IL29865A - Substituted-5-pyrimidine compounds - Google Patents

Description

SUBSTI -PYRIMIDINE COMPOUNDS 29865/4 This invention relates to substituted 5 -pyrimidine compounds of the formula:. - wherein R is Cj-Cjg alkyl, Cg-CgCycloalkyl,. or phenyl optionally substituted by one or more groups selected from chloro, bromo, fluoro, iodo, trifluoromethyl, hydroxy, methyl, ethyli methyoxy and nitrp; j thienyl, R is benzyl,/ furyl, C -C 1 1 A process for the preparation of the pyrimidine compounds of the formula X , w herein R is C1-C13alkyl, Cg-CgCycloalkyl, or phenyl; B is benzyl, phenyl, thienyl, or furyl, alkyl, cycloalkyl; cyano ~ alkoxy X is hydrogen, hydroxy, / lower acyloxy, /halo, . amino 29865/3 anilino, imidazolythlo, thienylthio,. furylthio or hydroxy amino; the nonphytotoxlc acid addition salts formable therewith; and excluding 5-isopropylpyrimidine and 5-isoheptylpyrimidine co>^<-»se.&: (A) when X is a hydroxy group, reacting a 5-halo-pyrimidine, a ketone of the formula R-C:0-R wherein R and . ·. , - · are as defined above, and an alkyl alkali metal in the cold in the presence of a low -melting polar organic solvent or mixture of solvents; (B) when X is a hydrogen atom, reacting (1) a substituted malonic acid ester of the formula , • ■ .. wherein R and R 1 are as defined above and R" and R1' * are lower alkyl radicals, wit urea or an appropriately substituted derivative thereof, reacting the barbituric acid derivative thus obtained with phosphorus oxyhalide, and hydro- genating the resulting trihalo-pyrimidine derivative thus obtained; or (2) an alcohol produced in accordance with step (A) . above with a reducing agent to replace the hydroxy group by a hydrogen atom; (C) when X is a cyano group, reacting a 5 -halopyrimidine with a compound of the formula H R-C-R1 CN wherein R and R1 are as defined above, in the presence of a solvent and an alkali metal amide; (D) when X Is a halogen atom, reacting an alcohol produced in accordance with step (A) with a halogenating agent to replace the hydroxy^ group of the alcohol with the corresponding halogen atom; (E) when X Is C^-C^ alkoxy, reacting a 5-a-halopyrimldine produced in accordance with step (D) above with the corresponding • alkali metal alkoxide in alkanol solution with a saturated solution of liquid ammonia in the corresponding dry alkanol; (F) when X is an amino group, reacting a 5- -ha;lopyrimldine produced in .accordance with step (D) above with liquid ammonia at an elevated temperature and pressure; • (G) when X is a hydroxy^amino group, reacting a 5-a-halopyrimi- dine produced in accordance with step (D) above with hydroxyl- amine In the presence of an alkali metal alkoxide and an alkanol; (H) when X is an anillno group, reacting a 5-a-halopyrimidine produced In accordance with step (D) above with aniline in the presence of an inert solvent at an elevated temperature; \ thio thio (I) when X is a alkylmorcapto or heterocyclomeroapto group, reacting the corresponding mercaptan with a 5-a-halopyrimidine produced in accordance with step (D) above in the presence of a base and an inert solvent; (J) when X is lower acyloxy or lower acylamino, reacting an alcohol produced in accordance with step (A) above or an amine produced In accordance with step (P) above, respectively, with the corresponding lower alkanolc acid or reactive derivative thereof; and optionally reacting the product obtained by any of said steps with an acid selected to provide a nonphytotoxic salt thereof.

C^-C^ Alkyl means methyl, ethyl, n-propyl or so-propyl.

Lower acyl means formyl, acetyl, propionyl, or butyryl.

Ci"C13 ^ky^ means saturated straight or branch-chain aliphatic hydrocarbon radicals and can be illustratively methyl, ethyl, n-propyl, lsppropyl, n-butyl, sec . -butyl, tert . -butyl, n-amyl, lsoamyl, sec. -amyl, tertiary amyl and other iso-merle amyl, n-hexyl, isohexyl, sec . -hexyl, and other isomeric hexyl, n-heptyl, and other isomeric heptyls, n-octyl, ispoctyl, and other isomeric octyls, n-primary nonyl (nonyl-l), nonylr2, nonyl-3, nonyl-5, 2-methyloctyl-2, 4-ethyl-heptyl-4,3-methyl-4-ethyl-hexyl-4,3-methyl-3-ethyl-pentyl-3, 2-ethyl -hexyl -1, n-primary decyl (decyl-l), decyl-4, 2-ethyl -octyl -3 (tertiary decyl), undecyl, n-dodecyl, n-tridecyl, and the like.

C1"C3 All<;oxy means methoxy, ethoxy, propoxy, or iso-propoxy .

C -C thio ■ thio thio -θ¾ C¾- Alkylmoroapto means methylmeroaptOj et ylmeii- thio thio cop Oj n-propylmoroopto, or isopropylmeroapto. thio · thio Heterocyclic meroapto means imldazplyl-mercapto, furylwieroapto, th1enyIm y %pt,Q, and the like.

Halo means brpmo, chloro, fluoro, or iodo.

C3-C3 Cycloalkyl means saturated mpnpcyclic aliphatic hydrocarbon radicals, having three to eight carbon atoms in the ring and can be illustratively cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Suitable nonphytotoxic acid addition salts of the bases represented by the above formula can be prepared employing those acids of sufficient acidity to form acid addition salts with the weakly basic pyrimldine group or with an amine substituent attached thereto. These include, inter alia, hy-drobromic, sulfuric, phosphoric, nitric, oxalic, methanesul-fonic, hydrochloric, hydriodic, benzenesulfonic , p_-toluene-sulfonlc, malelc, and the like.

In the prior art, Margot et al., U.S. Patent 2,839, 6 (June 17, 1958), teach novel pyrimidines which are said to possess fungicidal activity. The Margot compounds are distinguished by having at least one trichloromethane sul- thio phenyl«ercQ -o group preferably attached at the 2-positlon of the pyrimldine ring.

In addition, Ballard et al., U.S. Patent 2,658,895 (November 10, 1953), teach 2-alkylphenyl-3, , 5,6-tetrahydro-pyrimidines which are said to have fungicidal and detergent properties and also to have use as asphalt additives.

Brederick et al., Chem. Ber., 93, 230-35 (i960), teach the preparation of 5-isopropylpyrimidine and 5-isoheptyl -pyridimine, respectively. No utility is disclosed therefor.

Lowin et al., Arch. Biochem. and Biophysics, 101, 197-203 (19 3), teach the use of 5-hydroxymethylpyrimldlne as a substrate in studying the in vivo inhibition of thiamine synthesis.

The novel pyrimidines of the present invention have been found useful in controlling fungi which attack food crops, ornamental plants, and turf. The novel compounds have been found useful in combatting both airborne and soil -borne fungi which affect plants. Most unexpectedly and surprisingly, the novel pyrimldine compounds of this invention, unlike the closely related pyridine compounds, are systemically active as fungicidal agents That is, the pyrlmidlne compounds are absorbed by the plant and transported throughout the plant via the vascular system of the plant. Further, these novel pyrimidlnes have the ability to cause certain plants to produce, in a manner as yet unknown or understood, fungicidal substances of:an unknown structure which substances can be extracted from the plant tissues by methods known to the art and shown to possess fungicidal activity in standard fungicidal tests.

The systemic antifungal action of these pyrimidlnes has been demonstrated by the following remarkable experiment: Seeds of cucumber, for example, are soaked for a short period of time, about 10 minutes, in an ethanol-light isoparaffin oil solution of a 5-substituted pyrimldine. The seeds are removed, dried, and planted, and produce plants free from powder mildew and protected therefrom.

The novel compounds of the present Invention have been shown by suitable in vitro and in vivo tests to control such fungi as Eryslphe polygon!, the causative organism of bean powdery mildew; Colletotrlchum lagenarlum, the causative organism of cucumber anthracnose; Uromyces phaseoll, the causative organism of bean rust; Piricularls oryzae, the causative organism of rice blast; and Rhizoctonia solanl, the causative organism of damping-off in cotton.

In addition, ce,rta'in fungi which affect ornamental plants including Sphaerotheca pannosa var, rosae, the causative organism of powdery milde of rose; and Erysiphe graminis, the causative organism of powdery mildew of turf are controlled by the novel pyrlmi.dines of this invention,, The novel compounds of this invention are also active against certain turf pathogens which yearly inflict great damage to turf. These turf pathogens include Helmlnthosporium sativum, the causative organism of Leaf Spot; Rhizoctonia solani, the causative organism of Brown Patch; Sclerotinla homoeocarpa , the causative organism of Dollar Spot; Fusarium roseum, the causative organism of Root Rot; and Pythlum sp, , the causative organism of Pythium Blight.

The novel compounds of this invention are utilized as fungicides by applying them to infected or susceptible plant surfaces, or to the soil. This is conveniently accomplished by spraying, dipping, dusting, or drenching.

For such use, the compounds are formulated into compositions desirably containing, in addition to the 5-substi-tuted pyrimidine, one or more of a plurality of additaments Including water, polyhydroxy compounds, petroleum distillates, and other dispersion media, sur ace-active dispersing agents, emulsiflers, and finely divided inert solids. The concentration of the 5-substltuted pyrimidine compound in these compo-sltions may vary depending on whether the composition is intended as an emulsifiable concentrate or a wettable powder de^ signed to be subsequently diluted with additional inert carrier such as water to produce the ultimate treating composition or is Intended for direct application as a dust to plants.

The novel compounds of the present invention are applied to plants in effective amounts, varying somewhat with the particular organism, with the severity of the infection, and with other factors such as the environment in which treat -ment is conducted. In general, it is found that an aqueous spray containing from about 2 to about 400 ppm. of active material is satisfactory when treatment is to be carried out in the greenhouse.

As is well understood in the art, a somewhat higher concentration of the active compound is desirable when treatment is to be carried out in the field. In that case, the preferred range is from about 15 to about 1000 ppm. of 5-substituted pyrlrnidlne.

In the case of the turf pathogens, supra, control has been accomplished using an application rate of from about O.05 to about 1 .0 pound per acre of the 5-substituted pyrimi-dine. Control of the other soil -borne fungi mentioned above has been accomplished using a broadcast application rate of about 5 to 40 pounds per acre of the 5-substituted pyrimldines.

Unexpected antibacterial activity has been shown by certain of the novel compounds. Thus, α,a-diphenyl - -pyrlrnidlne-methanol and 2-methyl-5-diphenylmethy.-4 , 6-pyrimidinediol, are active against Agrobacterlum tumefaciens, the causative organism of crown gall. Other of the novel compounds, including 2, 4 , 6-trichloro-5-diphenylmethylpyrimidine, 5- ( -chlorodlphenyl-methyl) pyrlrnidlne, Q- ohloro-5 diphenylmothylpyridlmidine , and 5-bis (4-chlorophenyl)methylpyrimidine are active against Xanthomonas phaseoli var. sojensis, the causative organism of bacterial blight of soybean.

Besides the above properties, the novel pyrlmldines have shown unexpected herbicidal activity. In addition, the compounds possess interesting growth-inhibitor activity. Thus, 5 -(2-chlorodiphenylmethyl)pyrimidine has been shown to inhibit tobacco sucker growth.

Another of the novel compounds, a- (2-fluorophenyl) -a- (3-fluorophenyl) -5-pyrimidlnemethanol, possesses the ability to Inhibit the opening of the buds of cut flowers.

Still other of the compounds, for example, α,α-di-phenyl -5-pyrimidinemethanol and a- (2-chlorophenyl) -a- ( -chloro-phenyl) -5-pyrimidinemethanol, exhibit anti-auxin properties.

Certain of the novel pyrimidines, i.e., a- (2-fluorophenyl) -a- (3-fluorophenyl) -5-pyrlmldlnemethanol and a- (2- phenyl chlorophenyl) -a - ( -chloro hney-J,.) -5-pyrimidinemethanol, possess the completely unexpected and as yet unexplained ability to cause an increase in the number of flowers and fruit produced by tomato plants when said plants are treated with one of the compounds about 6 to 8 weeks prior to flower formation.

The novel 5-substituted pyrlmidinemethanols (X = OH in the generic formula, supra) are readily prepared in good yields by a synthesis exemplified as follows: A suitable ketone, for example, benzoylcyclohexane, is dissolved in a solvent composed of equal volumes of tetrahydrofuran and ethyl ether, the solution is cooled to -125°C, and while maintained at that temperature, a solution of 5-bromopyrimldine in equal volumes of tetrahydrofuran and ethyl ether is added thereto. While the mixture is maintained at about -125°C., a hexane solution of n-butyl lithium is added. The reaction mixture is stirred overnight in the cold, the reaction product mixture washed successively with -dilute aqueous ammonium chloride solution and water, and the organic layer separated and dried over a suitable drying agent. The dried organic layer is concentrated to dryness in vacuo and the solid residue extracted with ether to remove undesired by-products. The ether-insoluble material remaining is identified by elemental analysis as a- cyclohexyl -a-phenyl -5-pyrimidinemethanol .

An alternative method appears preferable in some instances and proceeds as follows: In a suitable reaction flask, dry ether is maintained in an atmosphere of dry nitrogen, cooled to about -ll8°C, and a solution of butyl lithium in hexane added, followed by a solution of 5-bromopyrimldine in tetrahydrofuran. The reaction mixture Is cooled to about -125°C. and a solution of a suitable ketone, for example, 4-fluorobenzophenone, in tetrahydrofuran is added at such a rate as to maintain the temperature of the reaction mixture at about -120°C. The reaction product mixture is stirred overnight and warmed gradually to room temperature. The mixture is neutralized with saturated aqueous ammonium chloride solution and ex-tracted with ether. The combined ether extracts are dried, concentrated to dryness in vacuo and the residual material dissolved in benzene and chromatographed over a silica gel column, eluting 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 identified as a- ( -fluorophenyl) -a -phenyl -5-pyrimidinemethanol .

When X = H in the generic formula, supra, some of the novel compounds can be prepared by heating the 5-substituted pyrlmidinemethanol (prepared as above) In a mixture of glacial ' · acetic acid and 7 percent aqueous hydriodic acid to reduce the hydroxy1 group and yield the 5-substituted pyrimldlne-methane.

In other compounds where X = H, the preparation is accomplished by the reaction of a suitably substituted malonic ester with urea or acetamidine, or the like. For example: A mixture of diethyl phenyl -£-tolylmethyl malonate and urea is allowed to react in an anhydrous alcohol such as methanol in the presence of sodium methylate to yield 2, ,6-trlhydroxy-5-phenyl -£-tolylmethylpyrimidine. This trihydroxy compound is allowed to react with excess phosphorus oxychloride to yield 2, ,6-trichloro-5-phenyl-p-tolylmethylpyrlmidlne. The tri-chloropyrimidine is then hydrogenated in the presence of tri-ethylamine and palladinized charcoal to yield 5-phenyl-p-tolylmethylpyrimidine.

Where X = cyano in the above generic formula, the novel compounds can be prepared in the following manner: A mixture of dlphenylacetonitrlle and 5-bromopyrimidine is allowed to react in the presence of potassium amide in a suitable solvent such as xylene to yield a,a-dlphenyl-5-pyrimidine-acetonltrlle .

Those compounds where X = ci"C3 alkoxy are prepared by allowing an alkali-metal lower alkoxide such as sodium methoxlde, potassium ethoxide, or sodium propoxide to react in alkanol solution with a 5-halo analogue of the desired product e.S-j 5-(a-chlorodiphenylmethyl)pyrimidine_7 to yield the desired product /e . g . , -(a-¾-C3 alkoxydlphenylmethyl ) pyrimi-dine_7.

Where X = amino, the compounds are prepared by heat- ing a mixture of the .analogous halo-substltute d pyrimidine, such as 5- (archlorodiphenylmethyl) pyrimidine, and excess liquid ammonia at an elevated temperature of about 100° C. in a sealed stainless-steel reaction vessel for a time sufficient to complete the reaction. The product can be isolated as the free base 5- (a-aminodiphenylmethyl ) pyrimidine, or in the form of a salt such as the hydrochloride, hydrobromide, or the like.

Correspondingly, 5- (a-hydroxy amlnodiphenylmethyl) -pyrimidine and related compounds are readily prepared by allowing hydroxylamlne to react with 5- (a-chlorodiphenylmethyl ) -pyrimidine or analogous 5-a-halo compounds.

Following the same general procedure, the' 5-/S"-(2-imidazolylthio)diphenylmethyl_7pyrimidine is readily synthesized by allowing 2-mercaptoimidazole to react with a-chloro^-5-diphenylmethylpyrimidine in the presence of a base such as sodium or potassium ethoxide in a suitable solvent such as absolute ethanol. The reaction product mixture is concentrated to dryness at reduced pressure and the solid residue slurried or extracted with a solvent such as hot benzene to dissolve the product, 5-/a- (2-imidazolylthio)dlphenylmethyl_7pyrimldine, which then crystallizes from the benzene.

Where X = anllino, the compounds are readily prepared by heating a 5-halo analogue such as 5- (a-chlorodiphenylmethyl) pyrimidine with aniline in an inert solvent such as ben-zene on the steam bath for a time sufficient to complete the reaction. The aniline hydrochloride which precipitates is filtered off, the filtrate concentrated In vacuo to dryness, and the residue recrystallized from a suitable solvent such as ethyl ether to yield 5-(a,a-diphenyl-a-anilinomethyl)pyrimi- dine.

While the compounds of the present invention have been defined in terms of a structural formula which depicts the novel structural features of the claimed compounds and which indicates the presence therein of certain well-known organic radicals including phenyl, alkyl, furyl, thienyl, cycloalkyl, -end pyrimidlne., it will be recognized by those skilled in the art that such radicals may bear one or more substituents without departing in any way from the spirit of the invention and- without altering the properties of the novel compounds in such a way as would set them apart from the invention or take them outside its scope. Compounds having the novel structure of the present invention and bearing such substituents are accordingly to be considered as equivalents of the unsubstituted compounds and are to be considered to lie within the scope of the invention. Among such substituent and in the case that said substituents stand atoms and radicals for R4 R1, X and the pyrlmidine ring of the-r a phenyl radical above ormula- a"re chloro, bromo, fluoro, lodo, tri luoromethyl , hydroxy, methyl, ethyl, methoxy, methylmercapto, methylsul-fonyl, nitro, dialkylamino, and the like.

The following examples describe in detail the methods used in preparing the novel compounds of this invention. However, the invention is not to be construed as limited thereby either in spirit or in scope, since it will be apparent to those skilled in the art that many modifications both of materials and methods may be practiced within the purpose and intent of this disclosure.

.Example 1 g-Cyclohexyl-g-phenyl -5-pyrlmldlnemethanol To a solution of 0.1 mole of benzoylcyclohexane in 250 ml. of a mixture of equal volumes of tetrahydrofuran and ether and cooled to -125°C. was added a solution of 0,1 mole of 5~bromopyrimidine in the same mixed solvent. The mixture was stirred and maintained at about -125° C. in a cooling bath composed of liquid nitrogen and ethanol, and to the cooled solution were added 60 ml. of a 15 percent solution of n-butyl lithium in n-hexane, and the reaction mixture was stirred overnight.

The reaction product mixture was washed successively with 10 percent aqueous ammonium chloride solution and water and dried over anhydrous potassium carbonate. The dried or-ganic solution was evaporated to dryness to yield a solid weighing about 14 g. The solid was extracted with ether and the undissolved solid washed twice with ether. The ether-insoluble material was identified as a-cyclohexyl-a-phenyl-5-pyrimidinemethanol having a melting point of about 156-157°C.

Following the general procedure of Example 1, with appropriate starting materials, the following compounds were prepared and Isolated as free bases or acid addition salts thereof: ,α-Bis (4-chlorophenyl ) -5-pyrimldinemethanol .

Melting point: Glass. a-Phenyl-α- (4-chlorophenyl) -5-pyrimidinemethanol hydrochloride. Melting point: Glass, , -Bis (cyclohexyl ) -5-pyrlmidinemethanol , Melting point: l42-l44°C, α,α-Bis (n-hexyl) -5-pyrimidinemethanol . Melting point: Viscous liquid. a-Cyclobutyl-a-phenyl -5-pyrimidinemethanol . Melting point: 115-117°C a-Methyl-a-phenyl -5-pyrimldinemethanol . Melting point: 70° C. α,α-Bis (3-fluorophenyl ) -5-pyrimldinemethanol . Melting point: Glass. a- (2-Chlorophenyl) -a- (3-chlorophenyl ) -5-pyrimidlne-methanol. Melting point: Amorphous, a ,α-Diphenyl -5-pyrimldinemethanol. Melting Point: 167-170°C. a- (2-Chlorophenyl) -a-phenyl-5-pyrimldinemethanol . Melting point: 15 -156°C. a- (n-Pentyl) -a-phenyl -5-pyrimldinemethanol . Melting point : Liquid , a- (2-Fluorophenyl) - -phenyl -5-pyrimidinemethanol . Melting point: 139-l4l°C. α, -Bis (3,4 -Dlchlorophenyl) -5-pyrimidinemethanol hemi-etherate. Melting point: 88-89°C. a- (Phenyl) -a- (2-thienyl) -5-pyrimidinemethanol . Melting point: l40-l42°C. α,α-Bis (isopropyl) -5-pyrlmldlnemethanol . Melting point: 115-ll8°C. a- (3,4-Diehiorophenyl) -a-phenyl -5-pyrlmidinemethanol . Melting point: Amorphous. a- (2,4-Dlchlorophenyl) -a-phenyl -5-pyrimidlnemethanol . Melting point: Viscous liquid. a- (4-Nitrophenyl) - -phenyl-5-pyrimldinemethanol , Melting point: Amorphous,, a- (2-Fluorophenyl) -a- (3-fluorophenyl ) -5-pyrimidine- methanol. Melting point: 104-108°C. α,α-Bis (p-tolyl) -5-pyrimldinemethanol . Melting point : Amorphous . a- (2, 4-Dimethylphenyl) -a-phenyl-5-pyrimidinemethanol . Melting point: Amorphous. a-Phenyl -a- (p-anisyl) -5-pyrimidinemethanol . Melting point: 95-97°C. a-Phenyl -a- ( -trifluoromethylphenyl) -5-pyrimldine- ' methanol. Melting point: 125-127°C. ~^o-J¾Lphor- l l\ s6 dio 3i^^"0--mot yi--§- Flmidl o^— ■mothanol ,— elting point i— 110 -112°C, / Example 2 , 5-Bis (4-chlorophenyl)methylpyrimidlne A mixture of 6 g. of α,α-bis (4-chlorophenyl) -5- pyrimidinemethanol., 200 ml. of glacial acetic acid, and 10 ml. of 47 percent hydriodlc acid was refluxed for 40 minutes, poured into water, and the aqueous mixture extracted several times with ether. The combined ether layers were washed successively with water, 5 percent aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and evaporated in vacuo to dryness. The residue was extracted with petroleum ether and the extracts concentrated. The prod- uct was obtained as a thick reddish oil identified by infrared and nuclear magnetic resonance (NMR) spectra as 5-bis (4-chlorophenyl )methylpyrimidine .

Following the same general procedure as in Example 2 , with appropriate starting materials, the following compounds were prepared: ©< - (^f-Fluorodiphenylmethyl ) pyrimidine . Melting point: Liquid.

- B1S (3, -dichlorophenyl)methyl7pyrimidine . elt- ing point: Liquid.

Example 3 a,a-Diphenyl-5-pyrimidineacetonitrile To 0.1 mole of potassium amide in liquid ammonia was added a solution of 0.1 mole of dlphenylacetonitrile in 300 ml. of xylene, and the mixture was heated to refluxing for about 30 minutes to remove excess ammonia. To the xylene solution was added, a solution of 0.1 mole of 5-bromopyrimidine in 100 ml. of xylene and the mixture stirred for about 20 minutes.

To the mixture were then added 20 ml. of dimethylformamide and the mixture was refluxed for about one hour. The reaction product 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, elutlon being carried out with ethyl acetate. The eluate was concentrated to yield α,α-dlphenyl -5-pyrimidine-acetonitrile as a solid having a melting point of about 98-100° C, identified by NMR spectrum and elemental analysis.

Example 2, 4, 6-Triehloro -5-phenyl -p-tolylmethy 1pyrimidine, To a solution of 22 g,. (Ο. 95 g.~atom) of sodium in 500 ml. absolute ethanol was added a solution of 33 g. (0.55 mole) of urea and 95 g, (0 , 28 mole) of ethyl phenyl-p-tolyl-methyl malonate in 500 ml. of absolute ethanol, and the mixture was refluxed for about two hours. The reaction product mixture was cooled and diluted with about 1000 ml. of water and 500 ml. of ether. The layers were separted. The aqueous layer was washed with about 200 ml. of ether. The ether washings were combined with the original organic layer and washed with 200 ml. water. The washed aqueous layer and the water washings were combined and acidified with concentrated aqueous hydrochloric acid. An oily layer separated which solidified under vacuum. The crude solid 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 yield a crystalline solid having a melting point of about 115°C. and identified by N R spectrum as 5 - (phenyl -^.-tolylmethyl) barbituric acid. Weight: 5 g.

A mixture of 39 g, (0.13 mole) of 5- (phenyl -j^-tolyl -methyl )barblturlc acid (prepared above), 116 g. (Ο.76 mole) of phosphorus oxychloride, and 56 g. (Ο.38 mole) of N}N-diethyl-anlline was heated at reflux temperature for about six hours, The reaction product mixture was cooled, diluted with a mixture of crushed ice and water, and allowed to stand for about an hour. The mixture was extracted five times with 300 ml. of ether, the combined extracts were dried, and the solvent was evaporated to dryness on the steam bath. The residue remaining was extracted with hot petroleum ether (b.p. = 60-70°C). The petroleum ether solution was cooled, and a crystalline product separated which had a melting point of about 112-113°C. and weighed about 30 g. It was identified by NMR spectrum and elemental analysis as 2 , 4, 6-trichloro-5- (phenyl -^p-tolylmethyl) -pyrimldine .

Following the general procedure of Example 4, with appropriate starting materials, other compounds were prepared and are listed as follows: 2,4,6-Trichloro-5- (diphenylmethyl ) pyrlmidine . Melting point: 105-106°C. 2,4,6-Trichloro-5-(phenyl-p-anlsylmethyl)pyrimidine, Melting point: 129-131°C 2,4,6-Trichloro-5- (phenyl -o-chlorophenylmethyl) - pyrlmidine. Melting point: l62-l63°C. 2, ,6-Trichloro-5- (l -phenyl -n-heptyl) yrlmidine „ Melting point: Oil. 2, , 6-Trichloro-5- (l -phenyl -n-tridecyl ) pyrlmidine . Melting point: Oil. 2,4,6-Trichloro-5- (l -phenyl -n^butyl) pyrlmidine .

Melting point: 72°C.

Example 5 - (Phenyl -jp_-tolylmethyl ) pyrlmidine A mixture of 15 g. (0.04l mole) of 2,4,6-trichloro-5- (phenyl-p-tolylmethyl) pyrlmidine, 12.5 g. (0.124 mole) tri-ethylamine, 100 ml. dry dioxane, and 1 g. of 5 percent palla-dinlzed charcoal was hydrogenated on a Paar shaker at an initial pressure of 15 p.s.i. for about 5 hours, during which time the theoretical amount of hydrogen was absorbed. When the hy-drogenatlon was complete, the reaction product mixture was concentrated in vacuo to dryness. The residue was dissolved in benzene and chromatographed on an alumina column, eluting with ethyl acetate. A solid was obtained which was recryst allized from petroleum ether to yield crystalline material . having a melting point of about 71-72°C, and identified by NMR spectrum and elemental analysis as 5- (phenyl -p-tolylmethyl) pyrlmidine.

Weight: 8 g, Following the general procedure of Example 5 with appropriate starting materials, other compounds were prepared and are listed as follows: -(Dlphenylmethyl)pyrimldine. Melting point: 83°C pyrimidine - (Pheny -p-anisylmethyl )gygjrmdl e-. Melting point: Oil, - (Phenyl -o-chlorophenylmethyl ) yrimidine , Melting point: 107-108°C. - (1 -Phenyl -n-heptyl) pyrimidine. Melting point: Oil. - (l -Phenyl-n-butyl) pyrimidine . Melting point: Oil. - (l-Phenyl-n-tridecyl) pyrimidine. Melting point: Oil.

Example 6 - (a-Chiorodl henylmethyl ) pyrimidine To a refluxing solution of 40 g. of q,q--diphenyl-5-pyrimldinemethanol in 200 ml. of xylene was added anhydrous hydrogen chloride gas via a bubbler tube, and the by-product water was collected in a Dean-Stark trap. The reaction product mixture was concentrated in vacuo to dryness. The dry residue was washed with ethyl ether to remove starting material, and the ethyl ether-insoluble residue was dissolved in hot petroleum ether. The petroleum ether was evaporated to dryness and the residue recrystalllzed from ether to yield solid product weighing 6 g. and having a melting point of about 92 -9^°C.

The product was identified as 5- (q-chlorodiphenylmethyl) -pyrimidine by elemental analysis and NMR spectrum.

Example 7 - (a, -Diphenyl- -anillnomethyl) pyrimidine A mixture of g, of 5- (q-chlorodiphenylmethyl ) pyrimidine, 10 ml. of aniline, and 40 ml. of benzene was warmed for about an hour on the steam bath. The reaction product mixture was cooled and filtered to remove aniline hy-drochloride, and the filtrate concentrated to dryness. The solid residue was recrystallized from ethyl ether to yield a yellow crystalline product weighing 2 g. and having a melting point of about l 0-l °C. The product was identified as 5- (α,a-diphenyl -a -anilinomethyl) pyrimidine by NMR spectrum.

Example 8 - (a , -Piphenyl -a -hydroxyjfamino) pyrlmidlne A mixture of 5 g. of 5- (α-chlorodiphenylmethyl) -pyrimidine and excess hydroxylamine in ethanolic sodium ethoxide was refluxed for about one hour. The reaction product mixture was evaporated to dryness and the residue ex-tracted with benzene. The benzene solution was filtered, concentrated to dryness, and the residue extracted with ether. The ether extract was concentrated to dryness, yielding a crude product having a melting point of about 110-125° C, Identified by NMR and infrared spectra as 5- (α,α-diphenyl-a-hydroxy/amino) pyrimidine .

Example 9 - (q-Ethoxydiphenylmethyl ) pyrlmidlne A mixture of 10 g. of 5- (α-chlorodiphenylmethyl) -pyrimidine and a saturated solution of liquid ammonia in ab-solute alcohol was prepared and an exothermic reaction took place. When the exothermic reaction had subsided, the reaction product mixture was filtered and the filtrate evaporated to dryness. The solid residue was extracted with chloroform and the chloroform solution allowed to stand overnight at ambient room temperature. The crude crystals which separated were dissolved in ethyl acetate and chromatographed over alumina using a mixture of hexane and ethyl acetate as eluting solvent. A solid having melting point of about 95-97° C. was ob-tained from the eluate and identified by NMR spectrum and elemental analysis as 5 - (a-ethoxydiphenylmethyl) pyrimidine .

Example 10 - (a -Aminodlphenylmethyl ) pyrimidine A mixture of 12 g. of 5- (a-chlprodiphenylmethyl) -pyrimidine and an excess of liquid ammonia was heated at a temperature of about 100°C. for about two hours in a closed stainless steel high-pressure reaction vessel. The reaction product was removed from the reaction vessel, the excess ammonia allowed to evaporate, and the residue extracted with benzene. The benzene solution was concentrated to yield a crystalline product having a melting point of about 135-137°C. The product was identified as 5-(a-aminodiphenylmethyl)pyrimi-dine by NMR spectrum and elemental analysis.

Example 11 - δΓ- (2-Imidazolylthio)diphenylmethyl7pyrimldine The potassium salt of 2-mercaptoimidazole was prepared by adding 10 g. of 2-mercaptoimldazole to an ethanol solution of potassium ethoxide prepared from 1 g. of potassium and 200 ml. of absolute ethanol. To the above mixture were added 5 g. of 5- (a-chlorodiphenylmethyl) pyrimidine and the reaction mixture heated to refluxing for about two hours. The reaction product mixture was concentrated in vacuo to dryness and the residue extracted with hot benzene. The benzene extract was cooled, and a solid product crystallized therefrom, weighing 3 g. and haying .a melting point of about l65-l67°C It was Identified as 5~ 5T- (2-imidazolylthio)dlphenylmethyl7-pyrimidine by elemental analysis and NMR spectrum.

Example 12 - (a-Pheny1phenethy1 ) pyrlmidine To sodamide In liquid ammonia prepared by the addition of 1.2 g. (0.05 g.-atom) of sodium to 500 ml. of liquid ammonia , were added 8.3 g. (0.05 mole) of 5-benzylpyrimidine, and the resulting redr-brown mixture was stirred for about 10 to 15 minutes. A solution of 6.3 g. (0.05 mole) of benzyl chloride in 15 ml. anhydrous ether was added and the reaction mixture stirred about one hour. To the reaction product mixture were added 200 ml. of ether and the mixture was evaporated to near dryness on the steam bath. The residue was slurried again with 200 ml. of ether and evaporated to dryness. The dry residue was dissolved in a mixture of about 500 ml. of ether and 200 ml. of water and the ether layer separated and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and from the ether solution a solid precipitated. The solid, on standing, became an oil, which was dissolved in benzene and chromatographed on an alumina column, elution being carried out with a mixture of ethyl acetate and benzene. From the eluate a solid product was obtained which, upon recrystal-lizatlon from petroleum ether, had a melting point of about 80-82°C. The crystalline product weighed about 5 g. and was Identified as 5- ( -phenylphenethyl ) pyrimldine by elemental analysis and NMR spectrum.

Example 13 2- ethoxy-5- (l--pphheennyyll --nn--tt]ridecyl ) pyrimidine 4-Methoxy•--f5j-- ((li--pihenyl -"n-trldecyl) pyrimidine To a mixture of 40 g. (0.09 mole) of 2,4,6-trlchloro-5- (l-phenyl-n-trldecyl ) pyrimidine in a solvent composed of 250 ml., of dry dioxane and 500 ml. of dry methanol were added 8 g. of palladinized charcoal and 15 g. of potassium hydroxide pellets, and the mixture was hydrogenated on a Paar shaker at a pressure of 40 pounds per square, inch of hydrogen. The reac-tion product mixture was filtered to remove catalyst and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in a mixture composed of 300 ml . of water and 300 ml. of ethyl ether, the ether layer was separated and dried, and the ether was evaporated to dryness on the steam bath. The residue was dissolved in benzene and chromatograph-ed on an alumina column. Elution was done with a mixture of benzene and ethyl acetate in proportions up to a concentration of about 10 percent ethyl acetate. A total of about 14 g. of an oil was obtained. The oil was dissolved in benzene and placed on a 3-foot alumina column containing about 800 g. of alumina. The material was eluted using a mixed solvent of about 2 percent of ethyl acetate in benzene. The first fractions were concentrated to 'yield 3.5 g. of product, identified by NMR spectrum as 2-methoxy-5- (l-phenyl -n-tridecyl ) pyrimidine .

The next fractions, totaling 4.0 g. on concentration to dryness, were combined, shown by NMR spectrum to be an undesirable mixture and discarded. The last fractions, weighing 5.5 g„, were obtained using an elutlng solvent of 10 percent ethyl acetate in benzene, and were identified by NMR spectrum as 4-methoxy-5- (l -phenyl -n-tridecyl ) pyrimldlne .

Example 14 - (a-Acetaminodlphenylmethyl ) pyrimldlne A mixture of ,5 g, of 5- (a-amlnodiphenylmethyl) - pyrimldlne and 50 ml. of acetic anhydride was heated until a homogeneous solution was obtained. The reaction product mixture was allowed to stand at ambient room temperature overnight and then was concentrated in vacuo to remove the solvent, leaving a dry residue. The residue was recrystallized from hot benzene to yield about 2.5 g. of crystalline product having a melting point of about l87-l89°C. The product was identified as 5- (a -acetamlnodiphenylmethyl) pyrimldlne by elemental analyses and NMR spectrum.

Example 15 a-7 ( -Fluorophenyl) -q-phenyl -5-pyrlmldinemethanol To 300 ml. of anhydrous ether maintained in an atmosphere of dry nitrogen gas in a suitably equipped 3-neck round-bottom reaction flask cooled to -1.18°C. by an alcohol-liquid nitrogen cooling bath, were added 170 ml. (0.3 mole) of a 15 percent solution of butyl lithium in hexane. Cooling and stirring and the dry nitrogen atmosphere were continued while a solution of 0.3 mole of 5-bromopyrlmidine in 150 ml. of dry tetrahydrofuran was added and the whole stirred for about two hours. The temperature of the reaction mixture was lowered to -125°C. and a solution of 0.3 mole of 4-fluorobenzophenone in 150 ml. of dry tetrahydrofuran was added slowly while maintaining the temperature of the mixture at about -120°C. The reaction product mixture was stirred overnight and warmed to ambient room temperature. The reaction product mixture was neu- tralized by the addit.ion of a saturated aqueous solution of ammonium chloride. The neutralized mixture was extracted with ether and the combined ether extracts dried over anhydrous potassium carbonate, filtered, and concentrated to dryness in vacuo and the residue dissolved in benzene. The benzene solution was chromatographed over 1500 g. of silica gel, elution being accomplished with an ethyl acetate-benzene mixture, using a gradient elution technique. The fraction obtained using a solvent containing 30: 50 ethyl acetate-benzene was concen- trated to dryness at reduced pressure, yielding 52 g. of product having a melting point of about 112-ll4°C. after recrystal- lization from ether. The product was identified by elemental analyses and N R spectrum as a- (4-fluorophenyl) -a-phenyl-5- pyrimidinemethanol . inti led by its NMR spectrum as a-methyl-4 , 6-dlhydroxy-5-

Claims (4)

1. 29865/4 +j pyrimidine compound of the formula: wherein R is C -CL -alkyl, C -C cycloalkyl, or phenyl optionally sub -stituted by one or more groups selected from chloro, bromo, fluoro, iodo, trifluoromethyl, hydroxy, methyl, ethyl, methoxy and nitro; imidazolylthio, thieny thio, furylthio or hydroxy amino; the nonphytotoxic acid addition salts formable therewith; and excluding 5-isopropylpyrimidine and 5-isoheptylpyrimidine.

2. The pyrimidlne compound of claim 1 being 5-(diphenylmethyl) pyrimidine; °t -(12-chlorophenyl)- ^ -(3-chlorophenyl)-5-pyri^ualinemethanol; c -(^-fluorophenyl)- ^ -(13fluorophenyl)-5-pyrimidinemethanol; o(, o£ -diphenyl-5-pyriAidmeaO^onitrile or (4 -fluorophenyl- *< -phenyl- 5-pyrimidinemethanol; < -(2-4dichloro henyl)°' -phenyl-5-pyriiftidine methanol.

3. The pyrimidine compounds of claim 1 substantially as herein described with paoiticular reference to the examples,

4. A pesticide wherein the active ingredient is the pyrimidine compound of any of claims 1 to 3.