The method of obtaining derivatives of pyrimidine

 

(57) Abstract:

Usage: as fungicides in agriculture. The inventive product: pyrimidine derivatives of the formula I , where any two of K, L and M are astami, and the third group CH=; C is hydrogen or halogen; X is hydrogen, halogen, unsubstituted; C1-C4is alkyl or substituted with halogen, hydroxyl or cyano; C2-C4alkenyl; C2-C4-quinil, trimethylsilylmethyl C2-C4alkenyl, C2-C4-alkenylamine C2-CH group, phenyl, cyanocycline the nitro-group, a group - NR1R2where R1and R2are hydrogen or C1-C4-alkyl, C1-C4-alkylcarboxylic, asiagraph, C1-C4-alkoxy, fenalce, benzyloxy, C1-C4-alkoxycarbonylmethyl, C1-C4-alkanoyloxy-, C1-C4-alkylsulfonate-, C1-C4-alkylsulfonyl, formyl, C1-C4-alkanoyl, hydroxyI-Mino - C1-C4alkyl group, carbarnoyl, thiocarbamoyl or the group CH3O2CC=CHOCH3Y is halogen, C1-C4-alkyl, C1-C4-alkoxyl, nitro, di (C1-C4alkilani phenyl ring, to which they are attached, form a naphthalene ring; A is halogen, hydrogen, C1-C4-alkyl or C1-C4-alkoxyl. Reagent 1: compound of formula II. Reagent 2: . Reaction conditions: in dimethylformamide at 0-110C. table 5.

The invention relates to a method for obtaining new pyrimidine derivatives possessing valuable fungicidal properties, which can find application in agriculture.

Known such compounds, fungicidal, as MANCOZEB, carboxin, proxyfor.

The disadvantage of these known tools is their relatively narrow spectrum of fungicidal action.

The purpose of the invention is a method of obtaining a new pyrimidine derivatives, with a broader spectrum of fungicidal action.

This goal is achieved by a method of obtaining pyrimidine derivatives of General formula I

where any two groups from among the K, L and M are astami, and the third group-CH=;

G is hydrogen or halogen;

X is hydrogen, halogen, unsubstituted WITH1-C4is alkyl or substituted with halogen by a hydroxyl or cyano WITH2-C4alkenyl,2-C4-quinil, trimethylsilylmethyl21R2where R1and R2are hydrogen or C1-C4-alkyl; C1-C4-alkylcarboxylic, asiagraph,1-C4-alkoxyl, phenoxy, benzyloxy,1-C4-alkoxycarbonylmethyl,1-C4-alkanoyloxy-FROM1-C4-alkylsulfonate-FROM1-C4-alkylthio-FROM1-C4-alkylsulfonyl-FROM1-C4-alkylsulfonyl, formyl, C1-C4-alkanoyl, hydroximino (C1-C4)alkyl group, carbarnoyl, thiocarbamoyl or group of CH3ABOUT2SS=SNON3;

Y is halogen, C1-C4-alkyl, C1-C4-alkoxyl, nitro, di(C1-C4)alkylamino or hydrogen;

or X and Y when they are in ortho-position relative to each other, together with the phenyl ring to which they are attached, form a naphthalene ring;

And - halogen, hydrogen, C1-C4-alkyl or C1-C4-alkoxyl.

The method consists in the fact that the compound of General formula II

where K, L, M and G have the above meanings, is subjected to the interaction with the compound of General formula III

where A, X and Y have the above meanings, and one of the groups Ruppel, where T is hydrogen or the cation of an alkali metal, in a solvent such as dimethylformamide at 0about-110aboutWith, possibly in the presence of a catalyst, such as chloride monovalent copper, and when T is hydrogen, in the presence of a base such as potassium carbonate.

P R I m e R 1. Obtaining /E/-methyl-2-[2-(4-phenoxypyridine-2-yloxy)-phenyl]-3-methoxypropionate (compound 1 in table.3).

To a suspension of 0.3 g (6,85 mmol, 50% dispersion in oil, pre-washed with n-hexane) of sodium hydride in 4 ml of DMF is added dropwise a solution of 0.59 g (6,23 mmol) of phenol in 1 ml of dry DMF. The resulting mixture was stirred in nitrogen atmosphere until then, until it stopped bubbling gas. The resulting mixture was diluted with 3 ml of dry DMF, and then added dropwise to a stirred solution of 1.0 g of 4-chloro-2-methylthiopyrimidine (6,23 mmol) in 3 ml of dry DMF at 0aboutC. exothermic reaction Occurs and the temperature of the reaction mixture rises to 5aboutC. After stirring under nitrogen atmosphere for 30 min with 10aboutWith GC-analysis indicates the formation of one product (98,8%). The reaction mixture was diluted with 15 ml of water and extracted with 2 x 20 ml ether. The combined ether extracts are washed with 2 x 15 ml of a 5% R. the results of 1.40 g (purity according to GC 94%) of 2-methylthio-4-phenoxypyridine in the form of a light yellow oil, which are used directly in the next stage. DMR : is 2.37 (3H, s) M. D.

To a stirred solution of 1.00 g (4,59 mmol) of 2-methyl-thio-4-phenoxypyridine in 15 ml of chloroform at -15aboutTo add 2,88 g (9,17 mmol) m-chloroperbenzoic acid in 35 ml of chloroform. Formed white turbid suspension. The reaction mixture is allowed to warm to room temperature and continue stirring for 4 h GC analysis indicates the formation of one product (95% ). The reaction mixture was washed with 2 x 25 ml saturated aqueous solution of sodium sulfite, 2 x 25 ml of a saturated solution of sodium carbonate and 25 ml of water. Separate the chloroform solution and dried. Evaporated the solvent to obtain a colorless oil, which crystallizes upon cooling and the seed, get 1,05 g 2-methanesulfonyl-4-phenoxypyridine in the form of a white solid product. Recrystallization from a mixture of chloroform and n-hexane gives white crystalline powder, so pl. 113-116aboutWith PMR, : 3,17 (3H, s), M. D. IR-spectrum (nujol): 1133, 1315 cm-1.

To a solution of 200 mg of 2-methanesulfonyl-4-phenoxypyridine (0.80 mmol) in 2 ml dry DMF at 0 C under nitrogen atmosphere was added 110 mg (0.80 mmol) of anhydrous potassium carbonate. A solution of 166 mg (0.80 mmol) /E/-methyl-2-[2-oxide the Ute to warm to room temperature, and then stirred for one day. The mixture is diluted with 15 ml of water, and then extracted with 2 x 20 ml ether. The combined ether extracts are washed with saturated salt solution, dried and evaporated, receives a yellow oil. Chromatography (eluent ether and n-hexane 5:1) to give light yellow turbid oil, which is triturated with ether, to obtain 0.10 g of a solid white color of the target product. Recrystallization from ether and n-hexane give 65 mg (yield 22%) of white solid product, so pl. 96-97aboutC; DMR : 3,57 (3H, s), 3,70 (3H, s), 6.48 in (1H, g), 7,12-7,45 (N, m), 7,42 (1H, s), 8,29 (1H, g) M. D.

IR-spectrum : 1708, 1632 cm-1.

P R I m m e R 2. Obtaining /E/-methyl-2-[2-(2-phenoxypyridine-4-yloxy)phenyl]-3-methoxypropionate (compound 1 in table.2).

To mix the solution 10,00 (62,3 mmol) 4-chloro-2-methylthiopyrimidine in 50 ml of glacial acetic acid at 10-15aboutWith added solution 12,50 g (79,15 mmol) of potassium permanganate in 100 ml of water. The reaction mixture was stirred overnight at room temperature, cooled to 5aboutC, and then treated with gaseous sulfur trioxide to until dark solution become colourless. Add water and the mixture extracted with chloroform. The combined organic layers washed feast upon the of sulfanilamide in the form of a white solid product, so pl. 91-3aboutC. Process of 7.00 g (36,33 mmol) 4-chloro-2-methanesulfonamido tenoxicam sodium (3,41 g (36,33 mmol) of phenol and of 1.74 g (39,97 mmol) of a 50% dispersion in oil of sodium hydride in 100 ml dry DMF) at 0-5aboutC. After 30 min of starting compound disappears (GC-analysis). The reaction mixture is diluted with water, and then extracted twice with ether. The combined extracts are washed 2 times with 5% aqueous sodium hydroxide solution and saturated saline, and then dried. Upon evaporation of the solvent obtain 5.35 g of a very light yellow mobile oil. Chromatography (eluent - esters: n-hexane 2:3) followed by crystallization give 3.50 g (84% pure by GC) 4-chloro-2-phenoxypyridine in the form of a white solid product. Subsequent chromatography gives pure product (2.50 g, 33%), so pl. 59-60aboutC.

To a stirred solution of 2.00 g (9,68 mmol) 4-chloro-2-phenoxypyridine in 15 ml of dry DMSO and 10 ml of DMF at 10aboutC in an atmosphere of nitrogen was added dropwise a suspension of 0.77 g (9,68 mmol) methanolate of sodium in 15 ml of dry DMSO and 5 ml of DMF. After about one hour at a temperature below 15aboutWith the reaction mixture is diluted with water, and then extracted 3 times with ether. The combined extracts washed with saturated saline races is in the form of a thick light yellow oil, which is used in the next stage without additional purification.

Process of 2.00 g (of 7.96 mmol) of 4-methylthio-2-phenoxypyridine in 12 ml of glacial acetic acid with a solution of 1.60 g (10,11 mmol) of potassium permanganate in 20 ml of water as described for 4-chloro-2-methylthiopyrimidine. After processing the receive light yellow oil, which was triturated with ether and n-hexane, obtaining a light yellow slightly dense powder (1,00 g). Recrystallization from carbon tetrachloride (chloroform (traces)) n-hexane gives 0,70 g (yield 35%) 4-methanesulfonyl-2-phenoxypyridine in the form of a white powder, so pl. 86-87aboutWith PMR, : 3,19 (3H, s) M. D.

IR-spectrum (nujol) : 1135, 1305 cm-1.

To a solution of 300 mg (1.20 mmol) of 4-methanesulfonyl-2-phenoxypyridine in 4 ml dry DMF was added 116 mg (1.20 mmol) of anhydrous potassium carbonate. A solution of 0.250 g (1.20 mmol) /E/-methyl-2-(2 oksifenil)-3-methoxypropionate in DMF was added and the reaction mixture was stirred overnight at room temperature. It was poured into water and extracted with ether. The ether extracts are washed with saturated salt solution, dried and concentrated, obtaining of 0.48 g of a yellow oil. Chromatography (eluent ether and n-hexane 3:1) leads to a 0.34 g of a white solid product. Perekrestenko powder (0.31 g, 69% yield); so pl. 114-115aboutWith, PMR (270 MHz): of 3.60 (3H, s), 3,74 (3H, s), to 6.43 (1H, g), 7,11-7,42 (N, m), 7,46 (1H, s) 8,28 (2N, g) and M. D.

Mass spectrum m/e 378 (M+).

P R I m e R 3. Obtaining (E)-methyl-2-(2-)6-(2-cianfrocca)pyrimidine-4-yloxy)Fe - Neil)-3-methoxypropionate (compound 9 of table.1).

To a solution 0,76 g (5,10 mmol) of 4,6-dichloropyrimidine in 4 ml of dry DMF at 0aboutTo add 0,70 g (5,10 mmol) of anhydrous potassium carbonate. Then dropwise with stirring was added a solution of 0.53 g (2.55 mmol) /E/-methyl-2-(2 oksifenil)-3-methoxypropionate in 2 ml of DMF. Upon completion of addition, the reaction mixture is allowed to warm to room temperature and continue stirring for one day. Then the reaction mixture was diluted with 15 ml of water and extracted with 3 x 20 ml ether. The combined ether extracts are washed with saturated salt solution and dried. After evaporation obtain 1.10 g of a brown liquid, which chromatographic (eluent ether and n-hexane, 3:2), get /E/-methyl-2-[2-(6-chloropyrimidine-4-yloxy) phenyl]-3-methoxypropionate in the form of heavy light yellow oil (0,58 g, 71% yield) which crystallized upon standing. Recrystallization from ether dichloromethane (traces)) n-hexane at -78aboutTo give the product as a white powder (0.25 g, so pl. 94-95

Heat during the night of 1.50 g (4,68 mmol) /E/-methyl-2-[2-(6-chloropyrimidine-4-yloxy)phenyl] -3-methoxypropionate at 95-100aboutWith 0,61 g (5,15 mmol) of 2-cyanophora and 0.71 g (5,15 mmol) of potassium carbonate in 35 ml of DMF in the presence of catalytic amounts odnoklasniki copper. Cool the reaction mixture was diluted with water, and then extracted with ether. The combined ether layers washed with 2 M sodium hydroxide solution and a saturated saline solution and then dried. Evaporation of solvent gives 1.52 g of light yellow oil. Recrystallization from ether (dichloromethane) n-hexane leads to the target product as a pale yellow powder (1.20 g, yield 64%), so pl. 110-111aboutC; DMR : 3,63 (3H, s), 3,74 (3H, s), 6.42 per (1H, s), 7,19-7,47 (6N, m) to 7.50 (1H, s), 7,62 to 7.75 (2H, m), 8,40 (1H, s) m D. When you prepare the target compounds recrystallization gives a white crystalline product, so pl. 118-119aboutC.

P R I m e R 4. Obtaining /E/-methyl-2-[2-(6-(2-oxygenase)pyrimidine-4-yloxy(Fe - Neil)-3 - methoxypropionate (compound 26 table.1).

A mixture of 6.6 g (0.06 mmol) of catechol and of 8.28 g (0.06 mmol) of anhydrous potassium carbonate in 100 ml of DMF is heated 1 h at 110aboutC. Then was added a catalytic amount (0.2 g) odnoklasniki copper, then the solution 12,82 g (0.04 mol) /E/ - is at 110aboutWith, leave overnight, and then poured into water. The resulting mixture was extracted with ether (extract). The remaining aqueous layer was acidified with concentrated hydrochloric acid, and then extracted with ether, then both of the extract washed with water (X3), dried and evaporated, get to 6.78 g of a brown resin ("extract"). Extract "And" washed with diluted sodium hydroxide solution, the resulting aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate, this an ethyl acetate extract is then washed with water, dried and evaporated, get of 6.68 g of a brown resin ("extract"). Extracts from "b" and "C"are combined and chromatographic (eluent ether), gain of 7.8 g (yield of 49.5%) of target compound in the form of a yellow solid product, which is identical to the sample obtained previously on a small scale, so pl. 159-161aboutWith the IR-spectrum : 3100, 1712, 1642 cm-1; DMR : 3,61 (3H, in), 3.75 (3H, s), 6,30 (1H, s), of 6.52 (1H, s), 6,91-6,97 (1H, m), 7,05-7,21 (4H, m), 7,26-of 7.48 (3H, m), 7,45 (1H, s), 8,44 (1H, s) M. D.

P R I m e R 5. Obtaining /E/-methyl-2-(2-)6-(2-methoxyphenoxy)pyrimidine-4-ilok - C[phenyl]-3 - methoxypropionate (compound 29 table.1).

To a stirred solution of 0.50 g (1,27 m) /E/-methyl-2-[2-](2-oxygenase)pyrimidine-4-yloxy(phenyl)-3-methoxyp - PMAS is tilited. The reaction mixture is allowed to warm to room temperature, stirred for two hours and then leave to stand for a day. The mixture is diluted with 20 ml of water, and then extracted with 3 x 25 ml ether. The combined ether extracts are washed with 2 x 20 ml of dilute sodium hydroxide solution and 20 ml of saturated saline, and then dried. After evaporation obtain 0.36 g of light pink foam, which chromatographic (eluent ether-hexane 7:1), obtaining the target compound as a white foam (0.21 g, 40% yield); PMR, : of 3.60 (3H, s), 3,76 (3H, c), of 3.78 (3H, c), and 6.25 (1H, s), 6,95-7,52 (3H, m), 7,49 (1H, s), 8,42 (1H, s) M. D.

In an alternative preparation /E/-methyl-2-[2-(6-chloropyrimidine-4-yloxy)Fe - Neil]-3-methoxypropane (1,00 g of 3.12 mmol), obtained as described in example 3, the process of 1.09 g (15,60 mmol) methanolate sodium at room temperature in 15 ml of chloroform and 10 ml of water in the presence of catalytic amounts of tetrabutylammonium. After stirring over night separate the chloroform layer and the remaining aqueous layer was then extracted with chloroform. The combined chloroform layers are washed with water, dried and evaporated, receiving, 1.56 g of orange oil. Chromatography (eluent ether-hexane 2: 1) leads to 0.92 g (yield 89%) /E/-methyl-2-[2-(6-methylthiopyrimidin is H, C), 7,20-of 7.55 (3H, m), 7,45 (1H, s), to 8.57 (1H, s) M. D.

Mix 0.20 g (0.6 mmol) of the obtained product and 0.38 g (55% purity) of meta-chloroperbenzoic acid in 25 ml of chloroform overnight at room temperature. Processing gives 0.26 g of the corresponding sulfone (purity 94% by GC) in the form of a heavy colorless oil, which was directly used in the next stage without additional purification. DMR : 3,25 (SO2CH3), 7,45 (olefinic proton) M. D.

To a stirred solution of 0.24 g of the sulfone in 6 ml of dry DMF was added 0,091 g of anhydrous potassium carbonate and the solution 0,082 g of 2-methoxyphenol in 2 ml dry DMF. The reaction mixture is stirred for 4 h and then overnight at room temperature, diluted with 15 ml water, then extracted with 3 x 20 ml ether. The combined ether extracts are washed with 2 x 15 ml of dilute sodium hydroxide solution and 15 ml of saturated saline, then dried. In the process of evaporation obtain 0.25 g of a dense pale yellow oil. Chromatography (eluent ether-hexane 7:1) leads to the target compound in the form of dense white foam (0.17 g, yield 63%). TMR is identical to the above.

P R I m e R 6. Obtaining /E/-methyl-2-[2-]6-(2-dicarboxyphenoxy) pyrimidine-4-yloxy[phenyl]-3-methoxypropanol the thief of 2.09 g (15,19 mmol) /E/-methyl-2-[2-(6-(2-cianfrocca)pyrimidine-4-yloxy)Fe - Neil]-3-methoxypropionate, obtained as described in example 3, and 0.52 g of triethylamine in 45 ml of dry pyridine at 50aboutC. for 4.5 h at 50aboutWith in one week at room temperature the excess of hydrogen sulfide is removed by blowing air through the reaction mixture. The resulting brown solution was evaporated and dried by azeotrope with toluene (2 x 50 ml), get a brown oil, which was triturated with 3 x 40 ml of water. The remainder chromatographic (eluent acetone-hexane 2:3), receive 0,79 g light yellow oil. A thorough rubbing with hexane leads to the target compound as a pale orange powder (0.68 g, yield 30%), so pl. 125-128aboutC. the Sample prepared after had so pl. 131-133aboutWith PMR, : 3,63 (3H, s), of 3.78 (3H, s), 6,27 (1H, s), 7,18 (1H, s), 7,10-7,60 (6N, (C), 7,49 (1H, s), 7,71 (1H, s), to $ 7.91 (1H, s), with 8.05 (1H, s), 8,39 (1H, s) M. D.

P R I m e R 7. Obtaining compounds

and

< / BR>
To stir the mixture 2,43 g /E/-methyl-2-(2 oksifenil)-3-methoxypropionate and 1.61 g of anhydrous potassium carbonate in 25 ml of dry DMF at 0aboutWith added dropwise a solution of 2,4,6-trichloropyridine in 5 ml of dry DMF. The reaction mixture was stirred for 30 min at 0aboutWith and within days at room temperature, and then poured into water and three times extracted with ether then dried. After evaporation receive 2,62 g orange resin that chromatographic (eluent a mixture of ether-hexane), to obtain 0.65 g /E/-methyl-2-2-(2,4-dichloropyrimidine-6-yloxy)Fe - Nile/-3-methoxypropionate in the form of a white solid product, so pl. 88-90aboutWith and 1.07 g of a mixture of about 1:1, containing

and

< / BR>
To a stirred solution of this mixture (0.97 g) in 25 ml THF was added 0.11 g of 5% Pd/C catalyst, and then within 5 minutes and added dropwise 0,405 g hypophosphite in 5 ml of water. After 2 h stirring at room temperature raise temperature to 60aboutWith and add additional portion of 0.41 g of hypophosphite of sodium in 5 ml of water after an additional 30 min) and from 0.76 g of potassium carbonate and 0.11 g of the catalyst (after hours). When starting material was consumed (GC and TLC analysis), the reaction mixture was filtered through a zeolite, washed on the filter with ether and water. Separate the layers of the filtrate and the aqueous layer was extracted more than once with ether. The combined ether layers washed twice with water, dried and evaporated, get 0,78 g of white foam. Chromatography (eluent ether) gives erwerbende first connection 123 table.1 in the form of a white solid product 0.34 g, so pl. 130-131aboutWith the IR-spectrum : 1705, 1693, 1636 cm-1; DMR : 3,59 (6N, (C), 3 60-70aboutWith the IR-spectrum : 1706, 1632 cm-1, PMR, : of 3.56 (3H, s), 3,70 (3H, s), 3,74 (3H, s), 6,34-6,37 (1H, g), 7,15-to 7.35 (8H, m), 7,44 (1H, s), 7,47 (1H, s), 8,21-8,24 (1H, s) M. D.

P R I m e R 8. Obtaining /E/-methyl-2-[2-(4-ftorpirimidinu-6-yloxy)phenyl]-3-methods - of copropagate (intermediate product).

A mixture of 6.50 g of 4,6-dichloropyrimidine, 20,8 g of sulfur tetrafluoride and 35 ml of Arcton 113 is heated at 50aboutWith stirring the reactor Monela capacity of 100 ml for 3,3 o'clock Raise the temperature to 100aboutC for 25 min and maintained at 100aboutC for an additional 3 hours the Temperature was raised to 151aboutC for 20 min and incubated at 151aboutC for 3 hours and Then the reactor was allowed to cool to room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. On the interface see solid product removed by filtration. Then separate the layers. The organic layer is washed with water, then distilled at atmospheric pressure to remove dichloromethane. Receive 400 mg of 4,6-giftability by distillation in vacuum 50aboutC/100 mm RT.article in the form of a light yellow oil (7.3% of output), PMR, : is 6.61 (1H, s) and 8,69 (1H, s) M. D.

To a solution of 359 mg (1,724 mmol) /E/-methyl-2-(2-EXIF wodnego potassium carbonate. The reaction mixture was stirred for 20 min at room temperature, then added a solution of 200 mg of 4,6-giftability in 2 ml of dry DMF) via syringe over 1 min Then the reaction mixture is stirred for another 20 min at room temperature, poured into 20 ml of water and extracted with 4 x 30 ml ethyl acetate. The combined extracts are successively washed with 2 x 100 ml of water and 1 100 ml saturated salt solution, then dried and concentrated, getting 464 mg of the target compound in the form of a thick yellow oil (yield 88%), PMR, : 3,59 (3H, s), of 3.73 (3H, s), 6,32 (1H, s), 7,16-the 7.43 (4H, m), 7,45 (1H, s), 8,51 (1H, g) M. D.

Similarly, the receive connection table.1 and 2.

The following examples are examples of compositions used for agricultural and horticultural purposes, which can be obtained from the proposed connections. The percentages in these examples are massive.

P R I m e R 9. Emulgirujushchie concentrate is prepared by mixing and stirring the ingredients until complete dissolution, %: Compound 9 (see tab. 1) 10 Benzyl alcohol 30 Dodecylbenzenesulfonate calcium 5 Nonylphenolethoxylate (13 mol of ethylene oxide) 10 alkyl benzenes 45

P R I m e R 10. The active ingredient is dissolved in methylenechloride and receive the annulled composition, %: Compound 9 (see tab.1) 5 Attapulgite granules 95

P R I m e R 11.A composition suitable for use for seed treatment, is prepared by grinding and mixing the three ingredients, %: Compound 9 (see tab.1) 50 Mineral oil 2 Chinese clay 48

P R I m e R 12. Dostawy powder is prepared by grinding and mixing the active ingredient with talc, %: Compound 9 (see tab.1) 5 Talc 95

P R I m e p 13. The suspension concentrate is prepared by grinding in a ball mill ingredients with the formation of the aqueous slurry of the crushed mixture in water, %: Compound 9 of table.1 40 sodium Lignosulphonate 10 Bentonite clay 1 Water 49

This recipe can be used for dispersion when diluted with water or applied directly to the seeds.

P R I m e R 14. Formulation wettable powder is prepared by mixing together and grinding ingredients as long as they all will be carefully moved, %: Compound 9 (see tab.1) 25 Laurylsulphate sodium 2 sodium Lignosulphonate 5, the silicon Oxide 25 China clay 43

P R I m e R 15. Compounds were tested against a variety of fungal diseases of leaves of plants. Used the following method.

The plants were grown iravani or by mixing in a ball mill with water Dispersol T or in the form of a solution in acetone or acetone/ethanol, which is then diluted to the desired concentration immediately before use. Diseases leaf recipes (100 m D. active ingredient) is sprayed on the leaves and applied to the plant roots in the soil. Sprayable solutions are applied to the maximum retention, and roots irrigate up to the maximum concentration, equivalent to about 40 feet on the dry ground. Add tween-20 to obtain a final concentration of 0.05% when the spray is applied on the cereal.

For most of the test compound applied to the soil (roots) and leaves (spray) for one or two days before inoculation of the plants with the pathogen. The exception is the test on Erysiphe graminis in which plants inoculant for 24 h before processing.

Leaf pathogens is applied by spraying a suspension of spores on the leaves of test plants. After inoculation plants are placed in the appropriate environment, in order to develop the infection, and then incubated until then, until the disease is easy to evaluate. The period between inoculation and evaluation varies from four to fourteen days, depending on disease and environmental conditions.

Evaluate disease control according to the following scale:

4 - no for tannich plants;

1 - 26-59% of disease on untreated plants;

0 - 60-100% of disease on untreated plants.

The results are shown in table.3 and 4.

Comparison of the breadth of the spectrum of fungicidal action of the compounds of formula I conducted similar to example 15 conditions for MANCOZEB, carboxin, proxyfor shows (see tab.5), which is obtained according to the proposed method according to the invention compounds have a broader spectrum of fungicidal action.

Way to OBTAIN the PYRIMIDINE DERIVATIVES of General formula

< / BR>
where any two groups from among the K, L and M are astami, and the third group-CH=;

G is hydrogen or halogen;

X is hydrogen, halogen, unsubstituted WITH1- C4is alkyl or substituted with halogen, hydroxyl, or cyano WITH2- C4alkenyl,2- C4-quinil, trimethylsilyl substituted C2- C4alkenyl,2- C4-alkenylacyl,2- C4-alkyloxy, phenyl, cyano-, thiocyanato - or nitro-group, a group-NR1R2where R1and R2is hydrogen or C1- C4-alkyl, C1- C4-alkylcarboxylic, asiagraph,1- C4-alkoxyl, phenoxy-Ben is 4-alkanoyloxy-FROM1- C4-alkylsulfonate-FROM1- C4-alkylthio-FROM1- C4-alkylsulfonyl-FROM1- C4-alkylsulfonyl, formyl, C1- C4-alkanoyl, hydroxyimino-(C1- C4)-alkyl group, carbarnoyl, thiocarbamoyl or group

CH3O2C = CHOCH3;

Y is halogen, C1- C4-alkyl, C1- C4-alkoxyl, nitro, di(C1- C4-alkylamino or hydrogen,

or X and Y when they are in ortho-position relative to each other, together with the phenyl ring to which they are attached, form naphtalene ring;

And - halogen, hydrogen, C1- C4-alkyl or C1- C4-alkoxy,

characterized in that the compound of General formula

< / BR>
where K, L, M and G have the values

subjected to interaction with the compound of General formula

< / BR>
where A, X and Y have the above meanings;

one of the groups Z1or Z2- leaving group from among chlorine or methanesulfonyl when the other group is a group where T is hydrogen or the cation of an alkali metal,

in a solvent such as dimethylformamide, at 0 - 110oPerhaps in prisutstvuet potassium carbonate.

 

Same patents:

The invention relates to pyrimidine derivative of the General formula I:

where R1- alkyl-(C1-C4), O-alkyl-(C1-C4), halogen;

R2- alkyl-(C1-C4), O-alkyl-(C1-C4);

n = 3-5;

Z = COOH, COO-alkyl-(C1-C4), CONHSO2C6H5with herbicide activity, and to a method of controlling undesirable vegetation by processing them in the locus, namely, that the treatment is carried out pyrimidine derivatives of General formula I:

where R1- alkyl-(C1-C4), O-alkyl-(C1-C4), halogen;

R2- alkyl-(C1-C4), O-alkyl(C1-C4);

n = 3-5;

Z = COOH, COO-alkyl-(C1-C4), CONHSO2C6H5in the amount of 1-10 kg/ha

The invention relates to methods of producing derivatives of 2-anilinopyrimidines or acid additive salts of novel biologically active compounds, which can find application in agriculture

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 5 tbl, 3 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing optically pure voriconazole via: a) coupling reaction of 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone with 4-(1-bromoethyl)-6-(4-chlorophenylsulphanyl)-5-fluoropyrimidine in Reformatsky reaction conditions to obtain the desired (2R,3S)/(2S,3R) enantiomeric pair, b) splitting the thiol fragment from the enantiomer to obtain racemic voriconazole; and c) extracting the desired optically pure voriconazole via optical separation of the enantiomer using an optically active acid.

EFFECT: improved method.

4 cl, 7 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine carboxylate derivatives having herbicidal activity, as well as agriculturally acceptable derivatives thereof from a carboxylic acid group, which are esters or salts. In formula (I): Q is halogen; R1 is H; W is H; X is halogen; Y is C1-C4alkoxy; Z is halogen.

EFFECT: invention also relates to a herbicidal composition containing said compounds and a method of inhibiting undesirable plants.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (I) X=N or C-R3; R1 stands for proton, saturated or unsaturated linear alkoxy radical, which has 2-5 carbon atoms; cycloalkyloxy radical, which has to 6 carbon atoms, saturated linear alkylmercapto radical, which has 1-3 carbon atoms; amino radical, having 1-10 carbon atoms, selected from saturated or unsaturated linear mono- or dialkylamino radical, or cycloalkylamino radical, cyclic amino radical, and each of cyclic groups can be substituted with 1-2 metal groups, or benzylaminogroup; R2 represents proton, saturated or unsaturated, linear alkyl radical, which has 1-5 carbon atoms, or cyclic aliphatic radical, which has to 6 carbon atoms, trifluoromethyl, stiryl or methylmercaptogroup; R3 stands for trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyanogroup or alkoxycarbonyl sunstituent, which has 1-3 carbon atoms in alkoxygroup.

EFFECT: obtaining novel 2-nitroheterylthiocyanates of general formula (I), or their pharmaceutically acceptable additive salts with acids or bases, probably in crystalline form, possessing activity with respect to strains of fungi, causative agents of fungal infections, their application for treatment of fungal infections, as well as obtaining based on them pharmaceutical composition.

8 cl, 3 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: method involves carrying out a seasonal single treatment of plant leaves with asymmetrical derivative of 4,6-bis-(aryloxy)pyrimidine of the formula: wherein X means chlorine atom (Cl), nitro- or cyano-group. Invention provides enhancing the long-term time of plants protection.

EFFECT: enhanced effectiveness and valuable properties of compounds.

6 cl, 6 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, herbicides, chemical technology.

SUBSTANCE: invention relates to derivatives of substituted sulfonylaminomethylbenzoic acid of the general formula (I): wherein R1 means hydrogen atom (H) or (C1-C8)-alkyl; R2 and R3 mean H; R4 and R5 mean H; R6 means H or (C1-C8)-alkyl; R7 means (C1-C8)-alkyl; R8 is similar or different and means (C1-C4)-alkyl or (C1-C4)-alkoxy-group; n means 0 or 1. Compounds of the formula (I) are intermediate substances in synthesis of biologically active compounds possessing the herbicide activity, in particular, in synthesis of sulfonylureas. Also, invention describes methods for synthesis of compounds of the formula (I) and their derivatives.

EFFECT: improved method of synthesis.

27 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new method of producing formerly unknown 1-(pyrimidine-2-il)propane-2-on of the general formula wherein R designates every time the C1-C10 alkyl group. The method consists in that the reaction of malone diimidate is carried out with the general formula , wherein R has the above-stated magnitudes, with dikenete of the formula . It is preferable to use malone diimidate (II) produced in situ from is appropriate salt and base. Here, the salt of used malone diimidate (II) is dihydrochloride, and tertiary amine. The preferable malone diimidate of the formula (II) is dimethyl malone diimidate.

EFFECT: new compounds feature useful biological properties.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new methylcetone pyrimidine -2 of the formula (I) and to the new method of their preparation. The compounds of the invention are intermediate products for synthesis of agronomical active effectors. The method of preparation of methylcetone pyrimidine -2 of general formula in which R1 and R2 define C1-C10 alkyl group in each case is that reaction malondiimidate of the general formula (II) , in which R1 has above mentioned value with β-ketoester of the general formula (III) , in which R2 has above mentioned value and R3 define C1-C10 alkyl group. Usually, water appeared during reaction are taken away from the reactor feed. Basic malondiimidate(II) can be derived in situ from the conforming salt and base. Preferably, used salt of malondiimidate (II) is dihydrochloride and used malondiimidate (II) is dimethylmalondiimidate. Preferably used β-ketoester (III) is acetacetic ester, 3-oxopentane ester.

EFFECT: method of the compound preparation is improved.

9 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new sulphamines with general formula (I) , where R1 represents (low) alkyl-O-(CH2)n-; R2 represents Ra-Y-(CH2)m-; R3 represents phenyl, which can be replaced by such substitutes as halogen, (low) alkyl or (low)alkoxy; R4 represents hydrogen; R6 represents hydrogen; X represents oxygen or a bond; Y represents a bond of -O-; n is equal to 2; m is equal to 2; Ra represents heteroaryl, in form of a 6-member aromatic ring, containing two nitrogen atoms, which can be substituted with such substitutes as halogen, thio(low)alkyl or (low)alkoxy; and their pharmaceutical salts. The invention also pertains to related objects, including the method of obtaining the following compounds formula II , formula III , formula IV , formula V , where radicals assume values indicated above or in the description.

EFFECT: invented compounds can be used as active ingredients for obtaining pharmaceutical compositions, which have inhibiting effect to endothelial receptors.

13 cl, 4 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing azoxystrobin by reacting a compound of formula (II): with 2-cyanophenol or a salt thereof in the presence of 2.5-40 mol. % 1,4-diazabicyclo[2,2,2]octane and an acid acceptor, where W is a methyl(E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3. 1,4-diazabicyclo[2,2,2]octane is mixed with a compound of formula (II) only in the presence of 2-cyanophenol or when conditions are such that the compound of formula (II) and 1,4-diazabicyclo[2,2,2]octane are not capable of reacting with each other.

EFFECT: method enables to obtain a product with high output using a certain order of adding components.

12 c, 18 ex

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