has been achieved by to use from about 6 to about 115 g per measure of the 5-substituted pyrimidines A control of other soil-borne fungi has been achieved by using from about 0.5 to about ;4 kg per measure of the above-mentioned 5-substituted pyrimidines Some of the new compounds have been shown to have unexpected antibacterial activity. Thus, α,α-diphenyl-5-pyrimidinemethanol and' 2-methyl-5-diphenylmethyl-4,6-pyrimidinediol have been shown to be active against Agrobacterium tumefaciens, the organism that produces "crown gall"' . Others, compounds such as 2,4,6-trichloro-5-diphenylmethyl-pyrimidine, 5~(2-chlorodiphenylmethyl)pyrimidine, 2-chloro-5-diphenylmethylpyrimidine and 5-bis(4-^';lorphenyl ) methylpyrimidine, are active against Xanthomonas phaseoli var. sojensis, the organism that causes bacterial blight in soybeans. In addition to the above-mentioned properties, the new pyrimidines have been shown to have unexpected herbicidal activity. The compounds also have an interesting growth-inhibiting activity. Thus, 5-(2-chlorodiphenylmethyl)-pyrimidine has been shown to inhibit root shoots in tobacco. Other compounds such as α-(2-fluorophenyl)-α-(3-fluorophenyl)-5-pyrimidinemethanol have been shown to have the ability to inhibit bud opening on cut flowers. ;Other compounds such as α,α-diphenyl-5-pyrimidinemethanol and α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol have been shown to have anti-auxin properties. Some of the new pyrimidines, such as α-(2-fluorophenyl)-α-(3-fluorophenyl)-5-pyrimidinemethanol and α-(2-chlorophenyl)-α-(4-chlorophenyl)-5-pyrimidinemethanol,. have been shown to have completely unexpected and hitherto unexplained abilities to cause an increase in the number of flowers and fruits produced by tomato plants, when these are treated with one of the above compounds from approx. 6 to 8 weeks for flower development. The new 5-substituted pyrimidine methanols (X = 0H in the above-mentioned general formula) are easily prepared with good yield by a synthesis which can be described as follows:- A suitable ketone, e.g. benzoylcyclohexane, is dissolved in a solvent composed of equal volumes of tetrahydrofuran and ethyl ether, the solution is cooled to -125°C and while it is at this temperature, a solution of 5-chromopyrimidine in equal volumes of tetrahydrofuran and ethyl ether is added. When the mixture is kept at approx. -125°C, a hexane solution of n-butyllithium is added. The reaction mixture is stirred overnight while cooling, the reaction mixture is washed successively with dilute aqueous ammonia chloride solution and water, the organic layer is separated and dried over a suitable desiccant. Hot-dried organic layers are concentrated to dryness in vacuo, and the solid residue is extracted with ether to remove unwanted by-products. The remaining ether-insoluble material is identified by elemental analysis as α-cyclohexyl-α-phenyl-5-pyrimidine methanol. In certain cases, an alternative method can preferably be used which can be described as follows: In a suitable reaction flask where dry ether is kept in an atmosphere of dry nitrogen and that. cooled to -11.8°C, a solution of butyllithium in hexane is added followed by a solution of 5-bromopyrimidine in tetrahydrofuran. The reactive ion mixture is cooled to approx. -125°C, and a solution of a suitable ketone, e.g. 4-i'luo^enzof enone, in tetrahydrofuran is added at such a rate that the temperature in the reaction mixture is kept at approx. -120°C. The reaction mixture is stirred overnight and gradually warmed to room temperature. The mixture is neutralized with a saturated aqueous ammonium chloride solution and extracted with ether. The combined otter extracts are dried, concentrated to dryness in vacuo, and the residual material is dissolved in benzene and chromatographed on a silicon dioxide/d column, which is then eluted with a mixture of ethyl acetate-benzene. The product obtained from the fraction eluted with 30:50 ethyl acetate-benzene was recrystallized from a solvent such as ether, and was then identified as α-(4-fluorophenyl)-α-phenyl-5-pyrimidinemethanol. ;When X = H in the general formula, some of the new compounds can be prepared by heating the 5-substituted pyrimidine methanol (prepared as described above) in a mixture of glacial acetic acid and 47% aqueous hydroiodic acid to reduce the hydroxyl group, thereby obtaining prepared 5~substituted pyrimidinemethane. In other compounds where X = H, the compounds can be obtained by reacting a suitable substituted malonic acid ester with urea or acetamidine or the like. E.g. a mixture of diethylphenyl-p-tolymethylmalonate and urea can be converted into an anhydrous alcohol such as e.g. methanol, in the presence of sodium methylate to 2,4,6-trihydroxy-5-phenyl-p-tolylmethylpyrimidine. This trihydroxy compound can then be reacted with an excess of phosphorus oxychloride to 2,4,6-trichloro-5-phenyl-p-tolylmethylpyrimidine. The latter compound is then hydrogenated in the presence of triethylamine and palladinized charcoal to 5-phenyl-p-tolylmethylpyrimidine The compounds where X = alkoxy with 1-3 carbon atoms can be prepared by reacting an alkali metal lower alkoxide such as sodium methoxide, potassium ethoxide or sodium propoxide in an alkanol solution with a 5-halogen analogue of the desired product (e.g., ^-(α-chlorodiphenylmethyl.)pyrimidine), to the desired product (e.g., ^-(α-C-^-C^-alkoxydiphenylmethyl)pyrimidine). ;When X = amino , then the compounds can be prepared by heating a mixture of the analogous halogen-substituted pyrimidine, e.g. 5-chlorodiphenylmethyl)pyrimidine, and an excess of liquid ammonia at an elevated temperature of about 100°C in a closed stainless steel reaction vessel' for a sufficiently long period of time for the reaction to be' complete. The product , can be isolated as the free base e.g. 5^rc-aminodi-phenylmethyl)pyrimidine, or in the form of a salt such as e.g. the hydrochloride, the hydrobromide or the like. Similarly, 5-(cc-hydroxylaminodiphenylmethyl)pyrimidine and related compounds can be easily prepared by reacting hydroxylamine. with 5-(oc-chlorodiphenylmethyl)pyrimidine. or analogous 5-α-halo compounds. ;Using the same general procedure, ^-/^~ a-(2-imidazolylthio)diphenylmethyl/pyrimidine can be readily synthesized by reacting 2-mercaptoimidazole with oc-chloro-5-diphenylmethylpyrimidine in the presence of a base such as e.g. sodium or potassium ethoxide in a suitable solvent such as e.g. absolute: ethanol. The reaction product is concentrated to dryness under reduced pressure, and the solid residue is dissolved in or extracted with a solvent such as e.g. hot benzene to dissolve the product, and from this solution '5-/~«-(2-imidazolylthio)diphenylmethyl/pyrimidine can then be crystallized.' ;When X = anilino, the compounds can be easily prepared by heating a 5-halogen analogue such as e.g. 5-(oc-chlorodiphenylmethyl)pyrimidine with aniline in an inert solvent such as e.g. benzene on a steam bath for a sufficiently long period of time for the reaction to be complete. The aniline hydrochloride that precipitates is filtered, the filtrate is concentrated in vacuo to dryness, and the residue is crystallized from - a suitable solvent such as e.g. ethyl ether to 5-(α>oc-diphenyl-oc-anilinomethyl)pyrimidine. The following examples concern in detail various methods which can be used to prepare compounds according to the present invention. - ;Example 1 «-cyclohexyl-oc-phenyl-5-pyrimidinemethanol;A solution of 0.1 mol of benzoylcyclohexane in 250 ml of a mixture of equal volumes of tetrahydrofuran and ether which had been cooled to -125°C, was added a solution of 0.1 mol of 5-bromopyrimidine in the same solvent mixture. The reactive ion mixture was stirred and kept at approx. -125°C in a bath composed of liquid nitrogen and ethanol, and to the deionized solution was added 60 ml of a 15% solution of n-butyl Utium in n-hexane, and the reaction mixture was then stirred overnight . The mixture was then washed successively with 10% aqueous ammonium chloride solution and water and then dried over anhydrous potassium carbonate. The dried organic solution was evaporated to dryness, giving as a residue a solid substance weighing approx. 14 g. This was extracted with ether and the undissolved solids washed twice with ether. The ether-insoluble substance was identified as α-cyclohexyl-α-phenyl-5-pyrimidine ethanol with a melting point of approx. I56<0> - 157°C. ;Using the same general procedure as described above, and using appropriate starting compounds, the following compounds were prepared and isolated as free bases or as acid addition salts thereof: ;α,α-bis(4-chlorophenyl)-5-pyrimidinemethano]. ;Melting point: Glass. α-phenyl-α-(4-chlorophenyl)-5-pyrimidine methanol hydrochloride. ;Melting point: Glass. ;α,α-bis(cyclohexyl)-5-pyrimidine methanol. ;Melting point: 142<0> - 144°C. ;α,α-bis(n-hexyl)-5-pyrimidine methanol . Melting point viscous; liquid. ;α-cyclobutyl-α-phenyl-5-pyrimidine methanol. ;Melting point 115° - 117°C. ;α-methyl-α-phenyl-5-pyrimidine methanol. Melting point: 70°C. α,α-bis(3-fluorophenyl)-5-pyrimidine methanol. ;Melting point: Glass. ;α-(2-chlorophenyl)-α-(3-chlorophenyl)-5-pyrimidinemethanol. ;Melting point: Amorphous. ;a,a-diphenyl-5-pyrimidine methanol: Melting point I670 - 170°C. α-(2-Chlorophenyl)-α-phenyl-5-pyrimidine methanol. ;Melting point I54<0> - 156°C. ;α-(n-pentyl)-α-phenyl-5-pyrimidine methanol. Melting point: Liquid. ;α-f 2-Fluorophenyl)-α-phenyl-5-pyrimidinemethanol. Melting point: 139° - 141°C. ;α,α-bis(3,4-dichlorophenyl)-5-pyrimidine methanol hemietherate. Melting point: 88° - 89°C. ;α-(phenyl)-α-(2-thienyl)-5-pyrimidine methanol. ;Melting point 140° - 142°C. ;α,α-bis(isopropyl)-5-pyrimidine methanol. Melting point 115°-118 C. ;α-(3,4-dichlorophenyl)-α-phenyl-5-pyrimidine methanol. ;Melting point: Amorphous. ;α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidine methanol. ;Melting point: Viscous liquid. ;α-(4-nitrophenyl)-α-phenyl-5-pyrimidine methanol. ;Melting point: Amorphous. ;α-f 2-fluorophenyl)-α-(3-fluorophenyl)-5-pyrimidinemethanol. Melting point: IO4<0> - 108°C. ;α,α-bis(p-tolyl)-5-pyrimidine methanol. Melting point: Amorphous. ;α-(2,4-dimethylphenyl)-α-phenyl-5-pyrimidine methanol. Melting point: Amorphous. ;α-phenyl-α-(p-anisyl)-5-pyrimidine methanol. Melting point 95°-97°C. ;α-phenyl-α-(4-trifluoromethylphenyl)-5-pyrimidinemethanol. Melting point: 125° - 127°C. ;α,α-diphenyl-4,6-dichloro-2-methyl-5-pyrimidinemethanol. Melting point: 110° - 112°C.. ;Example 2 5-bis(4-chlorophenyl)methylpyrimidine. A mixture of 6 g of α,α-bis(4-chlorophenyl)-5-pyrimidine methanol, 200 ml of glacial acetic acid and 10 ml of a 47% hydroiodic acid was boiled under reflux for 40 minutes, after which the mixture was poured into water , and the aqueous mixture extracted several times with ether. The combined ether solutions were washed successively with water, 5% aqueous sodium bicarbonate solution and then water, and then dried over anhydrous magnesium sulfate, and finally evaporated in vacuo to dryness. The residue was extracted with petroleum ether and the extracts were concentrated. The product was obtained as a thick root-like oil, and this was identified by infrared spectrum and nuclear magnetic resonance spectrum (NMR) as 5-his(4-chlorophenyl)methylpyrimidine. Using the same procedure as described above, and using appropriate starting compounds, the following compounds were prepared; ;5-(2-fluorodiphenylmethyl)pyrimidine.' Melting point: Liquid. 5-Z~bis(.3,4-dichlorophenyl)methyl/pyrimidine.' Melting point': Liquid. Example 3 a, a-diphenyl-5-pyrimidine acetonitrile,. 0.1 mol potassium amide in liquid ammonia was added to a solution of 0.1 mol diphenylacetonitrile in 300 ml xylene, and the mixture was heated to reflux for approx. 30 minutes to remove excess ammonia. A solution of 0.1 mol 5-bromopyrimidine in 100 ml of xylene was added to the xylene solution, and the total solution was stirred for approx. 20 minutes. The mixture was then added to 20 ml of dimethylformamide, and was then refluxed for approx. 1 hour. The reaction mixture was cooled in an ice bath and extracted with ether. The ether solution was evaporated to dryness, the residue dissolved in benzene and chromatographed on an alumina column, the elution being carried out with ethyl acetate. The eluate was concentrated and gave as product oc,a-diphenyl-5-pyrimidine acetonitrile as a solid whose melting point was approx. 98° - i00°C,. and it was identified by NMR spectrum and elemental analysis. Example 4 2,4i6-trichloro-5-phenyl-p-tolylmethylpyrimidine. ;A solution of 22 g (0.95 g-atom) of sodium in 500 ml of absolute ethanol was added to a solution of 33 g (0.55 mol) of urea and 95 g (0.28 mol) of ethylphenyl-p-tolylmethylmalonate in 500 ml of absolute ethanol, and the mixture was refluxed for approx. 2 hours. The reaction mixture was cooled down. and diluted, with approx. 1000 ml water and 500 ml ether. The layers were separated and the aqueous layer was washed with approx. 200 ml of ether. The ether solution from the washing was combined with the original organic layer and washed with 200 ml of water. The washed aqueous layer and the water-wash solutions were combined and acidified with concentrated aqueous hydrochloric acid. An oily layer separated, which solidified under vacuum. The impure product was dissolved in dilute aqueous sodium hydroxide, and the basic solution acidified with acetic acid. The solid which separated was recrystallized from acetic acid to give a crystalline substance melting at 115°C, which was identified by NMR spectrum as 5-(phenyl-p-tolylmethyl)barbituric acid. Weight: 45 g - ;A mixture of 39 g (0.13 mol) of 5-£'enyl.-P-'tolylmethyl)barbituric acid (prepared as described above), 116 g (0.76 mol) of phosphorus oxychloride and 56 g. (0.38 mol) of N,N-diethylaniline was heated to reflux temperature for approx. 6 hours. The reaction mixture was cooled, diluted with a mixture of crushed ice and water and left. then set aside for approx. ; 1 hour. The mixture was extracted 5 times with 300 ml of ether, the combined extracts were dried, and the solvent was removed by evaporation on a steam bath. The remaining residue was extracted with hot petroleum ether (boiling point 60° - 70°C). The petroleum solution was cooled, and a crystalline substance with a melting point of approx. ;112° - 113°C and weighed approx. 30 g. It was identified by NMR spectrum and elemental analysis as 2,4,6-trichloro-5-(phenyl-p-tolylmethyl)-pyrimidine. By applying the method described in example 4 with suitable starting compounds, the following compounds were prepared: 2,4,b-trichloro-5-(diphenylmethyl)pyrimidine. ;Melting point: 105° - 106°C. ;2,4,6-trichloro-5-(phenyl-p-anisylmethyl)pyrimidine. ;Melting point: 129° - 131°C. ;2,4,6-trichloro-5-(phenyl-o-chlorophenylmethyl)pyrimidine. Melting point: l62° - l63°C. ;2,4,6-trichloro-5-(1-phenyl-n-heptyl)pyrimidine. Melting point: Oil; 2,4,6-trichloro-5-(1-phenyl-n-tridecyl)pyrimidine. ;Melting point: Oil. ;2,4,6-trichloro-5-(1-phenyl-n-butyl)pyrimidine. Melting point: 72°C. Example 3 5-[enyl-P-tolylmethyl)pyrimidine. ;A mixture of 15 g (0.041 mol) 2,4,6-trichloro-5-(phenyl-p-tolylmethyl])pyrimidine, 12.5 g (0.124 mol) triethylamine, 100 ml dry dioxane and 1 g palladinized charcoal was hydrogenated in a shaking machine at an initial pressure of approx. 1.1 kg/cm 2 in approx. 5 hours, and during this time the theoretical amount of hydrogen was absorbed. When the hydrogenation was complete, the reaction product was concentrated in vacuo to dryness. The residue was dissolved in benzene and chromatographed on an alumina column using ethyl acetate as eluent. A solid substance was obtained which was recrystallized from petroleum ether to a crystalline substance whose melting point was 71° - 72°C, and this was identified by means of NMR spectrum and elemental analysis as 5-(phenyl-p-tolylmethyl)pyrimidine. Weight: 8 g. Using the same procedure as described in Example 5 with suitable starting compounds, the following compounds were prepared: 5-(diphenylmethyl)pyrimidine. Melting point: 83°C. 5-(phenyl-p-anisylmethyl)pyrimidine. Melting point: Oil. 5-(phenyl-o-chlorophenylmethyl)pyrimidine. Melting point: 107°-108°C. 5-(1-phenyl-n-heptyl)pyrimidine. Melting point: Oil. ;5-f 1-phenyl-n-butyl")pyrimidine. Melting point: Oil. 5-(l-phenyl-n-tridecyl)pyrimidine. Melting point:. Oil. ;Example 6 5-(a-chlorodiphenylmethyl)pyrimidine ;One to a refluxing solution of 40 g of α,α-diphenyl-5-pyrimidine methanol in 200 mL of xylene, anhydrous hydrogen chloride gas was added via a bubble tube, and the water formed was collected in a Dean-Start trap. The reaction mixture was then concentrated in vacuo to dryness. The dry the residue was washed with ethyl ether to remove starting compounds, and the ethyl ether-insoluble residue was dissolved in hot petroleum ether. The petroleum ether was removed by evaporation, and the residue was recrystallized from ether to give a solid product weighing 6 g and melting at about 92 ° - 94° C. The product was identified as 5-(α-chlorodiphenylmethyl)pyrimidine by elemental analysis and NMR spectrum. ;Example 7 5-('«.α-diphenyl-α-anilinomethyl)pyrimidine. ;A mixture of 5 g of 5-α-chlorodiphenylmethyl)pyrimidine, 10 ml of aniline and 4° ml of benzene were heated for about 1 hour on a steam bath d. The reaction mixture was cooled and filtered to remove aniline hydrochloride, after which the filtrate was concentrated to dryness. The solid residue was recrystallized from ethyl ether to a yellow crystalline product weighing 2 g and whose melting point was approx. I4O<0> - 144°C. The product was identified as 5-(oc,α-diphenyl-α-anilinomethyl)pyrimidine by NMR spectrum. Example 8 5-(α>α-diphenyl-α-hydroxylamino)pyrimidine. A mixture of 5 g of 5-(<x-chlorodiphenylmethyl)-pyrimidine and excess hydroxylamine in ethanolic sodium ethoxide was refluxed for approx. 1 hour. The reaction mixture was evaporated to dryness, and the residue extracted with benzene.- The benzene solution was filtered, concentrated to dryness, and the residue extracted with ether. The ether extract was concentrated to dryness, giving an impure product whose melting point was approx. 110° - 125°C, and this was identified by NMR and infrared spectrum as 5-(α,α-diphenyl-α-hydroxylamino)pyrimidine. Example 9 5-(α-ethoxydiphenylmethyl)pyrimidine. A mixture of 10 g of 5-(α-chlorodiphenylmethyl)pyrimidine and a saturated solution of liquid ammonia in absolute alcohol was prepared, and an exothermic reaction took place. When this was completed, the reaction mixture was filtered, and the filtrate was evaporated to dryness. The solid residue was extracted with chloroform, and the chloroform solution was left overnight at room temperature. The separated crystals were dissolved in ethyl acetate and chromatographed on aluminum oxide using a mixture of bexane and ethyl acetate as elution solution. A solid was obtained whose melting point was 95° - 97°C, and this was identified by means of NMR spectrum and elemental analysis as 5-(oc-ethoxydiphenylmethyl)pyrimidine. Example 10 5-(α-aminodiphenylmethyl)pyrimidine. A mixture of 12 g of 5-f a-chlorodiphenylmethyl)pyrimidine and an excess of liquid ammonia was heated to a temperature of approx. 100°C for approx. 2 hours in a closed stainless steel reaction vessel. The reaction product was removed from the vessel, the excess ammonia evaporated, and the residue extracted with benzene. The benzene solution was concentrated to give a crystalline product melting at 135°-137°C. The product was identified as 5-(α-aminodiphenylmethyl)pyrimidine by NMR spectrum and elemental analysis. Example 11 5-[α-(2-imidazolylthio)diphenylmethyl/pyrimidine. The potassium salt of 2-mercaptoimidazole was prepared by adding 10 g of 2-mercaptoimidazole to an ethanol solution of potassium ethoxide prepared from 1 g of potassium and 200 ml of absolute ethanol. The above mixture was then added 5 g of 5-alpha-chlorodiphenylmethyl)pyrimidine, and the reaction mixture was heated to reflux for approx. 2 hours. The reaction mixture was concentrated in vacuo to dryness, and the residue extracted with hot benzene. The benzene extract was cooled, and a solid product weighing 3 g and whose melting point was approx. 165<0->167°C. It was identified as 5-α-α-imidazolylthio)diphenylmethylβ-pyrimidine by elemental analysis and NMR spectrum. ;Example 12 5-(α-phenylphenethyl)pyrimidine ;Sodium amide in liquid ammonia prepared by adding 1.2 g (0.05 g atom) of sodium to 500 ml of liquid ammonia, 8.3 g (0.05 mol) of 5-benzylpyrimidine was added, and the resulting The red-brown mixture was stirred for approx. 10 to 15 minutes. A solution of 6.3 g (0.05 mol) benzyl chloride in 15 ml of anhydrous ether was added, and the reaction mixture was stirred for approx. 1 hour. The mixture was then added approx. 200 ml of ether, and was then evaporated to near dryness on a steam bath. The residue was again suspended in 200 ml of ether and evaporated to dryness. The dry residue was dissolved in a mixture of approx. 500 ml of ether and 200 ml of water, and the separated ether layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and a solid was separated from the ether solution. On standing, this turned into an oil which was dissolved in benzene and chromatographed on an alumina column using a mixture of ethyl acetate and benzene as eluent. From the eluate, a solid product was obtained which, when recrystallized from petroleum ether, had a melting point of approx. 80°-82°C. The crystalline product weighed approx. 5 g °g was identified as 5-(α-phenylphenethyl)pyrimidine by elemental analysis and NMR spectrum. EXAMPLE 13 2-Methoxy-5-(1-phenyl-n-tridecyl)pyrimidine 4-Methoxy-5-(1-phenyl-n-tridecyl)pyrimidine; A mixture of 40 g (0.09 mol)" 2,4,6 -trichloro-5-(l-phenyl-n-tridecyl)pyrimidine in a solvent prepared from 250 ml of dry dioxane and 500 ml of dry methanol was added to 8 g of palladinized charcoal and 15 g of callum hydroxide, and the mixture was hydrogenated in a Paar shaker with a hydrogen pressure of about 3 kg/cm . The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in a mixture of 300 ml of water and 300 ml of ethyl ether, after which the ether layer was separated and dried and the ether was removed by evaporation. The residue was dissolved in benzene and chromatographed on an alumina column. Elution was carried out with a mixture of benzene and ethyl acetate in a ratio up to a concentration of about 10% ethyl acetate. A total of 14 g of an oil was obtained. This was dissolved in benzene and placed on an approximately 3 m long alumina column which contained about. 800 g of aluminum. The compound was eluted using a mixed solvent of 2% ethyl acetate in benzene. The first fraction was concentrated to 3.5 g of a product, which was identified by NMR spectrum as 2-methoxy-5-(1-phenyl-n-tridecyl)pyrimidine. The next fractions, which weighed a total of 4-0 g at a concentration to dryness, were identified by NMR spectrum as a mixture of different substances and were discarded. The last fraction, weighing 5.5 g was obtained using an elution solution of 10% ethyl acetate in benzene, and this fraction was identified by MMR spectrum as 4-methoxy-5-(1-phenyl-n-tridecyl)pyrimidine .;Example 14 5~ ( cx-acetaminodiphenylmethyl )pyrimidine ;A mixture of 4*5 g of 5-foc-aminodiphenylmethyl)pyrimidine and

50 ml of acetic anhydride was heated until a homogeneous solution was obtained. The reaction mixture was allowed to stand at room temperature overnight and then concentrated in vacuo to remove the solvent.

The dry residue was recrystallized from hot benzene and gave approx. 2.5 g of crystalline product whose melting point was approx. 187° - 189°C. The product was identified as 5-(oc-acetaminodiphenylmethyl)pyrimidine by elemental analysis and NMR spectrum.

Example 15 a-(4-fluorophenyl)-a-phenyl-5-pyrimidine methanol

300 ml of anhydrous ether in an atmosphere of dry nitrogen gas in a suitable 3-necked flask cooled to -118°C by an alcohol-liquid nitrogen cooling bath, was added 170 ml (0.3 mol) of a 15 µg solution of butyllithium in hexane. Cooling and stirring as well as the supply of dry nitrogen were continued while a solution of 0.3 mol of 5-bromopyrimidine in 150 ml of dry tetrahydrofuran was added, and the whole mixture was stirred for approx. 2 hours. The temperature of the reaction mixture was lowered to -125°C and a solution of 0.3 mol of 4-fluorobenzophenone in 150 ml dry tetrahydrofuran was added slowly while the temperature of the mixture was kept at approx. -120°C. The reaction mixture was stirred overnight and then slowly warmed to room temperature. The mixture was neutralized by adding a saturated aqueous solution of ammonium chloride. The neutralized mixture was extracted with ether, and the combined ether extracts were dried over anhydrous potassium carbonate, filtered and concentrated to dryness in vacuo, after which the residue was dissolved in benzene. The benzene solution was chromatographed on 150 g of silica gel, and elution was carried out with tn ethyl acetate-benzene mixture using a gradient elution technique. The fraction obtained by a solvent containing 30:50 ethyl acetate-benzene was concentrated to dryness under reduced pressure, and gave 52 g of a product whose melting point was approx.

112° - 114°C after recrystallization from ether. The product was identified by elemental analysis and NMR spectrum as <x-(4-fluoro-phenyl)-α-phenyl-5-pyrimidine methanol.

Example 16 2-methyl-4.6-dichloro-5-(diphenylmethyl)pyrimidine

A mixture of 16 g of sodium methoxide, 28 g of ethyl diphenyl methyl malonate and 9-5 g of acetamidine hydrochloride in 250 ml of anhydrous methanol was stirred and refluxed for approx. 6 hours. The reaction mixture was evaporated to dryness in vacuo, the remaining residue dissolved in approx. 1 liter of water, and the mixture was acidified with concentrated hydrochloric acid whereby a white solid was precipitated. This was filtered off and recrystallized from boiling ammonium hydroxide, the product crystallising as the excess ammonia evaporates. The solid was filtered off and dried by immersion in boiling benzene to 17 g of a product whose melting point was approx. 355°c (decomp.) and it was identified by means of its NMR spectrum as 2-methyl-4,6-dihydroxy-5-(diphenylmethyl)pyrimidine.

A mixture of 12 g of 2-methyl-4,6-dihydroxy-5-'diphenylmethyl)-pyrimidine and 300 ml of phosphorus oxychloride was refluxed for approx. 1 hour. The reaction mixture was concentrated under reduced pressure to remove excess phosphorus oxychloride, and then poured into a mixture of crushed ice and water and then extracted several times with ethyl ether. The ether extracts were concentrated and gave 11 g of a product whose melting point was 112°-115°C, and the product was identified by means of the NMR spectrum as 2-methyl-4,6-dichloro-5-(diphenylmethyl)pyrimidine.

Claims (1)

Pyrimidine compounds with fungicidal action, characterized in that they have the formula: as well as non-phytotoxic acid addition salts thereof, where R is alkyl with 1-13 carbon atoms, cycloalkyl with 3-8 carbon atoms or phenyl, R1 is benzyl, phenyl, thienyl, furyl, alkyl with 1-13 carbon atoms or cycloalkyl with 3-8 carbon atoms, X is hydrogen, hydroxyl, lower acyloxy, halogen, amino, (lower acyl)amino, alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, 2-imidazolylthio, anilino or hydroxylamino, wherein the substituents R, R<1> and X can also be substituted with one or more of chlorine, fluorine, nitro, methyl, methoxy and trifluoromethyl, except 5-isopropylpyrimidine and 5-isoheptylpyrimidine.