Uracil derivatives, herbicide composition, method for control of weed and intermediate substances (variants)

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

 

The present invention relates to compounds of uracil (brazilan) and their application.

The aim of the present invention are compounds with excellent herbicide activity.

Currently sold and used for many herbicides, however, since there are many kinds of weeds, which must be fought, and their reproduction occurs over a long period of time, there is a need to herbicides with a stronger herbicide action and a broad spectrum herbicide action, not phyto-toxic for cultivated plants.

In U.S. patent 4859229, WO 92/11244, WO 97/01541, WO 97/05116, WO 98-41093 and other work indicates that some types of eniluracil have a weed-killing activity, however, their properties are not efficient enough for use as herbicides.

The authors of the present invention conducted intensive studies to find compounds with high herbicide activity and as a result found that orally following formula [I] have a high herbicide activity that led to the creation of the present invention. Thus, the present invention relates to brazilan formula [I] (hereinafter referred to as "compounds of the present invention")

[Q-R3is R3-substituted group, 5-membered or 6-membered Goethe is utilizacao ring with one or two nitrogen atoms, selected from the group represented by the following formula

(where the heterocyclic ring may be substituted by at least one Deputy species selected from the group consisting of halogen, (C1-C6)-alkyl, (C1-C6)-halogenoalkane, (C2-C6-alkenyl, (C2-C6)-halogenoalkane, (C2-C6)-quinil, (C2-C6)-halogenoalkane, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-halogenoalkane, (C1-C6-alkoxycarbonyl-(C1-C6)-alkoxy, (C1-C6-alkoxycarbonyl-(C1/sub> -C6)-alkyl, cyano, hydroxy, mercapto, oxo, thioxo),

Y represents oxygen, sulfur, imino or (C1-C3)-alkylamino,

R1is (C1-C3)-alkyl or (C1-C3-halogenated,

R2is (C1-C3)-alkyl,

R3is carboxy-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl- (C1-C6)-alkyl, (C1-C6-halogenosilanes-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl, (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl, (C3-C6-alkyloxyaryl-(C1-C6)-alkyl, (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl, OR7, SR8or N(R9R10,

X1represents halogen, cyano, thiocarbamoyl or nitro,

X2represents hydrogen or halogen,

[where each of R7, R8and R10is, independently, carboxy- (C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C1-C6-halogenosilanes- (C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl, (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl, (C3-C6)-alkinyl carbonyl-(C 1-C6)-alkyl, (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl, (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, (C3-C8-halogenlithiumcarbeniod-(C1-C6)-alkyl, (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, (C3-C8)-halogenically-meloxican-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C1-C8-alkylaminocarbonyl- (C1-C6)-alkyl, phenoxycarbonyl-(C1-C6)-alkyl which may be substituted, phenyl-(C1-C4)-alkoxycarbonyl-(C1-C6)-alkyl which may be substituted, (C1-C6-alkoxycarbonyl- (C1-C6)-alkyl, ( C1-C6)-alkoxy)((C1-C3)-alkyl)aminocarbonyl-(C1-C6)-alkyl, (C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, (C1-C6)-alkyl))(C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, phenylenecarbonyl-(C1-C6)-alkyl which may be substituted, or phenyl-(C1-C4-alkylaminocarbonyl-(C1-C6)-alkyl which may be substituted, and R9represents hydrogen or (C1-C6)-alkyl],

and a herbicide containing as the e compounds as the active ingredients.

In the present invention as the group represented by Q-R3for example, there may be groups listed below:

[where R3has the values listed above, each of the Z1and Z2independently, represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C6-halogenated, (C2-C6)-alkenyl, (C2-C6)-halogenoalkanes, (C2-C6)-quinil, (C2-C6-halogenoalkanes, (C1-C6)-alkoxy- (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-halogenoalkane, (C1-C6-alkoxycarbonyl-(C1-C6)-alkoxy or cyano (where the halogen represented by Z1or Z2means fluorine, chlorine, bromine or iodine, and examples (C1-C6)-alkyl are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like, examples (C1-C6)-halogenoalkane are methyl bromide, chloromethyl, vermeil, dichloromethyl, trichloromethyl, deformity, CHLOROFORMATES, bromodifluoromethyl, trifluoromethyl, pentafluoroethyl, 2-foretel, 1,1-dottorati, 2,2,2-trichloroethyl, 3,3,3-cryptochromes, 3,3,3-trichloropropane and similar groups, examples (C2-C6-alkenyl are allyl, 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 1-butenyl, 2-butenyl, 3-butenyl and the like, examples (C2-C6-halog alkenyl are 1-chlorallyl, 1-bromall, 2-chlorallyl, 3,3-dichlorethyl and similar groups, examples (C2-C6)-quinil are 2-PROPYNYL, 1-methyl-2-PROPYNYL, 1,1-dimethyl-2-PROPYNYL, 2-butynyl, 3-butynyl, 1-methyl-2-butenyl and similar groups, examples (C2-C6)-halogenoalkane are 3-bromo-2-PROPYNYL, 3-iodine-2-PROPYNYL, 1-fluoro-2-PROPYNYL, 1-chloro-2-PROPYNYL, 1-bromo-2-PROPYNYL, 1-chloro-2-butynyl and similar groups, examples (C1-C6)-alkoxy- (C1-C6)-alkyl are methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropan, isopropoxyphenyl, 2-isopropoxide and similar groups, examples (C1-C6)-alkoxy are methoxy, ethoxy, propoxy, isopropoxy, bucalossi, sec-Butylochka, tert-Butylochka and the like, examples (C1-C6)-halogenoalkane are chloromethoxy, bromoethoxy, dichloromethoxy, trichlorethylene, cryptometrics, 2-forations, 2,2,2-trichlorethylene and the like, examples (C1-C6-alkoxycarbonyl-(C1-C6)-alkoxy are ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl, 1 ethoxycarbonylmethoxy, 1 ethoxycarbonylmethoxy, 1 propoxycarbonyl, 1 isopropoxycarbonyl, 2-ethoxycarbonylmethoxy, 2-ethoxycarbonylmethoxy, 2-propoxycarbonyl, 2-isopropoxycarbonyl is ethoxy and similar groups, examples (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonylmethyl, abiloxicasinohotel7, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyl, 1-butoxycarbonylmethyl, 1-tert-butoxycarbonylmethyl and similar groups)].

Examples of the carboxy-(C1-C6)-alkyl represented by R3are carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and similar groups, examples (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylmethyl, isobutoxyethanol, tert-butoxycarbonylmethyl, abiloxicasinohotel7, isoamyloxyacetate, tert-abiloxicasinohotel7, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-tert-butoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl and similar groups, examples (C1-C6-halogenosilanes-(C1-C6)-alkyl are chloromethyloxirane, 2-veratexisabelle.html, 2-chloropropionitrile, 1-chloro-2-propyloxy boiler, 2,2,2-cryptreleasecontext and similar groups, examples (C3-C6-alkenylacyl-(C1-C6)-alkyl are allyloxycarbonyl, 1-methyl-2-propanecarboxylate, 2-methyl-2-propanecarboxylate, 2-butyloxycarbonyl, 1-allyloxycarbonyl, 1-(1-methyl-2-propenylboronic)ethyl, 1-(2-methyl-2-propenylboronic)ethyl, 2-allyloxycarbonyl, 2-(2-methyl-2-propenylboronic)ethyl and the like groups, examples (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl are 1-globalisationrelated, 1-(1-chlorellaceae)ethyl, 2-globalisationrelated, 1-(2-chlorellaceae)ethyl and the like groups, examples (C3-C6-alkyloxyaryl-(C1-C6)-alkyl are propylenecarbonate, 1-methyl-2-propynylbutylcarbamate, 1-propylenecarbonate, 1-(1-methyl-2-propenylboronic)ethyl, 2-propylenecarbonate, 2-(1-methyl-2-propenylboronic)ethyl and the like groups, examples (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl are (3-chloro-2-propenylboronic)methyl, 1-(3-chloro-2-propenylboronic)ethyl, (1-chloro-2-propenylboronic)methyl, 1-(1-chloro-2-propenylboronic)ethyl and the like groups,

examples (C1-C3)-alkylamino represented by Y, Vlada methylimino, ethylimino and similar groups,

(C1-C3)-alkyl represented by R1means methyl, ethyl, propyl, isopropyl, and examples (C1-C3)-halogenoalkane are methyl bromide, chloromethyl, vermeil, dichloromethyl, CHLOROFORMATES, trichloromethyl, deformity, trifluoromethyl, pentafluoroethyl, 1,1-dottorati, 2,2,2-triptorelin, 3,3,3-cryptochromes and similar groups,

(C1-C3)-alkyl represented by R2means methyl, ethyl, propyl or isopropyl,

examples of the carboxy-(C1-C6)-alkyl represented by R7, R8or R10are carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and the like, examples (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylmethyl, isobutoxyethanol, second-butoxycarbonylmethyl, tert-butoxycarbonylmethyl, abiloxicasinohotel7, isoamyloxyacetate, tert-abiloxicasinohotel7, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 1-propoxycarbonyl, 1-isopropoxycarbonyl, 1-butoxycarbonylmethyl, 1-isobutoxyethanol, 1-second-butoxycarbonylmethyl, 1-tert-butoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl and similar groups, examples (C1-C6-halogenosilanes-(C1C 6)-alkyl are chloromethyloxirane, 2-veratexisabelle.html, 2-chloropropionitrile, 1-chloro-2-propylenecarbonate, 2,2,2-cryptreleasecontext and similar groups, examples (C3-C6-alkenylacyl-(C1-C6)-alkyl are allyloxycarbonyl, 1-methyl-2-propanecarboxylate, 2-methyl-2-propanecarboxylate, 2-butyloxycarbonyl, 1-allyloxycarbonyl, 1-(1-methyl-2-propenylboronic)ethyl, 1-(2-methyl-2-propenylboronic)ethyl, 2-allyloxycarbonyl, 2-(1-methyl-2-propenylboronic)ethyl, 2-(2-methyl-2-propenylboronic)ethyl and the like groups, examples (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl is 1-chloro-2-propanecarboxylate, 1-(2-chloro-2-propenylboronic)ethyl and the like groups, examples (C3-C6-alkyloxyaryl-(C1-C6)-alkyl are propylenecarbonate, 1-methyl-2-propanecarboxylate, 1-propylenecarbonate, 1-(1-methyl-2-propenylboronic)ethyl, 2-propylenecarbonate, 2-(1-methyl-2-propenylboronic)ethyl and the like groups, examples (C3-C6-gelegenheitsarbeit-(C1-C6)-alkyl is 1-bromo-2-propynylbutylcarbamate, 1-(1-chloro-2-propenylboronic)ethyl and the like, examples (C3-C8 -cycloalkylcarbonyl-(C1-C6)-alkyl are cyclopropanecarboxylate, cyclopentanecarbonyl, 1-(cyclobutanecarbonyl)ethyl and the like groups, examples (C3-C8-halogenlithiumcarbeniod-(C1-C6)-alkyl are 2,2-debtor-cyclopentanecarboxylate, 2-braziliantelecommunications, 1-(2-chlorocyclohexanone)ethyl and the like groups, examples (C3-C8-cycloalkylcarbonyl- (C1-C6)-alkyl are 2-cyclopentanecarbonyl, 1-(2-cyclobutanecarbonyl)ethyl and the like groups, examples (C3-C8-halogensilberemulsionen- (C1-C6)-are alkyl 4-bromo-2-cyclobutanedicarboxylate and 1-(4-bromo-2-cyclopentanecarbonyl)ethyl and the like groups, examples (C1-C6-alkoxycarbonyl-(C1-C6-alkoxycarbonyl-(C1-C6)-alkyl are methoxycarbonylmethylene, 2-(methoxycarbonyl)-2-propoxycarbonyl, 1-[1-(etoxycarbonyl)etoxycarbonyl]ethyl and the like groups, examples (C1-C8-alkylaminocarbonyl-(C1-C6)-alkyl are isopropylaminocarbonyl, 2-(isopropylaminocarbonyl)ethyl and the like groups, examples of phenoxycarbonyl-(C1-C6)-alkyl which may be substituted, Vlada phenoxycarbonylamino, 1-phenoxycarbonyl and the like, examples of the phenyl-(C1-C4-alkoxycarbonyl-(C1-C6)-alkyl which may be substituted, are benzyloxycarbonylation, 1-benzyloxycarbonylation and the like, examples (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl are methoxyaminomethyl, 1-methoxyaminomethyl, amoxilintolerance, 1-amoxilintolerance and similar groups, examples ((C1-C6)-alkoxy)((C1-C6)-alkyl)aminocarbonyl-(C1-C6)-alkyl are (methoxy)(methyl)aminocarbonylmethyl, 1-(methoxy)(methyl)aminocarbonylmethyl (ethoxy)(methyl)aminocarbonylmethyl, 1-(ethoxy)(methyl)aminocarbonylmethyl and similar groups, examples (C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl are methylaminomethyl, ethylaminomethyl, isopropylaminocarbonyl, 1-methylaminomethyl, 1-isobutyleneisoprene and similar groups, examples ((C1-C6)-alkyl)((C1-C6)-alkyl)aminocarbonyl-(C1-C6)-alkyl are dimethylaminocarbonylmethyl, 1-dimethylaminocarbonylmethyl and similar groups, examples of phenylenecarbonyl-(C1-C6)-alkyl which may be substituted, are phenylenecarbonyl, 1-phenylenecarbonyl and the like, and examples of phenyl-(C1-C6)-and killinochchi-(C 1-C6)-alkyl which may be substituted, are benzylaminocarbonyl, 1-Ben-selenocarbonates and similar groups,

examples (C1-C6)-alkyl represented by R9are methyl, ethyl, propyl, isopropyl, butyl and the like, and

the halogen represented by X1and X2means fluorine, chlorine, bromine or iodine.

From among the compounds of the present invention is preferable from the viewpoint of herbicide activity, are compounds where Q-R3represents Q-1, Q-2 or Q-6, Y represents oxygen or sulfur, preferably oxygen, R1represents methyl substituted by fluorine (for example, trifluoromethyl, chlorodifluoromethyl, deformity or similar group, or ethyl substituted by fluorine (for example, pentafluoroethyl, 1,1-dottorati or similar group), preferably trifluoromethyl, R2represents methyl or ethyl, preferably methyl, R3is a (C1-C4-alkoxycarbonyl-(C1-C4)-alkyl, (C1-C4-alkoxycarbonyl-(C1-C4)-alkoxy, (C3-C7-cycloalkylcarbonyl-(C1-C4)-alkoxy, (C1-C4-alkoxycarbonyl-(C1-C4)-alkylthio or (C1-C4-alkoxycarbonyl-(C1-C4)-alkylamino, preferably (C1-C2-alkoxycarbonyl-(C 1-C2)-alkoxy, X1represents a halogen, preferably chlorine, and/or X2represents halogen, preferably fluorine.

In some cases, the compounds of the present invention may exist as geometric isomers due to the presence of a double bond, optical isomers and diastereoisomers due to the presence of an asymmetric carbon atom, and these isomers and their mixtures also apply to the compounds of the present invention.

The following is an explanation of the methods of obtaining the compounds of the present invention.

Compounds of the present invention can be obtained, for example, following the methods of obtaining 1-10.

The method of obtaining 1

Compounds of the present invention [I], where R3is a OR7, SR8or N(R9R10you can get through interaction of the compounds of formula [III]

[where R1, R2, Y, Q, X1and X2have the meanings specified above, and W represents oxygen, sulfur, imino or (C1-C3)-alkylamino, such as methylamino, etc.]

with the compound of the formula [IV]

[where R11is carboxy-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C1-C6-halogenosilanes-(C1-C )-alkyl, (C1-C6-alkenylacyl-(C1-C6)-alkyl, (C3-C6-alkyloxyaryl-(C1-C6)-alkyl, phenoxycarbonyl-(C1-C6)-alkyl which may be substituted, phenyl-(C1-C4-alkoxycarbonyl-(C1-C6)-alkyl which may be substituted, (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C1-C6)-alkoxy)((C1-C3)-alkyl)aminocarbonyl-(C1-C6)-alkyl, (C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, (C1-C6)-alkyl) (C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, phenylenecarbonyl-(C1-C6)-alkyl which may be substituted, or phenyl-(C1-C4-alkylaminocarbonyl-(C1-C6), which may be substituted, and R12is useplease group, such as chlorine, bromine, iodine, methanesulfonate, p-toluensulfonate etc.]

in the presence of a base.

This reaction is usually carried out in a solvent, and the reaction temperature generally is in the range from 0 to 200°and the reaction time usually ranges from minutes to 72 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [IV] is 1 mol and the amount of the base is 1 mol 1 mo the R compounds [III], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, quinoline, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-dia-sabillo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, tri-n-Propylamine, triisopropanolamine, tri-n-butylamine, diisopropylethylamine and similar compounds, and inorganic bases such as lithium carbonate, sodium carbonate sodium, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters, such as aciform is at, ethyl acetate, butyl acetate, diethylmalonate and the like, nitro compounds such as nitromethane, nitrobenzene and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization, etc.

The method of obtaining 2

Compounds of the present invention [I], where R3is a OR7you can get through interaction of the compounds of formula [V]

[where R1, R2, Y, Q, X1and X2have the values specified above]

with alcohol of the formula [VI]

[where R7matter above]

in presets is under dehydrating reagent. This reaction is usually carried out in a solvent, and the reaction temperature generally is in the range from -20 to 150°C, preferably from 0 to 100°and the reaction time is usually from minutes to 48 hours.

As the dehydrating reagent can be used, for example, a combination of triarylphosphine, such as triphenylphosphine and the like, and di(lower alkyl)azodicarboxylate, such as diethylazodicarboxylate, diisopropylsalicylic etc.

As for the amounts of reactants that react, the amount of alcohol [VI] is from 1 to 3 mol, preferably from 1 to 1.5 mol, the number of triarylphosphine used as the dehydrating reagent is 1 to 3 mol, preferably from 1 to 1.5 mol, and the amount of di(lower alkyl)azodicarboxylate is from 1 to 3 mol, preferably from 1 to 1.5 mol, per 1 mol of compound [V]. The ratio of these reagents can optionally be changed depending on the reaction conditions.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diatrofi the ether, diisopropyl ether, dioxane, THF, dimethyl ether of ethylene glycol and the like, esters such as ethyl acetate and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated, the residue is subjected to chromatography.

2) the Reaction solution concentrate in the form in which it is, and the residue is subjected to chromatography.

The obtained compound of the present invention in some cases can also be cleaned by an operation such as recrystallization, etc.

The method of obtaining 3

Some of the compounds of the present invention can be obtained by using as the raw material carboxylic acid of the formula [VII]

[where R1, R2, Y, Q, X1X2and W have the meanings stated above, R13is (C1-C6-alkylidene or (C2-C6-alkylene, and m is 0 or 1]

and alcohol of formula [VIII]

[where R14is (C1-C6)-alkyl, (C1-C6-halogenated, (C3-C6)-alkenyl, (C3-C6)-halogenoalkanes, (C3-Csub> 6)-quinil or (C3-C6-halogenoalkanes]

as raw materials.

This reaction is carried out, for example, when interacting carboxylic acid [VII] gloriouse agent to obtain the acid chloride (hereinafter referred to as <3-1>), followed by interaction of the acid chloride with alcohol [VIII] in the presence of a base (hereinafter referred to as <3-2>).

<3-1> is carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from 0 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number glorieuses agent is 1 mol per 1 mol of carboxylic acid [VII], however, the ratio can optionally be changed depending on the reaction conditions.

As glorieuses agent can be used, for example, thionyl chloride, sulfurylchloride, phosgene, oxalicacid, trichloride phosphorus, pentachloride phosphorus oxychloride phosphorus and similar connections.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, Noonan, Dean, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene and the like, aliphatic halo is encodergasm hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2,3-trichloropropane and the like, halogenated aromatic hydrocarbons, such as monochlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, esters such as ethyl acetate and the like, or mixtures thereof.

After completion of the reaction the reaction solution, for example, concentrated, and the concentrated residue is used in this form as it is in <a process 3-2>.

<3-2> is carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from -20 to 100°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of alcohol [VIII] and the base is 1 mol, respectively, per 1 mol of carboxylic acid [VII]used in <a process 3-1>, however, the ratio can optionally be changed depending on the reaction conditions.

As the base used, for example, inorganic bases such as sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate and the like, nitrogen-containing aromatics the e connection such as pyridine, quinoline, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3-chloropyridine, 2-ethyl-C-ethylpyridine, 5-ethyl-2-methylpyridine and the like, and tertiary amines, such as triethylamine, diisopropylethylamine, tri-n-Propylamine, tri-n-butylamine, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, Noonan, Dean, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene and the like, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2,3-trichloropropane and the like, halogenated aromatic hydrocarbons, such as monochlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, esters such as ethyl acetate and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) and 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization, etc.

This reaction can be carried out in the interaction of compound [VII] with the compound [VIII] in the presence of a condensing agent in a solvent in the presence of a base or without. The reaction temperature usually ranges from 0 to 100°and the reaction time usually ranges from minutes to 48 hours.

As the condensing agent used carbonyldiimidazole, dicyclohexylcarbodiimide, the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and similar connections.

As the Foundation of the use of organic bases, such as triethylamine, diisopropylethylamine and similar connections.

As for the amounts of reactants that react, the amount of compound [VIII] is from 1 to 3 mol, the amount of the condensing agent is 1 to 3 mol, and the amount of base is from 0.5 to 3 mol per 1 mol of compound [VII]. The ratio of these is agenthow can, not necessarily to change depending on the reaction conditions.

As the solvent used dichloromethane, amide, such as N,N-dimethylformamide, ethers such as tetrahydrofuran and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, pouring the reaction solution into water, extragere the resulting mixture with an organic solvent and subjecting the organic layer is dried and concentrated. The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization, etc.

In addition, besides the above methods, this reaction can be carried out according to the method in which the reaction is carried out in the presence of an acid catalyst, and in other ways.

The method of obtaining 4

Compounds of the present invention [I], where X1represents cyano, can be obtained by reaction of uracil of the formula [IX]

[where R1, R2and X2have the meanings indicated above and R15represents fluorine, chlorine, bromine or iodine]

with the compound of the formula [X]

[where Y, Q, and R3have the values specified above]

in the presence of a base.

This reaction is usually carried out in missing the e solvent or in a solvent, and the reaction temperature generally is in the range from 0 to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [X] is 1 mol and the amount of the base is 1 mol per 1 mol of uracil [IX], however, the ratio can optionally be changed depending on the reaction conditions.

As the base used, for example, organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane and the like, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as methyl isobutyl ketone and the like, complicated the esters, such as ethyl acetate, butyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, or mixtures thereof.

This reaction can sometimes be accelerated by using a catalyst. As catalyst, use of copper iodide, copper bromide, copper chloride, copper powder and the like, the amount of catalyst used in the reaction is from 0.0001 to 1 mole per 1 mole of the uracil [IX], and this ratio can optionally be changed depending on the reaction conditions.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization, etc.

The method of obtaining 5

The compound of the present invention can be obtained by reaction of uracil compounds of the formula [XI]

[where R1, R2, Y, X1and X2have the values specified above]

with the compound of the formula [XII]

[where R16is useplease group, such as fluorine, chlorine, bromine, iodine, methanesulfonate, p-toluensulfonate and the like, and R3matter above]

in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally ranges from room temperature to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of the compound [XII] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XI], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as N-methylmorpholine, 1,8-diazabicyclo[5.4.0]UN-Dec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, sodium hydroxide, the hydroxide is Aliya and similar connections.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate, butyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, or mixtures thereof.

This reaction can sometimes be accelerated by using a catalyst.

The amount of catalyst used in the reaction, is preferably from 0.0001 to 1 mol per 1 mol of compound [XI], and this ratio can optionally be changed depending on the reaction conditions.

As catalyst, use of copper compounds such as copper iodide, copper bromide, copper chloride, copper powder and the like, and crown ethers such as 12-crown-4, 15-crown-5, 18-crown-6, etc.

After completion of the reaction the alleged connection of the present invention can is about to receive, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization and the like of the operation.

The method of obtaining 6

The compound of the present invention can be obtained by reaction of uracil of the formula [XXXI]

[where R1, R3, Y, Q, X1and X2have the values specified above ]

with the compound of the formula [XXXX]

[where R2and R12have the values specified above]

in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from -20 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of connections [XXXX] is 1 mol and the amount of the base is 1 mol per 1 mol of uracil [XXXI], however, the ratio can be, but is obazatelno, to change depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, quinoline, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-dia-sabillo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, tri-n-Propylamine, triisopropanolamine, tri-n-butylamine, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium, tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, word is these esters, such as ethyl acetate, butyl acetate and the like, nitro compounds such as nitromethane, nitrobenzene and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, alcohols such as methanol, ethanol, ethylene glycol, isopropanol, tert-butanol and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1), 2) or 3).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2), the Reaction mixture was poured into water and the precipitated precipitate is collected by filtration.

3) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization and the like of the operation.

The method of obtaining 7

Compounds of the present invention [I], where Q is pyrazolidine group, can be obtained by the method shown in the following diagram.

[This is the schema R 1, R2, R11, R12X1and X2have the meanings stated above, R20represents lower alkyl, such as methyl, ethyl and the like, R21represents hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-quinil, R22is (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-quinil, and Y1represents oxygen, sulfur or alkylamino].

<stage a>: the method of producing compound [XXXIII] from the compound [XXXII].

The compound [XXXIII] can be obtained by reaction of compound [XXXII] with the compound [XXXXII] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from 0 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of connections [XXXXII] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXII], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, three is tillin, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, petroleum ether and the like, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as dietology ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, alcohols such as methanol, ethanol, tert-butanol and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer dried the focus.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization and the like of the operation.

<stage b>: the method of obtaining the compound [XXXIV] from compound [XXXIII].

The compound [XXXIV] can be obtained by reaction of compound [XXXIII] agent formirovaniya in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature usually ranges from 0 to 100°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of agent formirovaniya is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXIII], however, the ratio can, but not necessarily, be changed depending on the reaction conditions.

As the base used alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, and inorganic bases such as sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate, butyl acetate and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization, etc.

<stage C (R21is not hydrogen)>: the method of obtaining the compound [XXXIV] from the compound [XXXII].

The compound [XXXIV] can be obtained by reaction of compound [XXXII] with the compound [XXXXIII] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from 0 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of connections [XXXXIII] the leaves 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXII], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, quinoline, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dime-calaminarian, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, alkoxides of metals such as tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, petroleum ether and the like, aromatic hydrocarbons such as toluene, xylene and the like, aromatic galogensoderjashimi hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate, butyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, or mixtures thereof.

After the eakly the alleged connection of the present invention can be obtained, for example, using the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization, etc.

<stage d>: the method of producing compound [XXXV] from the compound [XXXIV].

The compound [XXXIV] can be obtained, for example, by reaction of the compound [XXXIV] with hydrazine in the presence of a base.

The reaction temperature is in the range from 0 to 200°C, preferably from room temperature to the boiling temperature, and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of hydrazine is 1 mol per 1 mol of compound [XXXIV], however, the ratio can optionally be changed depending on the reaction conditions.

As the use of hydrazine monohydrate, hydrazine, methylcarbonate etc.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, petroleum ether and the like, aromatic shall Uglevodorody, such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, alcohols such as methanol, ethanol, and similar compounds.

The reaction solution after completion of the reaction may be poured into the water and collect the precipitated precipitated crystals by filtration, or be subjected to normal for the final stage of processing, such as extraction with an organic solvent, neutralization, concentration and the like, and to obtain the expected compound.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization, and similar operations.

<stage e>: the method of producing compound [XXXVI] from compound [XXXV].

The compound [XXXVI] can be obtained by reaction of compound [XXXV] A) with the compound [IV] in the presence of base or with alcohol [VI] in the presence of a dehydrating reagent.

A) This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from 0 to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [IV] is 1 mol and the amount of the base is 1 mol 1 mol connection is in [XXXV], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate, butyl acetate, etc., nitro compounds such as nitromethane, nitrobenzene and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, alcohols such as methanol, ethanol, ethylene glycol, isopropanol, tert-butanol and the like, or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, pouring the reaction solution into water, extragere the resulting mixture with an organic solvent, and subjecting the organic layer is dried and concentrated.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization and the like of the operation.

C) the Reaction is typically carried out in a solvent, and the reaction temperature typically lies in the range from -20 to 150°C, preferably from 0 to 100°and the reaction time usually ranges from minutes to 48 hours.

As the dehydrating reagent is used, for example, combinations of triarylphosphine, such as triphenylphosphine and the like, di(lower alkyl)azodicarboxylate, such as diethylazodicarboxylate, diisopropylsalicylic etc.

As for the amounts of reactants that react, the amount of alcohol [VI] is from 1 to 3 mol, preferably from 1 to 1.5 mol, the number of triarylphosphine used as the dehydrating reagent is 1 to 3 mol, preferably from 1 to 1.5 mol, and the amount of di(lower alkyl)is dodecaborate is from 1 to 3 mol, preferably from 1 to 1.5 mol per 1 mol of compound [XXXV]. The ratio of these reagents can optionally be changed depending on the reaction conditions.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, diisopropyl ether, dioxane, THF, dimethyl ether of ethylene glycol, diglyme and the like, esters such as ethyl acetate and the like, or mixtures thereof.

After completion of the reaction to obtain the expected compound can, subjecting the reaction solution normal for the final stage of processing, such as addition of water and subsequent extraction with an organic solvent, con-centering, etc.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization and the like operation.

<stage f>: the method of producing compound [XXXVII] from compound [XXXVI].

The compound [XXXVII] can be obtained by reaction of compound [XXXVI] with the compound of the formula [XXXXIV]

[where R12and R22have the values specified above]

in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, the reaction temperature is in the range from 0 to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the number of connections [XXXXIV] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXVI], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

As the solvent used, for example, aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride etc., ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, alcohols such as methanol, ethanol, ethylene glycol, tert-butanol and the like, or mixtures thereof.

After completion of the reaction the expected compound can be obtained by pouring the reaction solution into water and collecting the precipitated precipitated crystals by filtration or pouring the reaction solution into water and then subjecting the resulting mixture normal processing at the final stage, such as extraction with an organic solvent, concentration, etc.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization and the like of the operation.

The way to obtain 8

The compound of the present invention can be obtained according to the method shown in the following diagram.

[In this scheme, R1, R2, R11, W, Y, Q, X1and X2have the meanings specified above, and-is contrarian iodine, deason what I such as Cl-BF4-, CF3SO3-etc.].

<stage 8-1>: the method of producing compound [XXXXVI] from the compound [XXIII].

Connection [XXXXVI] can be obtained, for example, by reaction of the compound [XXIII] with a diazotization agent and an acid in a solvent.

The reaction temperature is from -30 to 30°and the reaction time usually ranges from minutes to 10 hours.

As for the amounts of reactants that react, the amount of the diazotization agent is from 1 to 3 mol, and the amount of acid is from 1 to 6 mol per 1 mol of compound [XXIII]however, the ratio can optionally be changed depending on the reaction conditions.

The diazotization agent: nitrites such as sodium nitrite, isoamylase, tert-butylnitrite etc.

Acid: inorganic acid, such as tetrafluoroborate acid, chloromethane acid, etc. and organic acids such as triftormetilfullerenov acid and the like, a Lewis acid such as diethylether of boron TRIFLUORIDE, etc.

Solvent: aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, 1,2,3-trichloropropane and the like, ethers such as diethyl ether, dioxane, THF, dimethyl ether of ethylene glycol and the like, hydrochloric acid, aqueous Hydrobromic acid is, an aqueous solution of sulfuric acid, etc. or mixtures thereof.

After completion of the reaction, the reaction solution used in the subsequent reaction in the form in which it is, or to the reaction solution was added a non-polar organic solvent, such as n-pentane, n-hexane, etc. and collect the precipitation, for example, by filtering.

<stage 8-2>: the method of producing compound [XIV] from compound [XXXXVI].

The compound [XIV] can be obtained, for example, by reaction of diazonium salt compounds [XXXXVI] with the compound [XIII] in a solvent.

The reaction temperature is from 0 to 120°and the reaction time usually ranges from minutes to 20 hours.

As for the amounts of reactants that react, the amount of compound [XIII] is from 1 to 10 mol per 1 mol of compound [XXXXVI], however, the ratio can optionally be changed depending on the reaction conditions.

Solvent: aromatic hydrocarbons, such as toluene and the like, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like, ethers such as diethyl ether, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following is piracy 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

In addition, the compound of the present invention can also be cleaned by such procedures as chromatography, recrystallization, etc.

The method of obtaining 9

Compounds of the present invention [I], where X1is a nitro (compound [XVI]) or halogen (compound [XVIII]), can be obtained by the method shown in the following diagram.

[In this scheme, R1, R2, R3, R15, Q, Y and X2have the meanings stated above, R25represents fluorine, chlorine, bromine or iodine].

<Process 9-1>. The compound [XVI] can be obtained, for example, by reaction of the compound [XV] with the compound [X] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature is 0 to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [X] is 1 mol and the amount of the warping is 1 mole per 1 mole of the uracil [XV], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, quinoline, benzyldimethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-dia-sabillo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, tri-n-Propylamine, triisopropanolamine, tri-n-butylamine, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium, tert-piperonyl potassium and the like, and inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like compounds.

Examples of the used solvents are aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin, cyclohexane, petroleum ether and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aromatic halogenated hydrocarbons such as chlorobenzene, benzotrifluoride and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like; ketones, such as acetone, 2-butanone, Elizabethton etc.; esters, such as ethyl acetate, butyl acetate and the like; NITRILES, such as acetonitrile, isobutyronitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone and the like; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like; alcohols such as methanol, ethanol, ethylene glycol, isopropanol, tert-butanol and the like; or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, using the following operations 1), 2) or 3).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was poured into water and the precipitated precipitate is collected by filtration.

3) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

In addition, the compound of the present invention can also be cleaned by such procedures as chromatography, recrystallization, etc.

<Process 9-2>. The compound [XVII] can be obtained, for example, by reduction of the compound [XVI] in a solvent And using iron powder and the presence of acid and b) with hydrogen in the presence of a catalyst.

A) This reaction is usually carried out in a dissolve is barely, the reaction temperature usually ranges from 0 to 150°C, preferably from room temperature to the boiling point. The reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants used in the reaction, the amount of iron powder is from 3 mol to excess, and the amount of acid is from 1 to 10 mol per 1 mol of compound [XVI], however, the ratio can, but not necessarily, be changed depending on the reaction conditions.

As acid using acetic acid and the like acid.

As the solvent used, for example, water, acetic acid, ethyl acetate, etc. or mixtures thereof.

After completion of the reaction alleged substance can be obtained using the normal operations of the last stages, such as filtering, followed by pouring the reaction solution into water and collecting the precipitated precipitated crystals by filtration or extraction with an organic solvent, neutralizing the extract, drying, concentration, etc.

B) This reaction is usually carried out in a solvent, the reaction temperature usually ranges from -20 to 150°C, preferably from 0 to 50°C. the reaction Time usually ranges from minutes to 48 hours.

This reaction can also be carried out under pressure, and the reaction is carried out, as a rule, when Yes is of from 1 to 5 ATM.

The amount of catalyst used in this reaction is from 0.001 to 10 wt.% relative to the compound [XVI].

As catalyst in the reaction using anhydrous palladium on coal, water-containing palladium on charcoal, platinum oxide, etc.

To solvents include carboxylic acids such as formic acid, acetic acid, propionic acid and the like, esters such as ethyl formate, ethyl acetate, butyl acetate and the like, ethers such as 1,4-dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, alcohols such as methanol, ethanol and the like, or mixtures thereof.

After completion of the reaction alleged substance can be obtained using the normal operations of the last stages, such as filtering the reaction solution is concentrated before the solution, etc.

Estimated substance can also be cleaned using this procedure as chromatography, recrystallization, etc.

<Process 9-3>. The compound [XVIII] can be obtained from compound [XVII], for example,

(A) through (i) the diazotization of the compound [XVII] in solvent ii) subsequent interaction with halogenation agent in the solvent;

C) by reaction of compound [XVII] with a diazotization agent in a solvent in the presence of a halogenation agent (see Heterocycles, 38, 1581 (1994), and so on).

(A) (i) Peracchi the diazotization in the first stage, the reaction temperature, usually ranges from -20 to 10°and the reaction time usually ranges from minutes to 5 hours.

As for the amounts of reactants involved in the reaction, then theoretically the number of diazotization agent is 1 mol per 1 mol of compound [XVII]however, the ratio can optionally be changed depending on the reaction conditions.

As the diazotization agent is used nitrites such as sodium nitrite, potassium nitrite, isoamylase, tert-butylnitrite etc.

As the solvent used, for example, acetonitrile, Hydrobromic acid, chloroethanol acid, sulfuric acid, water, etc. or mixtures thereof.

The reaction solution after completion of the reaction used in the subsequent reaction as it was.

ii) the reaction of the second stage, the reaction temperature usually ranges from 0 to 80°and the reaction time usually ranges from minutes to 48 hours.

With regard to the amount of the reagents used in this reaction, the amount of halogenation agent is from 1 to 3 mol per 1 mol of compound [XVII], and the number can be changed optionally depending on the reaction conditions.

As the halogenation agent, you can use potassium iodide, copper bromide(I) (or compound with copper bromide (II), copper chloride(I) (or a mixture of chloride of copper(II)or a mixture of hydrogen fluoride is Oh acid and boric acid (hereinafter referred to portorotondo acid), etc.

As the solvent used, for example, acetonitrile, diethyl ether, Hydrobromic acid, chloroethanol acid, sulfuric acid, water, etc. or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, by the following processing: the reaction solution was poured into water and, if necessary, an acid such as hydrochloric acid, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated (see Org. Syn. Coll., Vol. 2, 604 (1943), Vol. 1, 136 (1932)).

C) the Temperature of this reaction usually ranges from -20 to 50°C, preferably from -10°C to room temperature, and the reaction time usually ranges from minutes to 48 hours.

As for the amounts of reactants involved in the reaction, the amount of halogenation agent is from 1 to 3 mol, the number of diazotization agent is from 1 to 3 mol, respectively, per 1 mol of compound [XVII]however, the ratio can be changed optionally depending on the reaction conditions.

As the halogenation agent used, for example, iodine, copper bromide(I) (or compound with copper bromide(II), copper chloride(I) (or a mixture of chloride of copper(II)) or portorotondo acid, etc.

As the diazotization agent is used nitrites, such as isoamylase, tert-butylnitrite etc.

As the solvent used, for example, acetonitrile, benzene, toluene, etc. or mixtures thereof.

After completion of the reaction the alleged connection of the present invention can be obtained, for example, by the following processing: the reaction solution was poured into water, and add, if necessary, an acid such as hydrochloric acid, then the mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

In addition, the compound of the present invention can also be cleaned using this procedure as chromatography, recrystallization, etc.

The method of obtaining 10

Compounds of the present invention [I], where X1represents cyano (connection [10-3]), can be obtained by the method shown in the following diagram.

where R1, R2, R3, Q, X2and Y have the meanings indicated above, X10is bromine or iodine and M1represents a metal, such as copper, potassium, sodium, etc.

Connection [10-3] can be obtained by reaction of compound [10-1] with the compound [10-2].

This reaction is usually carried out in a solvent. The reaction temperature generally is in the range from 130 to 250°C, preferably from 150°to the fact the temperature of boiling and the reaction time usually ranges from minutes to 24 hours.

Connection [10-2]used in the reaction is the copper cyanide, potassium cyanide, sodium cyanide, etc.

The number of connections [10-2] is from 1 mol to excess, preferably from 1 to 3 mol per 1 mol of compound [10-1], however, the ratio can optionally be changed depending on the reaction conditions.

Examples of the used solvent are ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and the like; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like; or mixtures thereof.

After completion of the reaction, the target compound can be obtained, for example, carrying out the usual last processing stage, subjecting the mixture to one of the following procedures.

1), the Reaction mixture was filtered and concentrated.

2), the Reaction mixture was poured into water, extracted with an organic solvent, the extract washed with water, dried and concentrated.

In addition, the target compound can also be cleaned by such procedures as chromatography, recrystallization, etc.

The compound [IV], alcohol [VI], alcohol [VIII], compound [X], the compound [XII], the compound [XV], connection [XXXX], connection [XXXXII], connection [XXXXIII], connection [XXXXIV], used in the methods of producing compounds of the present invention, are available commercially or can be obtained by known methods.

For example, the compound [IX] it is known from DE4412079 A.

Carboxylic acid [VII] can be obtained by acidolysis compounds of the present invention [I], where the center is an ester group.

The compound [XI] is known, for example, JP-A No. 63-41466, 61-40261 and WO 98/47904 or it can be obtained by the methods described in these publications.

Some of the intermediate compounds used in the methods of manufacturing the present invention can be obtained, for example, by the following methods: method 1 to obtain an intermediate compound to method 12 receiving the intermediate connection.

(Method 1) receiving the intermediate connections)

The compound [XII], where R3is a OR7, SR8or N(R9R10you can get way shown in the following diagram.

[where R26is useplease group, such as fluorine, chlorine, bromine, iodine, methanesulfonate, p-toluensulfonate and the like, and R11, R16, Q and W have the values listed above].

Connection [X1-2] you can get the e l e C for example, by reaction of compound [X1-1] with the compound [XIII] in a solvent in the presence of a base.

Conditions for this reaction are, for example, the following:

the reaction temperature is from 0 to 180°C

the response time from minutes to 24 hours,

the amount of compound [XIII] from 1 mol to 1.5 mol per 1 mol of compound [X1-1],

the amount of base is from 1 mol to 1.5 mol per 1 mol of compound [X1-1],

however, the ratio of reactants can, optionally,

to change depending on the reaction conditions,

the base is triethylamine, diisopropylethylamine, potassium carbonate, sodium hydride and the like,

the solvent is dioxane, tetrahydrofuran, N,N-dimethylformamide, 1-methyl-2-pyrrolidinone etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, etc.

(Method 2 produce an intermediate connections)

The compound [III], where W represents NH (compound [XXIII]), can be obtained by the method shown in the following diagram.

[where R1, R2, R16, Y, Q, X1 and X 2have the values specified above].

<Process A2-1>: the method of producing compound [XXII] from the compound [XI].

The compound [XXII] can be obtained by reaction of compound [XI] with the compound [XXI] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature is in the range from 0 to 200°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [XI] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XI], however, the ratio can optionally be changed depending on the reaction conditions.

Base: triethylamine, diisopropylethylamine, potassium carbonate, sodium hydride, sodium hydroxide, etc.

Solvent: toluene, dioxane, tetrahydrofuran, N,N-dimethylformamide, 1-methyl-2-pyrrolidinone, dimethylsulfoxide, sulfolane, etc. or mixtures thereof.

This reaction can sometimes be accelerated by adding a catalyst.

The preferred amount of catalyst used in the reaction, from 0.0001 to 0.1 mol per 1 mol of compound [XI], and this ratio can optionally be changed depending on the reaction conditions.

As catalyst, use copper compounds, such as the iodide of copper, the copper bromide, copper chloride, copper powder and the like, and crown ethers such as 15-crown-5, 18-crown-6, etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, recrystallization, etc.

<Process A2-2>: the method of obtaining the compound [XXIII] from the compound [XXII].

The compound [XXIII] can be obtained, for example, by reduction of the compound [XXII] solvent A) using iron powder in the presence of acid and b) with hydrogen in the presence of a catalyst.

A) the reaction Temperature usually ranges from 0 to 150°C, preferably from room temperature to the boiling temperature, and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants used in the reaction, the amount of iron powder is from 3 mol to excess, and the amount of acid is from 1 mol to 10 mol per 1 mol of compound [XXII], however, the ratio can optionally be changed depending on the reaction conditions.

As acid using acetic acid and the like acid.

As the solvent used, for example, water, acetic acid, ethyl acetate, etc. or mixtures thereof.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering, followed by pouring the reaction solution into water and collecting the precipitated precipitated crystals by filtration, or by extraction of the solution with an organic solvent, neutralization, drying and concentrating the organic layer, etc.

C) the reaction Temperature usually ranges from -20 to 150°C, preferably from 0 to 50°C. the reaction Time usually ranges from minutes to 48 hours.

This hydrogenation reaction can also be carried out under pressure, and hold it, usually at a pressure of from 1 to 5 ATM.

The amount of catalyst used in this reaction is from 0.01 to 10 wt.% relative to the compound [XXII].

As catalyst in this reaction using palladium-on-charcoal, platinum oxide, etc.

The solvent is acetic acid, ethyl acetate, methanol, ethanol, etc. or mixtures thereof.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering the reaction solution before concentrating the solution, and so on

Estimated soybean is inania can also be cleaned by such operation, as chromatography, recrystallization, etc.

(Method 3 obtain intermediate connections)

The compound [III], where W represents oxygen (compound [V]), can be obtained by the method shown in the following diagram.

[where R1, R2, Y, Q, X1and X2have the values specified above].

The compound [V] can be obtained by (i) interaction of the compound [XXIII] with a diazotization agent in a solvent in the presence or in the absence of acid, followed ii) heating the reaction product in an acid solvent or salt of copper in the reaction product in the presence or in the absence of a copper catalyst.

1) by the reaction in the first stage, the reaction temperature is in the range from -20 to 10°and the reaction time usually ranges from minutes to 5 hours.

As for the amounts of reactants that react, then theoretically the number of diazotization agent is 1 mol and the amount of acid is 1 mol per 1 mol of compound [XXIII]however, the ratio can optionally be changed depending on the reaction conditions.

As the diazotization agent using a nitrite such as sodium nitrite, potassium nitrite, isoamylase, tert-butylnitrite etc.

As the acid used, for example, tetracarbon the second acid, chloroethanol acid, triftormetilfullerenov acid, a Lewis acid, such as diethylether of boron TRIFLUORIDE, etc.

As the solvent used, for example, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2,3-trichloropropane and the like, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, diglyme and the like, acetonitrile, hydrochloric acid, aqueous Hydrobromic acid, aqueous solution of sulfuric acid, etc. or mixtures thereof.

The reaction solution after completion of the reaction used in the subsequent reaction, for example, in the form in which it exists.

ii) by the reaction in the second stage, which is heated in an acid solvent, the reaction temperature is in the range from 60°C to the boiling temperature, and the reaction time usually ranges from minutes to 24 hours.

As the acid solvent used, for example, an aqueous solution of hydrochloric acid, aqueous Hydrobromic acid, aqueous solution of sulfuric acid, etc.

After completion of the reaction alleged substance can be obtained, for example, subjecting the reaction solution usual for the last stages of processing, such as filtering the reaction solution is, extraction with an organic solvent, drying and concentrating the organic layer, and the like (see Org. Syn. Coll., Vol.2, 604 (1943), Vol.1, 136 (1932)).

The reaction in the second stage, in which the salt of copper acts as a catalyst in the presence or in the absence of acid, carried out in a solvent, the reaction temperature is in the range from 0°C to the boiling temperature, and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, the amount of the copper catalyst is from 0.001 to 5 mol and the amount of copper salt is from 1 to 100 mol per 1 mol of compound [XXIII]however, the ratio can optionally be changed depending on the reaction conditions.

As the copper catalyst is used, the copper oxide(I), etc. and as a salt of copper sulfate is used copper(II)nitrate copper(II), etc.

As the solvent used, for example, water, an aqueous solution of hydrochloric acid, an aqueous solution of sulfuric acid, acetic acid, etc. or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, subjecting the reaction solution usual for the last stages of processing, such as filtering the reaction solution, neutralization, extraction with an organic solvent, drying, concentration, etc.

The alleged connection t is also clear by this operation, as chromatography, recrystallization, etc.

(Method 4 getting intermediate connections)

The compound [X], where R3is a OR7or SR8(compound [XXVI]), can be obtained by the method shown in the following diagram.

[where R11, R12, Y and Q have the meanings indicated above and R17represents oxygen or sulfur].

The compound [XXVI] can be obtained by reaction of compound [XXV] with the compound [IV] in the presence of a base.

This reaction is usually carried out in a solvent, and the reaction temperature is in the range from 0 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of the base is 1 mol and the amount of acid is 1 mol per 1 mol of compound [XXV]however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, etc.

As the solvent used, for example the EP, aromatic hydrocarbons, such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate and the like, NITRILES such as acetonitrile and the like, amides such as N,N-dimethylformamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as dimethylsulfoxide and the like, alcohols, such as methanol, ethanol and the like, or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be cleaned by an operation such as chromatography, recrystallization, etc.

(Method 5 obtain intermediate connections)

The compound [X], where R3is a OR7or SR8or N(R9R10and Y represents oxygen or sulfur (compound [XXX]), can the get method, shown in the following diagram.

[where R11, R12, R17, W and Q have the meanings indicated above and R19represents a protective group such as tert-butyldimethylsilyl, tert-butyl, benzyl, methyl or similar group].

<Process A5-1>: the method of producing compound [XXVIII] from compound [XXVII].

The compound [XXVIII] can be obtained by reaction of compound [XXVII] with tert-butyldimethylsilyloxy, Isobutanol, benzylchloride, benzylbromide or the like (see "Yuki Called Jikken no Tebiki", vol.4 (published by Called Dojin), Protective Groups in Organic Synthesis (published by JOHN WILEY & SONS, INC.)).

<Process A5-2>: the method of obtaining the compound [XXIX] from compound [XXVIII].

The compound [XXIX] can be obtained by reaction of compound [XXVIII] with the compound [IV] in the presence of a base.

This reaction is usually carried out in a solvent, and the reaction temperature generally is in the range from 0 to 150°and the reaction time usually ranges from minutes to 24 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [IV] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXVIII], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organically the base, such as pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, etc.

As the solvent used, for example, aromatic hydrocarbons such as toluene, xylene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene, benzotrifluoride and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, ketones such as acetone and the like, esters such as ethyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide, N-methyl-2-pyrrolidone and the like, sulfur-containing compounds such as the sulfoxide and the like, alcohols such as methanol, ethanol and the like, or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The alleged connection can also be clear on what redstem such operation, as chromatography, recrystallization, etc.

<Process A5-3>: the method of producing compound [XXX] from the compound [XXIX].

The compound [XXX] can be obtained by removal of the protective group from the compound [XXIX]for example, according to the method described in "Yuki Called Jikken no Tebiki", vol.4 (published by Called Dojin), Protective Groups in Organic Synthesis (published by JOHN WILEY & SONS, INC.).

(Method 6 obtain intermediate connections)

The compound [III], where W represents oxygen (compound [V]), can be obtained by the method shown in the following diagram.

[where R1, R2, A-, Y, Q, X1and X2have the meanings indicated above and R24represents alkyl, such as methyl, or halogenated, such as trifluoromethyl, etc].

<stage A6-1>: the method of producing compound [XXXXVIII] from compound [XXXXVI].

Connection [XXXXVIII] can be obtained, for example, by reaction of diazonium salt compounds [XXXXVI] with the compound [XXXXVII].

This reaction is usually carried out in the absence of solvent or in a solvent, the reaction temperature is from room temperature to 120°C, preferably from 50 to 90°and the reaction time ranges from minutes to 5 hours.

As for the amounts of reactants that react, the amount of compound [XXXXVII] is from 1 mol to excess the and 1 mol of compound [XXXXVI], however, the ratio can optionally be changed depending on the reaction conditions.

As the solvent used acetic acid, etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was concentrated in as it is, the residue diluted with water, the resulting mixture is extracted with an organic solvent and the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, recrystallization, etc.

<stage A6-2>: the method of obtaining the compound [V] from the compound [XXXXVIII].

The compound [V] can be obtained, for example, by introducing into the reaction of the compound [XXXXVIII] in a solvent in the presence of a base.

The reaction temperature usually ranges from 0 to 100°C, preferably from room temperature to 60°and the reaction time usually ranges from 0.5 to 20 hours.

As for the amounts of reactants that react, the amount of base is from 0.1 mol to 10 mol per 1 mol of compound [XXXXVIII], however, the ratio can optionally be changed depending on the reaction conditions.

As the base used inorganic bases such as sodium carbonate, the carbonate to the lia, sodium bicarbonate, etc.

As the solvent used, for example, methanol, ethanol, water and the like or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was concentrated in as it is, the residue diluted with water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, recrystallization, etc.

(Method 7 obtain intermediate connections)

The compound [XXXI] can be obtained by the method shown in the following diagram.

[where R1, R3, R15, Y, Q, X1and X2have the meanings stated above, R18represents lower alkyl, such as methyl, ethyl and the like, and R27is (C1-C6)-alkyl, such as methyl, ethyl and the like, or phenyl which may be substituted, i.e., phenyl and the like].

<Process A7-1>: the method of producing compound [XXXXXI] from compound [XXXXX].

Connection [XXXXXI] can be obtained, for example, by reaction of compound [XXXXX] with the compound [X] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, the reaction temperature, as a rule, is in the range from 0 to 150°and the reaction time usually ranges from minutes to 48 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [X] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXXX], however, the ratio can optionally be changed depending on the reaction conditions.

As the Foundation of the use of organic bases, such as pyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and the like, and inorganic bases such as potassium carbonate, sodium bicarbonate, sodium hydride, lithium hydroxide, sodium hydroxide, etc.

As the solvent used, for example, aromatic hydrocarbons such as toluene, xylene and the like, ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, ketones such as acetone, 2-butanone, methyl isobutyl ketone and the like, esters such as ethyl acetate and the like, NITRILES such as acetonitrile, isobutyronitrile and the like, amides such as N,N-dimethylformamide and the like, sulfur-containing compounds such as dimethylsulfoxide and the like, alcohols such as methanol, ethanol and the like, or mixtures thereof.

After completion of the reaction predpolagaemoe connection you can get, for example, the following operations 1) or 2).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent and the organic layer is dried and concentrated.

2) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

The obtained compound of the present invention can also be cleaned by an operation such as chromatography, recrystallization, etc.

<Process A7-2>: the method of producing compound [XXXXXIII] from compound [XXXXXI].

Connection [XXXXXIII] can be obtained by sozialarbeit connection [XXXXXI] in a solvent or in the absence of solvent.

Agent sozialarbeit: phosgene, trichloromethylcarbonate, triphosgene, oxalicacid etc.

The number of agent sozialarbeit: from 1 mol to excess, preferably from 1.0 to 3 mol, per 1 mol of compound [XXXXXI].

Solvent: aromatic hydrocarbons, such as benzene, toluene and the like, halogenated aromatic hydrocarbons, such as chlorobenzene and the like, esters such as ethyl acetate, etc.

The reaction temperature from room temperature to the boiling point.

The response time from minutes to 48 hours.

This reaction can sometimes be accelerated by adding a catalyst.

The amount of catalyst IP is althemore when this reaction, costs from 0.001 to 300 wt.% regarding the connection [XXXXXI], and its amount can optionally be changed depending on the reaction conditions.

As the catalyst used charcoal (activated), amines such as triethylamine, etc.

After completion of the reaction alleged substance can be obtained by concentrating the reaction solution, and the like, This connection can also be cleaned by an operation such as recrystallization, etc.

<Process A7-3>: the method of producing compound [XXXXXII] from compound [XXXXXI].

Connection [XXXXXII] can be obtained by reaction of compound [XXXXXI] with the compound of the formula [A7-1]

[where R27matter above and X12represents fluorine, chlorine, bromine or iodine] in the presence of a base. This reaction is carried out usually in a solvent and also it can be done in the absence of solvent. The reaction temperature usually ranges from -20 to 200°C. the reaction Time usually ranges from minutes to 48 hours.

The number of connections [A7-1]used in the reaction is from 0.5 mol to excess, preferably from 1.0 to 1.2 mol per 1 mol of compound [XXXXXI].

The base is an inorganic base, such as sodium carbonate, sodium hydroxide and the like, organic about the article, such as pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine etc.

Solvents are halogenated aliphatic hydrocarbons, such as chloroform and the like, ethers such as tetrahydrofuran, 1,4-dioxane and the like, NITRILES such as acetonitrile and the like, esters such as ethyl acetate and the like, water or their mixtures, etc.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering the reaction solution before concentrating the solution, or pouring the reaction solution into water and collecting the resulting crystals by filtration, or pouring the reaction solution into water followed by extraction with an organic solvent, drying, concentration, etc. This connection can also be cleaned by an operation such as recrystallization, chromatography and so on

<Process A7-4>: the method of producing compound [XXXI] from compound [XXXXXIII].

The compound [XXXI] can be obtained by reaction of compound [XXXXXIII] with the compound [XXXXXIV] in a solvent in the presence of a base.

The number of connections [XXXXXIV]: from 0.5 mol to excess, preferably from 0.8 to 1.2 mol, per 1 mol of compound [XXXXXIII].

Base: inorganic bases, such the AK sodium hydride and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium, etc.

A number of reasons: from 0.5 mol to excess, preferably from 0.8 to 1.2 mol, per 1 mol of compound [XXXXXIII].

Solvent: aromatic hydrocarbons, such as benzene, toluene and the like; halogenated aromatic hydrocarbons such as chlorobenzene and the like; amides such as N,N-dimethylformamide and the like; ethers such as tetrahydrofuran and the like; halogenated aliphatic hydrocarbons such as chloroform and the like; sulfur-containing compounds such as dimethylsulfoxide and the like, and mixtures thereof.

The reaction temperature: -40°C to the boiling point of the solvent.

The response time from minutes to 72 hours.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering the reaction solution before concentrating the solution, or adding an acid to the reaction solution, and collecting the resulting crystals by filtration, or adding an acid to the reaction solution followed by extraction of the mixture with an organic solvent, concentration, etc. as the added acid can be used chloroethanol acid, acetic acid, triperoxonane acid, p-toluensulfonate acid or their aqueous solutions, etc. This is the connection also can be cleared by this operation, as recrystallization, chromatography and so on

The obtained compound [XXXI], without performing the above processing in the last stages, you can also enter into interaction with the compound [XXXX] according to the method described in production method of 6, and to obtain the compound of the present invention.

<Process A7-5>: the method of producing compound [XXXI] from compound [XXXXXII].

The compound [XXXI] can be obtained by reaction of compound [XXXXXII] with the compound [XXXXXIV] in the presence of a base.

This reaction is carried out usually in a solvent, and the reaction temperature usually ranges from -20 to 200°C, preferably from 0 to 130°C. the reaction Time usually ranges from minutes to 72 hours.

The number of connections [XXXXXIV]used in the reaction is from 0.5 mol to excess, preferably from 0.8 to 1.2 mol, per 1 mol of compound [XXXXXII].

The amount of base used in the reaction is from 0.5 mol to excess, preferably from 0.8 to 1.2 mol, per 1 mol of compound [XXXXXII].

The base are organic bases such as 4-dimethylaminopyridine, diisopropylethylamine and the like, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like, alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, etc.

RA is the founders are ketones, such as acetone, methyl isobutyl ketone and the like; aliphatic hydrocarbons such as hexane, heptane, petroleum ether and the like; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, mesitylene and the like; ethers such as diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol, methyl tert-butyl ether and the like; acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; tertiary amines such as pyridine, N,N-dimethylaniline N,N-diethylaniline, triethylamine, diisopropylethylamine and the like; sulfur-containing compounds such as dimethylsulfoxide, sulfolane and the like, or mixtures thereof.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering the reaction solution is concentrated before the solution, or adding an acid to the reaction solution, and collecting the resulting crystals by filtration, or adding an acid to the reaction solution followed by extraction of the mixture with an organic solvent, concentration, etc. as the added acid can be used chloroethanol acid, acetic acid, triperoxonane acid, p-toluensulfonate acid or their aqueous solutions, etc. This connection can also be cleaned by the aka the operation, as recrystallization, chromatography and so on

The obtained compound [XXXI], without performing the above processing in the last stages, you can also enter into interaction with the compound [XXXX] according to the method described in production method of 6, and to obtain the compound of the present invention.

(Method 8 obtain intermediate connections)

The compound [X], where Y is oxygen, Q is a pyridine ring and R3is a OR7, SR8or N(R9R10(compound [XXXXX]), can be obtained by the method shown in the following diagram.

[where R11, R12, R24, Z1, Z2W and-have the values specified above].

<A8 stage-1>. Connection [XXXXXVI] can be obtained, for example, by reaction of compound [XXXXXV] with the compound [XIII] in the presence of a base.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature is 0 to 200°and the reaction time usually ranges from minutes to 48 hours.

As for the amounts of reactants that react, then theoretically the amount of compound [XIII] is 1 mol and the amount of the base is 1 mol per 1 mol of compound [XXXXXV], however, the ratio can, neoba the consequently, to change depending on the reaction conditions.

Used refers to organic bases such as pyridine, quinoline, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, triethylamine, diisopropylethylamine and the like, and inorganic bases such as lithium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, etc.

Examples of the used solvents are aromatic hydrocarbons, such as toluene, xylene and the like; aromatic halogenated hydrocarbons such as benzotrifluoride and the like; ethers such as tetrahydrofuran, dimethyl ether of ethylene glycol and the like; ketones, such as acetone, 2-butanone, methyl isobutyl ketone and the like; esters such as ethyl acetate, butyl acetate and the like; NITRILES, such as acetonitrile, isobutyronitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone and the like; sulfur-containing compounds such as dimethyl sulfoxide, sulfolane and the like, or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, the following operations 1), 2) or 3).

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2) the Reaction p is the target poured into water and the precipitated precipitate is collected by filtration.

3) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

In addition, the compound of the present invention can also be cleaned by such procedures as chromatography, recrystallization, etc.

<A8 stage-2>. Connection [XXXXXVII] can be obtained, for example, through reconnection [XXXXXVI] solvent A) using iron powder in the presence of acid and b) with hydrogen in the presence of a catalyst.

This reaction is usually carried out in a solvent, and the reaction temperature usually ranges from 0 to 100°C, preferably from room temperature to the boiling point. The reaction time usually ranges from minutes to 48 hours.

As for the amounts of reactants used in the reaction, the amount of iron powder is from 3 mol to excess, and the amount of acid is from 1 mol to 10 mol per 1 mol of compound [XXXXXVI], however, the ratio can optionally be changed depending on the reaction conditions.

As acid using acetic acid and the like acid.

As the solvent used, for example, water, acetic acid, ethyl acetate, etc. or mixtures thereof.

After completion of the reaction alleged substance can be obtained by obychnyj the last stages of operations, such as filtering, followed by pouring the reaction solution into water and collecting the precipitated precipitated crystals by filtration, or by extraction of the solution with an organic solvent and neutralization, drying and concentrating the organic layer, etc.

In This reaction, usually carried out in a solvent. The reaction temperature usually ranges from -20 to 150°C, preferably from 0 to 50°C. the reaction Time usually ranges from minutes to 48 hours.

This reaction can also be carried out under pressure, and hold it preferably at a pressure of from 1 to 5 ATM.

The amount of catalyst used in this reaction is from 0.001 to 10 wt.% regarding the connection [XXXXXVI].

As catalyst in this reaction using anhydrous palladium-on-charcoal, aqueous palladium-on-charcoal, platinum oxide, etc.

Solvents are carboxylic acids such as formic acid, acetic acid, propionic acid and the like, esters such as ethyl acetate, butyl acetate and the like, alcohols such as methanol, ethanol and the like, or mixtures thereof.

After completion of the reaction alleged substance can be obtained through usual for the last stages of operations, such as filtering the reaction solution before concentrating the solution, and so on

Estimated Obedinenie can also be cleaned by this procedure, as chromatography, recrystallization, etc.

<stage A8-3>. Connection [XXXXXVIII] can be obtained, for example, by reaction of compound [XXXXXVII] with a diazotization agent and an acid in a solvent.

The reaction temperature is from -30 to 30°and the reaction time usually ranges from minutes to 5 hours.

As for the amounts of reactants that react, the amount of the diazotization agent is from 1 mol to 3 mol, and the amount of acid is from 1 mol to 6 mol per 1 mol of compound [XXXXXVII], however, the ratio can optionally be changed depending on the reaction conditions.

As the diazotization agent is used, for example, a nitrite such as sodium nitrite, isoamylase, tert-butyl nitrite, etc.

As the acid used, for example, inorganic acids such as tetraphobia acid, chloromethane acid, etc. and organic acids such as triftormetilfullerenov acid and the like, a Lewis acid such as diethylether of boron TRIFLUORIDE, etc.

As the solvent used, for example, aliphatic halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, 1,2,3-trichloropropane and the like, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and the like, or mixtures thereof.

p> The reaction solution after completion of the reaction used in the subsequent reaction in the form in which it is, or, for example, to the reaction solution was added a non-polar organic solvent, such as n-pentane, n-hexane and the like, and the precipitation is collected by filtering.

<stage A8-4>. Connection [XXXXXIX] can be obtained, for example, by reaction of diazonium salt compounds [XXXXXVIII] with the compound [XXXXVII].

This reaction is usually carried out in the absence of solvent or in a solvent, the reaction temperature is from room temperature to 120°C, preferably from 50 to 90°and the reaction time ranges from minutes to 5 hours.

As for the amounts of reactants that react, the amount of compound [XXXXVII] is from 1 mole to excess per 1 mole of compound [XXXXVI], however, the ratio can optionally be changed depending on the reaction conditions.

As the solvent used acetic acid, etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was concentrated in that form in which he is, the residue diluted with water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection mo is but also cleaned by this procedure, as chromatography, recrystallization, etc.

<stage A8-5>. Connection [XXXXXX] can be obtained, for example, by introducing into the reaction of the compound [XXXXXIX] in a solvent in the presence of a base.

The reaction temperature is from 0 to 100°C, preferably from room temperature to 60°and the reaction time usually ranges from 0.5 to 20 hours.

As for the amounts of reactants that react, the amount of base is from 0.1 mol to 10 mol per 1 mol of compound [XXXXXIX], however, the ratio can optionally be changed depending on the reaction conditions.

As the base used inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc.

As the solvent used, for example, methanol, ethanol, water and the like or mixtures thereof.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was concentrated in as it is, the residue diluted with water, the resulting mixture is extracted with an organic solvent and the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, recrystallization, etc.

(Method 9 to obtain the intermediate connections)

Obedinenie [X] where Y is oxygen, Q is a pyrimidine ring and R3is a OR7, SR8or N(R9R10(compound [19-4]), can be obtained by the method shown in the following diagram

[where R11, R19, R25W and Z1have the values specified above].

<stage A9-1>. Connection [I9-2] can be obtained, for example, by reaction of compound [I9-1] with a halogenation agent in the absence of solvent or in a solvent.

The reaction temperature: 50°C to the boiling point.

The response time from minutes to 36 hours.

Halogenation agent: oxybromide phosphorus oxychloride phosphorus, etc.

The amount of halogenation agent is from 1 mole to excess per 1 mole of compound [I9-1], however, the ratio can optionally be changed depending on the reaction conditions.

Solvent: toluene, etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was concentrated in as it is, the residue diluted with water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, Perek italisize etc.

<stage A9-2>. Connection [I9-3] can be obtained, for example, by reaction of compound [I9-2] with the compound [XIII] in a solvent in the presence of a base.

The reaction temperature is from 0 to 180°C.

The response time from minutes to 24 hours.

The amount of compound [XIII]: from 1 mol to 1.5 mol per 1 mol of compound [I9-2].

A number of reasons: from 1 mol to 1.5 mol per 1 mol of compound [I9-2].

However, the ratio of reagents can optionally be changed depending on the reaction conditions.

Base: triethylamine, diisopropylethylamine, potassium carbonate, sodium hydride, etc.

Solvent: dioxane, tetrahydrofuran, N,N-dimethylformamide, 1-methyl-2-pyrrolidinone etc.

After completion of the reaction alleged connection can be obtained, for example, by the following processing: the reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated. In addition, the connection can also be cleaned by such procedures as chromatography, etc.

<stage A9-3>. Connection [I9-4] can be obtained by removal of the protective group from the compound [I9-3], for example, according to the method described in "Yuki Called Jikken no Tebiki", vol.4 (published by Called Dojin), Protective Groups in Organic Synthesis (published by JOHN WILEY & SONS, INC.).

(Method 10 receiving the intermediate link is)

[where R11W and Z1have the meanings stated above, R28is (C1-C6)-alkyl, such as methyl, ethyl and the like, or phenyl which may be substituted, such as phenyl, 4 -, etc. were, and R30is (C1-C6)-alkyl, such as methyl, ethyl and the like, or (C1-C6-halogenated, such as trifluoromethyl, and the like, Y2represents oxygen or sulfur, n is 1 or 2].

(Method 11 receiving the intermediate connections)

Connection [XXXXXI], where X1represents nitro, fluorine, chlorine, bromine or iodine (compound [I11-5]), can be obtained by the method shown in the following diagram.

[where R3, R15, R25, Y, Q and X2have the meanings stated above, R32is (C1-C6)-alkyl which may be substituted, such as methyl, ethyl, trifluoromethyl, trichloromethyl and the like, and R33represents nitro, fluorine, chlorine, bromine or iodine].

(Method 12 receiving the intermediate connections)

The compound [XXXI] can be obtained by the method shown in the following diagram

where Q, R1, R3X1X2and Y have the values listed above.

<Process A12-1>: the method of producing compound [I12-1] from the compound [XXXXXI].

Connection [12-1] can be obtained by reaction of compound [XXXXXI] with the compound [I12-2] formula [I12-2]

where R1has the values given above and R31is (C1-C6)-alkyl, such as methyl, ethyl, etc.

This reaction is usually carried out in the absence of solvent or in a solvent, and the reaction temperature generally ranges from room temperature to 150°or up to the boiling point of the solvent.

The number of connections [I12-2] can be from 1 to 5 mol per 1 mol of compound [XXXXXI].

Examples of the used solvent are aliphatic hydrocarbons such as n-hexane, n-heptane, ligroin and the like, aromatic hydrocarbons such as toluene, xylene, etc.

This reaction can be accelerated using spontoonies tools, such as molecular sieves 4Å and 5Å etc.

After completion of the reaction, the target compound can be obtained, for example, subjecting the reaction mixture normal processing at later stages by using the procedures that follow.

1), the Reaction mixture was filtered and concentrated.

2), the Reaction mixture was poured into water and collecting the precipitated crystals.

3) the Reaction mixture was added to the acid, such as concentrated hydrochloric acid, etc. or to water, the resulting mixture is extracted with an organic solvent, the organic layer washed with water, dried and will contentresult.

In addition, the target compound can also be cleaned by such procedures as chromatography, recrystallization, etc.

Connection [I12-1] can exist in the form of enol isomers and as a hydrate of the compound [I12-3]

where Q, R1, R3X1X2and Y have the meanings indicated above,

or mixtures thereof.

<Process A12-2>: the method of producing compound [XXXI] from compound [I12-1].

The compound [XXXI] can be obtained, for example, by reaction of compound [I12-1] with cyanate in the presence of acids.

This reaction is carried out in the absence of solvent or in a solvent, and the reaction temperature generally is in the range from 55 to 150°or the boiling point of the solvent, preferably the reaction is first carried out at a temperature in the range from room temperature up to 50°and then, in the interval from 55 to 150°or the boiling point of the solvent.

Used by cyanate is potassium cyanate and sodium cyanate, etc.

Used acid is acetic acid, etc.

The number of cyanate used in this reaction is 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of compound [I12-1].

The amount of acid used in this reaction is from 1 to a large excess relative to 1 mole of compound [I12-1].

The use of the AMI used solvent are aliphatic hydrocarbons, such as n-hexane, n-heptane and the like, aromatic hydrocarbons such as benzene, toluene, xylene, etc.

After completion of the reaction, the target compound can be obtained, for example, through operations 1), 2) or 3)below.

1) the Reaction solution was poured into water, the resulting mixture is extracted with an organic solvent, the organic layer is dried and concentrated.

2), the Reaction mixture was poured into water and the precipitated precipitate is collected by filtration.

3) the Reaction solution was concentrated in that form in which he is, or, if necessary, filter and concentrate the filtrate.

In addition, the target compound can also be cleaned by such procedures as chromatography, recrystallization, etc.

Compound [XXI], [XXV], [XXVI], [XXXXX], [XXXXXIV], [XXXXXV], [I9-1], [I10-1] and [I11-1] are commercially available or can be obtained by known methods.

Compounds of the present invention have excellent herbicide activity, and some of them can show excellent selectivity in respect of cultivated plants and weeds. In other words, the compounds of the present invention have a weed-killing activity during the processing of foliage and soil treatment on upland fields, with respect to the various weeds that can cause certain diseases, such as those listed below.

large-leaved evening primrose (Oenothera erythrosepala), russianlolita evening primrose (Oenothera lactiniata);

Ranunculaceae plants:

Buttercup by krupnoseriynoe (Ranunculus muricatus), hairy Buttercup (Ranunculus sardous);

buckwheat plants:

grekiska vonkova (Polygonum convolvulus), Highlander wavellite (Polygonum lapathifilium), Highlander Pennsylvania (Polygonum pencylvanicum), Highlander pochechuynogo (Polygonum persicaria), sorrel curly (Rumex crispus), sorrel tupolisty (Rumex obtusifolius), Japanese knotweed (Polygonum cuspidatum);

portulacaceae vascular plants:

the garden purslane (Portulaca oleracea);

gvozdenovic vascular plants:

woodlouse (Stellaria media), sticky starwort (Cerastium glomeratum);

lebedova vascular plants:

the white pigweed (Chenopodium album), Kochia (Kochia scoparia);

amaranth weeds:

amaranth spiked (Amaranthus retroflexus, Amaranthus hybrid (Amaranthus hybridus);

cruciferous weeds:

the wild radish (Raphanus raphanistrum), mustard field (Sinapis arvensis), shepherd's purse (Capsella bursapastoris), Virginia peppergrass (Lepidium virginicum);

leguminous plants:

sesbania (Sesbania exaltata), wall-cress (Cassia obtusifolia), Florida clover (Desmodium tortuosum), clover creeping (Trifolium repens), pea seed (Vicia sativa), alfalfa cholevidae (Medicago lupulina);

Malvaceae weeds:

canetic Theophrastus (Abutilon theophrasti), breast prickly Sida spinosa);

violet weed plants:

violet field (Viola arvensis), wild Pansy (Viola tricolr);

Rubiaceae plants:

cleaver (Galium aparine);

vonkova vascular plants:

morning glory plusline (Ipomoea hederacea), morning glory high (Ipomoea purpurea), morning glory zelenolistnoe (Ipomoea hederacea, kind integriuscula), pitted morning glory (Ipomoea lacunosa), field bindweed (Convolvulus arvensis);

Labiatae plants:

purple dead-nettle (Lamium purpureum), dead-nettle (Lamium amplexicaule);

solanaceous weeds:

the dope ordinary (Datura stramonium), black nightshade (Solanum nigrum);

Nalichnaya vascular plants:

Veronica Persian (Veronica persica), Veronica field (Veronica arvensis), Veronica plusline (Veronica hederaefolia);

summary vascular plants:

the common cocklebur (Xanthium pensylvanicum), annual sunflower (Helianthus annuus), chamomile (Matricaria chamomilla), chamomile odorless (Matricaria perforata or inodora), chrysanthemum crop (Chrysanthemum segetum), chamomile Romashkova (Matricaria matricarioides), ragweed (Ambrosia artemisiifolia), ragweed trenatresan (Ambrosia trifida), melkosopochnik canadian (Erigeron canadensis), Japanese wormwood (Artemisia princeps), goldenrod high (Solidago altissima), dandelion pharmacy (Taraxacum officinale);

burashnikov vascular plants:

the forget-me-not (Myosotis arvensis);

utocnikove vascular plants:

walochnik Syrian (Asclepias syriaca);

Euphorbiaceae plants:

milkweed cancelled (Euphorbia helioscopia), spotted spurge (Euphorbia maculata);

geranium weed the plants:

the Carolina geranium (Geranium carolinianum);

sorrel weed plants:

the pink sorrel (Oxalis corymbosa);

pumpkin plants:

angular cucumber (Sicyos angulatus);

grass weeds:

millet plushie (Echinochloa crus-galli), millet (Setaria viridis), spickle giant (Setaria faberi), creeping weed (Digitaria sanguinalis), southern weed (Digitaria ciliaris), Elefsina Indian (Eleusine indica), annual bluegrass (Poa annua), Alopecurus myservername (Alopecurus myosuroides), wild oat (Avena fatus), jonssonova grass (Sorghum halepense), quack grass (Agropyron repens), fire roofing (Bromus tectorum), Bermuda grass (Cynodon dactylon), millet razdvoeniem (Panicum dichotomiflorum), millet Texas (Panicum texanum), sorghum ordinary (Sorghum vulgare), Alopecurus crankshaft (Alopecurus geniculatus);

commelinidae vascular plants:

commelina ordinary (Commelina communis);

Equisetum plants:

horsetail (Equisetum arvense);

sedge weeds:

syt rice (Cyperus iria, Cyperus round (Cyperus rotondus), Cyperus yellow (Cyperus esculentus).

In addition, some compounds of the present invention do not show a significant phytotoxicity with respect to major crops such as corn (Zea mays), wheat (Triticum aestivum), barley (Hordeum vulgare), rice (Oryza sativa), Sogo (Sorgum bicolor), soybean (Glycine max), cotton (Gossypium species), sugar beet (Beta vulgaris), peanut (Arachis hypogaea), sunflower (Helianthus annus) and canola (Brassica napus); the garden to the of ltur, such as flowers, ornamental plants and vegetable crops. Compounds of the present invention can also effectively suppress various weeds that can cause diseases in no-till cultivation of soybean (Glycine max), corn (Zea mays), wheat (Triticum aestivum) and other crops. In addition, some of the compounds of the present invention do not show a significant phytotoxicity against crops.

Compounds of the present invention also possess herbicide activity against various weeds that can cause some diseases in flooded rice fields, such as those listed below.

Grass weeds:

millet plushie (Echinochloa oryzicola);

Nalichnaya vascular plants:

luciennohealani ordinary (Lindernia procumbens);

Grebennikova vascular plants:

rotala Indian (Rotala indica), red stem (Ammania multiflora);

pokoinickaya vascular plants:

povoinik (Elatine triandra);

sedge weeds:

sedge small-flowered bell-shaped (Cyperus difformis), reed tverdotoplivnye (Scirpus juncoides), bolotnitsa acicular (Eleocharis acicularis), Cyperus water (Cyperus serotinus), water chestnut (Eleocharis kuroguwai);

pontederiaceae vascular plants:

Monochoria (Monochoria vaginalis);

czestochowie vascular plants:

the arrowhead (Sagittaria pygmaea), arrowheads (Sagittaria trifolia), Alisma ordinary (Alisma canalicuatum);

Gustavia vascular plants:

Potamogeton rotundifolia (Potamogeton distinctus);

umbrella plants:

view omezhnik Javanese (Oenanthe javanica).

In addition, some compounds of the present invention do not exhibit significant phytotoxicity in relation to seedling rice.

Compounds of the present invention can also suppress a wide range of weeds, growing, or that will grow on other uncultivated land on which it is required to control weeds, such as embankments, rivers, roadsides, Railways, green areas parks, areas around the houses, Parking lots, airports, industrial zones (e.g., factory, warehouse), fallow lands, vacant lands, etc., orchards, pastures, lawns, forests. Compounds of the present invention also have a weed-killing activity against a variety of aquatic weeds such as water hyacinth (Eichhornia crassipes), which are growing or may grow, for example, along the banks of rivers, channels, conduits or reservoirs.

Compounds of the present invention have essentially the same properties as herbicide compounds described in published application for international patent WO 95/34659. When cultivated plants, acquired tolerance by the introduction of a gene for tolerance to herbicides that are described in the request is e, compounds of the present invention can be used at high standards than the standards used in the cultivation of conventional crops without tolerance, allowing you to more effectively deal with noxious weeds.

When the compounds of the present invention are used as active ingredients, they are usually mixed with solid or liquid carriers or diluents, surfactants and other auxiliary substances for the production of concentrates of emulsions, wettable powders, flowable powders, granular preparations of concentrated emulsions, dispersible in water granules or other compositions.

Such compositions may contain as an active ingredient any connection of the present invention in amounts of 0.001 to 80 wt.%, preferably from 0.005 to 70 wt.%, relative to the total weight of the composition.

A solid carrier can include fine powders of minerals, such as kaolin clay, attapulgite clay, bentonite, bleaching clay, pyrophyllite, talc, diatomaceous earth and calcite; fine powders of organic substances, such as powdered walnut shell media; fine powders of water-soluble organic substances such as urea; fine powders of inorganic salts, such as ammonium sulfate; and fine powders syntheti the ski hydrated silicon oxide. The liquid carrier may include aromatic hydrocarbons, such as methylnaphthalene, phenylxylylethane and alkylbenzene (e.g., xylene), alcohols, such as isopropanol, ethylene glycol and 2-ethoxyethanol; ethers such as dialkyl ethers phthalic acid; ketones, such as acetone, cyclohexanone and isophorone; mineral oils such as machine oil; vegetable oils such as soybean oil and cottonseed oil; dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, N-an organic, water, etc.

The surface-active agent used for emulsification, dispersion or spreading may include surfactants of the anionic type, such as alkyl sulphates, alkyl sulphonates, alkylarylsulphonates, diallylmalonate and phosphates simple polyoxyethylenesorbitan esters; surfactants of the nonionic type, such as polyoxyethylenesorbitan esters, polyoxyethylenesorbitan esters, block copolymers of polyoxyethylene and polyoxypropylene, sorbitane esters of fatty acids and polyoxyethylenesorbitan esters of fatty acids.

Other excipients include ligninsulfonate, alginates, polyvinyl alcohol, Arabian gum, CMC (carboxymethylcellulose) and PAP (acidic isopropylacetate).

Compounds of the present invention, as a rule, enter the composition and then used for tillage, leaves when watering before or after germination of weeds. Soil treatment may include surface treatment and soil application. Processing of foliage may include applying to the plants and sent the application in which the chemical is applied only to the weeds so as not to affect cultivated plants.

Compounds of the present invention often show increased herbicide activity when used in mixture with other herbicides. They can also be used in mixture with insecticides, acaricides, nematicides, fungicides, bactericides, plant growth regulators, fertilizers and soil amendments.

These herbicides include

atrazine, cyanazine, deltamethrin, metribuzin, prometryn, Simazine, simetryn, chlorotoluron, Diuron, fluometuron, Isoproturon, linuron, methabenzthiazuron, propanil, bentazon, bromoxynil, ioxynil, peridot, butamifos, dithiopyr, ethalfluralin, pendimethalin, thiazopyr, trifluralin, acetochlor, alachlor, butachlor, diethylether, dimethenamid, flutamide, mefenacet, metolachlor, pretilachlor, propachlor, cinmetacin, acifluorfen, acifluorfen, bestindian, bifenox, butoverall, gametocidal, fomesafen, lactofen, oxadiazon, oxadiargyl, oxyfluorfen, carfentrazone, flatlet, flamelurker, flumioxazin, platesetter, isopropanol, sulfentrazone, tidia Imin, azafenidin, perflourinated, tendonitis, difenzoquat, Diquat, paraquat, 2,4-D, 2,4-DB, clopyralid, dicamba, fluroxypyr, MSRA, MSRB, mecoprop, quinclorac, triclopyr, azimsulfuron, benzylbromide, chloroaromatic, chlorsulfuron, karenalloy, cycloaliphatic, diclazuril, ethoxysulfuron, flazasulfuron, flucarbazone, flumetsulam, flupyrsulfuron, halosulfuron, imazosulfuron, endosulfan, metosulam, metsulfuron, nicosulfuron, oxasulfuron, primisulfuron, procarbazine, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, triasulfuron, tribenuronmethyl, tritosulfuron, thifensulfuron, triflusulfuron, perbenzoic, esperimenti, PerkinElmer, pericolanti, mazamet, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, tepraloxydim, alexidine, clethodim, gladiatorial, chalapati, dichloromethyl, fenoxaprop, fenoxaprop-p-ethyl, fluazifop, fluazifop-p-butyl, galaxytool, quizapp-p-ethyl, sethoxydim, tralkoxydim,

diflufenican, flurtamone, norflurazon, benzefoam, ISO-xaluca, pyrazolate, paradoxien, sulcotrione, clomazone, mesotrione, isoxaflutole,

bialaphos, glufosinateammonium, glyphosate, sulfosate, dichlobenil, isoxaben, benthiocarb, Buti is at, timepart, ARTS, asbroker, molinet, perimutter, triallate, diflubenzuron, bromated, DSMA, MSMA, cafestol, damron, apoprotein, flupoxam, metaventure, phenoxazone, piperophos, triazolam,

beflubutamid, benzamycin, clomipram, phentramin, flufenacet, florasulam, indianian, isoxadifen, mesotrione, naphthanilide, oxacyclobutane, pethoxamid, petiol, perinatol.

The above compounds are described in the catalog of Farm Chemical Handbook, 1995 (Meister Publishing Company); AG CHEM NEW COMPOUND REVIEW, vol.13, 1995, vol.15, 1997, vol.16, 1998, vol.17, 1999 (AG CHEM INFORMATION SERVICES), or in Josouzai Kenkyu Souran (Hakuyu-sha).

When the compounds of the present invention are used as active ingredients of herbicides applied amount, although it may vary depending on weather conditions, types of compositions, timing of use, application methods, soil conditions, crops, protecting, and weeds, which are struggling as a rule, is in the range from 0.01 to 20,000 g, preferably from 1 to 12000 g, per hectare. In the case of compositions in the form of concentrates, emulsions, wettable powders, concentrated emulsions, dispersible in water pellet or similar forms, they are usually applied after dilution with their established quantity of water (optionally containing adjuvant, such as substance-spreader, which increases the wetting ability) in kolichestvo-1000 litres per hectare. In the case of granules or certain types of wettable powders they are used, usually in the form in which they are, without any dilution.

Adjuvant, which can be used may include, in addition to the surfactants described above, polyoxyethylenes acid (esters), ligninsulfonate, abietate, dinaftiletilena, concentrates oils derived from crops, and vegetable oils such as soybean oil, corn oil, cottonseed oil and sunflower oil.

The following examples of making connections, examples of compositions and examples of tests etc. will be to illustrate the present invention in more detail, but they are not intended to limit the scope of the present invention.

First examples of obtaining and examples of the preparation of the intermediate compounds. Rooms compounds of the present invention are given in the following tables 1-10.

Example of getting 1. Obtaining compounds 1-12 of the present invention

In 1.0 ml of dimethyl sulfoxide was dissolved 109 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 70 mg of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine, to this solution was added 10 mg of copper bromide(I) and 12 mg of anhydrous lithium carbonate, and the mixture is stirred during the 2 hours at 120° C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive 10 mg of methyl 2-([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine-5-yl]oxy)propionate [compound 1-12 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.65 (d, 3H, J=7.0 Hz), of 3.56 (s, 3H), of 3.78 (s, 3H), 4.72 in (K, 1H, J=7,0 Hz), 6,36 (s, 1H), 7,21 (d, 1H, J=6,8 Hz), 7,39 (d, 1H, J=8.7 Hz), to 8.20 (s, 2H).

Example 1 obtain the intermediate compounds. Getting 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine used in the example of a 1

A mixture of 0.17 g of 2-chloro-5-hydroxypyrimidine and 0.22 g of methyl 2-bromopropionate, 0.20 g of anhydrous potassium carbonate and 2.6 ml of N,N-dimethylformamide was stirred at 60°C for 1 hour. The reaction solution is cooled to room temperature, then the solution is poured into water and extracted with tert-butylmethylamine ether. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.17 g of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine.

1H-NMR (CDCl3/300 MHz) B4; (ppm): 1,68 (d, 3H, J=6.6 Hz), 3,79 (s, 3H), 4,82 (K, 1H, J=6,7 Hz), of 8.27 (s, 2H).

Example of getting a 2. Getting connection 7-125 of the present invention

A mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention], 0.06 g of sodium carbonate and 3.0 ml of Cyclopentanol stirred for 1.5 hours at 100°and then for 2 hours at 120°C. the Reaction solution is cooled to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.15 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(cyclopentanecarbonyl)methoxypyridine [connection 7-125 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.5-1.9 (m, 8H), 3,50 (K, 3H, J=1.1 Hz), 4,7-5,0 (m, 2H), 5,1-5,2 (m, 1H), 6,29 (s, 1H), 6,91 (DD, 1H, J=7,8, and 4.9 Hz), 6,94 (d, 1H, J=6.5 Hz), 7,30 (DD, 1H, J=7,8, and 1.6 Hz), 7,37 (d, 1H, J=8,9 Hz), to $ 7.91 (DD, 1H, J= 4,9, 1,6 Hz).

Example of getting a 3. Getting connection 1-2 of the present invention

In 2 ml of N,N-dimethylformamide is dissolved 339 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 217 mg of 2-chloro-4-[1-(methoxycarbonyl)e is the hydroxy]pyrimidine, to this solution was added 150 mg of potassium carbonate and the mixture is stirred for 2 hours at 80°C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 256 mg of methyl 2-([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimi-DIN-4-yl]oxy)propionate [compound 1-2 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.56 (d, 3H, J=7,1 Hz), 3,55 (s, 3H), of 3.69 (s, 3H), 5,32 (K, 1H, J=6.3 Hz), 6.35mm (s, 1H), 6,59 (d, 1H, J=5.6 Hz), 7,18 (d, 1H, J=6,1 Hz), 7,39 (d, 1H, J=9.1 Hz), of 8.28 (d, 1H, J=5.7 Hz).

Example 4. Getting connection 3-2 of the present invention

In 1 ml of N,N-dimethylformamide is dissolved 156 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 100 mg 4-chloro-2-[1-(methoxycarbonyl)ethoxy]pyrimidine, to this solution was added 75 mg of potassium carbonate and the mixture is stirred for 2 hours at room temperature. The reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. OST the current is subjected to column chromatography on silica gel and obtain 69 mg of methyl 2-([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine-2-yl]oxy)propionate [compound 3-2 of this the invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.56 (d, 3H, J=7,1 Hz), 3,55 (s, 3H), of 3.65 (s, 3H), 5,0-5,3 (m, 1H), 6.35mm (s, 1H), 6,63 (d, 1H, J=5.8 Hz), 7,20 (d, 1H, J=6.4 Hz), 7,39 (d, 1H, J=8.6 Hz), scored 8.38 (d, 1H, J=5.8 Hz).

Example 2 obtain the intermediate compounds. Getting 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine and 4-chloro-2-[1-(methoxycarbonyl)ethoxy]pyrimidine used in the examples for the preparation of 3 and 4

A mixture of 3.12 g metallichica and 10 ml of acetonitrile under ice cooling is added dropwise to a mixture of 1.2 g of sodium hydride and 40 ml of acetonitrile, the mixture is stirred for 30 minutes. To the mixture is added dropwise at the same temperature 4,47 g of 2,4-dichloropyrimidine and 10 ml of acetonitrile and the mixture is stirred at 60°C for 2 hours. The reaction solution is cooled to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 2.5 g of 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine and 0.25 g of 4-chloro-2-[1-(methoxycarbonyl)ethoxy]pyrimidine.

2-Chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,51 (K, 3H, J=1.2 Hz), 5,04 (s, 2H), of 6.31 (s, 1H), 6.87 in (d, 1H, J=5,9 Hz), 6,9-7,1 (m, 4H), 7.3 to 7.5 (m, 5H), to 7.84 (d, 1H, J=8.6 Hz).

4-Chloro-2-[1-(methoxycarbonyl)ethoxy]pyrimidine

H-NMR (CDCl3/250 MHz) δ (ppm): 1,67 (d, 3H, J=7,0 Hz in), 3.75 (s, 3H), 5,33 (K, 1H, J=7,0 Hz), 7,03 (d, 1H, J=5.3 Hz), scored 8.38 (d, 1H, J=5.3 Hz).

Example of getting a 5. Getting connections 7-7 of the present invention

The first stage

To a solution of 3.0 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine and 2.95 g of N-(2,5-debtor-4-nitrophenyl)ndimethylacetamide in 40 ml of N,N-dimethylformamide type of 2.08 g of potassium carbonate. The mixture is stirred for 2 hours at a temperature of from 60 to 70°C. the mixture is Then cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated receive crude crystalline substance. This crude substance was washed with diisopropyl ether and get to 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]ndimethylacetamide.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 2.21 (s, 3H), and 3.72 (s, 3H), of 4.90 (s, 2H), of 6.96 (DD, 1H, J=7,8, 5.0 Hz), 7,35 (DD, 1H, J=7,8, and 1.6 Hz), and 7.5 and 7.6 (ush, 1H), of 7.90 (d, 1H, J=a 10.6 Hz), of 7.97 (DD, 1H, J=5.0 and 1.6 Hz), 8,15 (d, 1H, J=6,8 Hz).

Similarly receive the following connections:

N-[2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide", she

N-(2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]-4-nitrophenyl)acetamide", she

N-(2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]-4-nitrophenyl)ndimethylacetamide.

The second stage

To a mixture of 3.6 g of a yellow powder is for, 10 ml of acetic acid and 1 ml of water is added dropwise with stirring a solution to 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]ndimethylacetamide in 12 ml of acetic acid and 2 ml of ethyl acetate, while maintaining the temperature of the reaction solution at 45°With or below. Upon completion of the addition the mixture is stirred for 1 hour at 40°C, then the reaction mixture was filtered through celite and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. Then the obtained residue was washed with diisopropyl ether and get to 3.09 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]ndimethylacetamide.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 2.15 (s, 3H), of 3.77 (s, 3H), 3,9-4,1 (ush, 2H), to 5.03 (s, 2H), 6,56 (d, 1H, J=11.8 Hz), at 6.84 (DD, 1H, J=7,9, 5.0 Hz), 7,0-7,2 (ush, 1H), 7,14 (DD, 1H, J=7,9, 1.5 Hz), 7,80 (DD, 1H, J=5,0 and 1.5 Hz), to 7.84 (d, 1H, J= 7,6 Hz).

Similarly receive the following connections:

N-[4-amino-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide", she

N-(4-amino-2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]phenyl)acetamide", she

N-(4-amino-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]phenyl)ndimethylacetamide.

The third stage

To a mixture of 2.0 g of N-[4-amino-2-fluoro-5-{2-(ethoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide", she 1.13 g of copper chloride(I), 2,31 g of copper chloride(II) and 20 ml of acetonitrile is added dropwise at room temperature add a solution 2,01 g isoamylamine in 1 ml of acetonitrile and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl] ndimethylacetamide.

1H-NMR (CDCl3/250 MHz) δ (ppm): to 2.18 (s, 3H), of 3.75 (s, 3H), to 4.98 (s, 2H), 6.87 in (DD, 1H, J=7,8, and 4.9 Hz), was 7.08 (DD, 1H, J=7,8, and 1.4 Hz), of 7.23 (d, 1H, J=10.3 Hz), 7.3 to 7.4 (ush, 1H), 7,86 (DD, 1H, J=4,9, 1,4 Hz), 8,07 (d, 1H, J=7,3 Hz).

Similarly receive the following connections:

N-[4-chloro-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide", she

N-(4-chloro-2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]phenyl)acetamide", she

N-(4-chloro-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]phenyl)ndimethylacetamide.

The fourth stage

A mixture of 20 ml of a solution of a complex of boron TRIFLUORIDE and methanol in methanol and 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl] ndimethylacetamide stirred for 3 hours at a temperature of from 60 to 70°C. Then the reaction solution is concentrated and the residue diluted with saturated aqueous Bica is bonate sodium and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrating, the resulting residue purified by column chromatography, concentrate and obtain 0.87 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.77 (s, 3H), of 3.7-3.9 (ush, 2H), 5,00 (s, 2H), of 6.49 (d, 1H, J=8,2 Hz), to 6.88 (DD, 1H, J=7,9, 5.0 Hz), was 7.08 (d, 1H, J=10.3 Hz), 7,10 (DD, 1H, J=7,9, and 1.6 Hz), 7,87 (DD, 1H, J=5.0 and 1.6 Hz).

Similarly receive the following connections:

4-chloro-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}aniline,

4-chloro-2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]aniline,

4-chloro-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]aniline.

Fifth stage

A mixture of 0.50 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline, 0.28 g of ethyltrichlorosilane and 10 ml of toluene is subjected to azeotropic reaction with removal of ethanol by passing through molecular sieves 5Å within 3 hours. After cooling, the reaction solution was concentrated and obtain 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl] trifenatate-tamide. TPL 158,8°C.

Sixth stage

To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl )methoxy-3-pyridyloxy}phenyl]cryptorchidectomy and 2 ml acetic acid is added 0.33 g of potassium cyanate, the mixture was stirred at 50°t the value of 1 hour and then at 110° C for 1.5 hours. After cooling, to the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel and get to 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,70 (s, 3H), is 4.93 (s, 2/2N), 4,94 (s, 2/2N), to 6.19 (s, 1H), 6,9-7,0 (m, 2H), 7.3 to 7.4 (m, 1H), 7,38 (d, 1H, J=8,9 Hz), to 7.93 (DD, 1H, J=4,9, 1,6 Hz).

TPL 75,3°C.

The seventh stage

To a mixture of 0.10 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 1 ml of acetonitrile and 31 mg of potassium carbonate added 32 mg under the conditions and the mixture is stirred at room temperature for 1.5 hours. To the mixture is added 64 mg under the conditions and the mixture is stirred at 50°C for 1 hour. The mixture is filtered and the filtrate concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel and obtain 97 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention].

the example of obtaining 6. Getting connections 3-12 of the present invention

In 2 ml of N,N-dimethylformamide is dissolved 338 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 216 mg of 4-chloro-6-[1-(methoxycarbonyl)ethoxy]pyrimidine, to this solution was added 150 mg of potassium carbonate and the mixture is stirred for 2 hours at 60°C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into a mixture of water with ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 101 mg of methyl 2-([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine-6-yl]oxy)propionate [compound 3-12 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.62 (d, 3H, J=7.0 Hz), of 3.56 (s, 3H), of 3.75 (s, 3H), 5,41 (K, 1H, J=7,0 Hz), 6,36 (s, 1H), 6,37 (s, 1H), 7,17 (d, 1H, J=6.5 Hz), 7,40 (d, 1H, J=9.1 Hz), a 8.34 (s, 1H).

Example of getting a 7. Getting connection 5-17 of the present invention

To a solution of 0.21 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 1.0 ml of N,N-dimethylformamide add 0.10 g of methylpropanoate and 0.20 g of potassium carbonate and the mixture is stirred for 3 hours at room is the temperature. This reaction solution was poured diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. This solution is subjected to column chromatography on silica gel and obtain 0.06 g of 3-(methoxycarbonyl)methoxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [connection 5-17 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 2.16 (s, 3H), 3,51 (s, 3H), of 3.69 (s, 3H), of 4.77 (s, 2H), 6.30-in (s, 1H), 7,12 (d, 1H, J=6.5 Hz), 7,31 (d, 1H, J=9.0 Hz).

Example of getting 8. Obtaining optical R-isomer compounds 5-12 of the present invention

To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate added 0.10 g (S)-(-)-metallichica, 0.26 g of triphenylphosphine and 0.5 ml of 40% solution of diisopropylcarbodiimide in toluene, the mixture is stirred for 3 hours at room temperature. In this reaction solution pour in 6 ml n-hexane and filtered precipitated precipitated insoluble substance. This solution is subjected to column chromatography on silica gel and obtain 0.09 g of (R)-3-{1-(label-dicarbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [optical R connection 5-12 of the present invention, hereinafter called 5-12-R].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,51 (m, 3H), of 2.15 (s, 3H), of 3.48 (s, 3/2H), 3,52 (s, 3/2H), to 3.67 (s, 3H), of 5.05 (m, 1H), 6.30-in (s, 1/2H)a, of 6.31 (s, 1/2H), 7,13 (d, 1/2H, J=6.5 Hz), 7,18 (d, 1/2H, J=and 6.6 Hz), 7,31 (d, 1H, J=8.7 Hz).

[α]D+16,4° (0.5, methanol).

Example of getting a 9. Obtaining optical S-isomer compounds 5-12 of the present invention

To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate added 0.10 g (R)-(+)-metallichica, 0.26 g of triphenylphosphine and 0.5 ml of 40% solution of diisopropylcarbodiimide in toluene and the mixture is stirred for 3 hours at room temperature. In this reaction solution pour in 6 ml n-hexane and filtered precipitated precipitated insoluble substance. This solution is subjected to column chromatography on silica gel and obtain 0.08 g (S)-3-{1-(methoxy-carbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [optical S-isomer compounds 5-12 of the present invention, hereinafter called 5-12-S].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,51 (m, 3H), of 2.15 (s, 3H), 3,49 (s, 3/2H), 3,52 (s, 3/2H), to 3.67 (s, 3H), of 5.05 (m, 1H), 6.30-in (s, 1/2H)a, of 6.31 (s, 1/2H), 7,13 (d, 1/2H, J=6.8 Hz), 7,18 (d, 1/2H, J=a 6.5 Hz), 7,31 (d, 1H, J=8,8 Hz).

[α]D-16,0° (0.5, methanol).

Example 3 obtaining an intermediate connection is in. Getting 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole used in the examples get 7-9

The first stage

In 30 ml of N,N-dimethylformamide was dissolved 10.0 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, to this solution add 5.0 ml of triethylamine and then to the resulting mixture at room temperature with stirring 5.0 g of methyl 2-chloroacetoacetate. Then continue stirring for 10 minutes at room temperature and for 1 hour at 60°C. To this solution add 2.0 ml of triethylamine and 2.0 g of methyl 2-chloroacetoacetate, then the mixture is stirred for 1 hour at 60°C. the Reaction solution is stirred over night at room temperature, then the reaction solution is poured into a mixture of ice water and diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 7,86 g of methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxybutyrate.

1H-NMR (CDCl3/300 MHz) δ (ppm): a 2.01 (s, 3/2H), 2,47 (s, 3/2H), 3,55 (s, 3H), of 3.75 (s, 3/2H), 3,81 (s, 3/2H), 4,99 (s, 1/2H), 6,34 (s, 1/2H), 6.35mm (s, 1/2 is), of 6.65 (d, 1/2H, J=6.4 Hz), 6,83 (m, 1/2H), 7,35 (m, 1H).

The second stage

In 30 ml of toluene is suspended to 3.09 g of methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxybutyrate and of 1.23 g of methyl-carbazate and the mixture is refluxed for 5 hours. The solution is cooled to room temperature, then the reaction solution is poured into a mixture of ice water and diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is washed with a mixture of n-hexane and ethyl acetate (3:1) and get to 2.94 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole.

1H-NMR (CDCl3+CD3OD/250 MHz) δ (ppm): 2,08 (s, 3H), 3,51 (s, 3H), 6,32 (s, 1H), for 6.81 (d, 1H, J=6.5 Hz), 7,32 (d, 1H, J=8,8 Hz).

Example 10. Getting connection 6-2 of the present invention

In 6 ml of acetonitrile was dissolved 0.40 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylmercaptan, to this solution was added 0.31 g of potassium carbonate and the mixture is stirred for 30 minutes, then add to 0.29 g of 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine and the mixture is stirred for 3 hours. This reaction solution was poured into a mixture of ice water and extracted with these is acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive and 0.46 g of methyl 2-([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylthio}pyrimidine-4-yl]oxy)propionate [compound 6-2 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,49 (d, 3H, J=7,1 Hz), of 3.56 (d, 3H, J=1.1 Hz), to 3.67 (d, 3H, J=1.3 Hz), 5,23 (m, 1H), 6,36 (s, 1H), of 6.52 (d, 1H, J=5.7 Hz), 7,46 (d, 1H, J=9,2 Hz), a 7.62 (m, 1H), compared to 8.26 (d, 1H, J=5.7 Hz).

TPL 60,2°C.

Example 4 to obtain the intermediate compounds. Getting 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylmercaptan used in example 10

In 16 ml of acetic acid are dissolved of 1.65 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]benzosulfimide, to this solution was added 4.4 g of zinc, and then substances react while boiling under reflux. Upon completion of the reaction, the reaction solution is cooled, then poured into a mixture of ice water, extracted with ethyl acetate and filtered. The filtrate is separated, then the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, to obtain 1.35 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydrofur midin-1-yl]phenylmercaptan.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,55 (m, 3H), 3,86 (s, 1H), 6,36 (s, 1H), 7,27 (d, 1H, J=6.4 Hz), 7,33 (d, 1H, J=9.1 Hz).

TPL 132,5°C.

Example of getting 11. Getting connection 2-2 of the present invention

In acetonitrile is dissolved 200 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 80 mg of methyl 2-bromopropionate, to this solution was added 66 mg of potassium carbonate and the mixture is stirred for 2 hours at 60°C. This reaction solution was poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 77 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-{1-(methoxycarbonyl)ethoxy}pyridine [compound 2-2 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm): 1,67 (d, 3H, J=6, 8 Hz), 3,55 (m, 3H), 3,76 (s, 3H), 4,94 (K, 1H, J=6.9 Hz), 6.35mm (s, 1H), 6,95 (m, 1H), 7,20 (d, 1H, J=6,8 Hz), 7,28 (m, 1H), 7,39 (d, 1H, J=9.0 Hz), to 7.75 (m, 1H).

Example 12. Getting connections 2-7 of the present invention

In 2 ml of acetonitrile was dissolved 60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 20 mg methylpropanoate, to this solution add Aut 20 mg of potassium carbonate and the mixture is stirred for 2 hours at 60° C. This reaction solution was poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive 60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-(methoxycarbonyl)methoxypyridine [connection 2-7 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,55 (s, 3H), of 3.80 (s, 3H), to 4.81 (s, 2H), 6.35mm (s, 1H), 6,97 (m, 1H), 7,21 (d, 1H, J=6,8 Hz), 7,27 (m, 1H), 7,39 (d, 1H, J=9.1 Hz), of 7.75 (d, 1H, J=4,1 Hz).

Example 5 to obtain the intermediate compounds. Getting 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine used in the examples get 11 and 12

The first stage

In 10 ml of toluene is dissolved and 11.8 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 5.2 g of 2-chloro-3-nitropyridine, to this solution was added 2.3 g of potassium hydroxide and 56 mg of 18-crown-6 and the mixture is stirred for 3 hours at 90°C. the Reaction solution is cooled to room temperature, then the solvent is distilled off, the residue is poured into a mixture of ice water and precipitated precipitated crystalline substance is collected by filtration, gain of 11.5 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(t is iformity)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-nitropyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm ): of 3.56 (m, 3H), 6,36 (s, 1H), and 7.4 to 7.2 (m, 2H), 7,41 (d, 1H, J=8,9 Hz), and 8.3 (m, 1H), and 8.4 (m, 1H).

The second stage

To a mixture of 3.8 g of iron powder, 50 ml of acetic acid and 5 ml of water is added dropwise a solution of 3.8 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-nitropyridine in 5.0 ml of acetic acid, maintaining the temperature of the reaction solution at 35°With or below. After completion of the addition the mixture is stirred for 2 hours, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and obtain 3.4 g of 3-amino-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.53 (s, 3H), 4.00 points (s, 2H), 6,34 (s, 1H), PC 6.82 (m, 1H), 6,99 (m, 1H), 7,29 (d, 1H, J=6,7 Hz), 7,35 (d, 1H, J=9.0 Hz), 7,47 (m, 1H).

The third stage

To a mixture of 3.4 g of 3-amino-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 3 ml of 1,2-dimethoxyethane and 1 ml of methylene chloride at -5°With added dropwise 0,76 ml of titlefirst of boron TRIFLUORIDE, a mixture of premesis who are within 5 minutes then to the mixture is added dropwise to 0.44 ml of tert-butylnitrite and the mixture is stirred for 30 minutes at the same temperature. The mixture pour in n-pentane and collected by filtration 2.0 g of precipitated precipitated crystalline substance.

Then 200 mg of the above crystalline substances dissolved in 1 ml of acetic anhydride and the mixture is stirred for 2 hours at 70°C. After removal of the solvent, the obtained residue is subjected to chromatography on silica gel and obtain 89 mg of 3-acetoxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 2,43 (s, 3H), 3,55 (s, 3H), 6.35mm (s, 1H), 7,05 (m, 1H), 7,21 (d, 1H, J=6.9 Hz), 7,39 (d, 1H, J=8,8 Hz), 7,47 (m, 1H), 7,97 (m, 1H).

The fourth stage

A mixture of 100 mg of 3-acetoxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 15 mg of potassium carbonate and 1 ml of methanol is stirred for 3 hours at room temperature. The reaction solution was poured into ice water and then the resulting mixture was poured acetic acid. Precipitated precipitated crystalline substance is collected by filtration and obtain 65 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine.

Example of receipt 13. The connection is 7-7 this image is etenia

The first stage

To a mixture of 1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methylglycol and 10 ml of 1,4-dioxane at 10°add 0.4 g of sodium hydride. The mixture is stirred at room temperature for 2 hours, then the reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine. TPL 61,5°C.

The second stage

A mixture of 0.3 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine, 20 mg of platinum oxide and 1.4 ml of ethanol is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get to 0.22 g of 3-amino-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.77 (s, 3H), 3,85 (USS, 2H), 4.95 points (s, 2H), 6.75 in (DD, 1H, J=7,5, 5.0 Hz), 6,91 (DD, 1H, J=7,5, and 1.6 Hz), to 7.50 (DD, 1H, J=5.0 and 1.6 Hz).

The third stage

To a mixture of 1.0 g of 3-amino-2-(methoxycarbonyl)methoxypyridine, 3 ml of 1,2-dimethoxyethane and 1 ml of dichloromethane at -10°With added dropwise 1.6 g of titlefirst of boron TRIFLUORIDE. The mixture is stirred for 10 minutes at the same temperature and then the reaction is in solution at -5° With or lower temperature is added dropwise a solution of 0.68 g of tert-butylnitrite in 1 ml of 1,2-dimethoxyethane. The mixture is stirred for 30 minutes at the same temperature and then the mixture pour in n-pentane. The bottom layer of the two divided layers are dissolved in 5 ml of acetic anhydride and the mixture is stirred for 1 hour at 80°C. the Solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and obtain 0.45 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 2.33 (s, 3H), of 3.75 (s, 3H), 4.92 in (s, 2H), 6,93 (DD, 1H, J=7,7, 5.0 Hz), 7,38 (DD, 1H, J=7,7, 1,6 Hz), of 7.97 (DD, 1H, J=5.0 and 1.6 Hz).

Similarly, a 3-acetoxy-2-(methoxycarbonyl)methylthiopyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): at 2.36 (s, 3H), 3,74 (s, 3H), 4.00 points (s, 2H), 7,07 (DD, 1H, J=8.0 a, 4,7 Hz), 7,37 (DD, 1H, J=8,0, 1.5 Hz), 8,29 (DD, 1H, J=4,7, 1.5 Hz).

The fourth stage

A mixture of 0.1 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine, 31 mg of potassium carbonate and 1 ml of methanol is stirred for 3 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 73 mg of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.78 (s, 3H), to 4.98 (s, 2H), at 6.84 (DD, 1H, J=7,7, 5.0 Hz), 7,17 (DD, 1H, J=7,7, 1.3 Hz), 7,63 (DD, 1H, J=5.0 and 1.3 Hz).

Similarly, a 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,74 (s, 3H), 3,92 (s, 2H), 7,02 (DD, 1H, J=8,1, 4.6 Hz), 7,13 (d, 1H, J=8.1 Hz), of 8.06 (d, 1H, J=4,6 Hz).

Similarly, a 3-hydroxy-2-(etoxycarbonyl)methylthiopyridine.

Fifth stage

To a mixture of 0.29 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0,23 g 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 3.2 ml of N,N-dimethylformamide added 0.11 g of potassium carbonate and the mixture is stirred for 2 hours at 70°C. Add 0.12 g of 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 0.05 g of potassium carbonate and the mixture is stirred for 1 hour at 70°C. the Solution is cooled to room temperature, poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.39 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine [connection 9-45 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,51 (K, 3H, J=1.1 Hz), 3,68 (s, 3H), a 4.86 (d, 1H), to 4.98 (d, 1H), 6,29 (1H), of 6.99 (DD, 1H, J=7,8, and 4.9 Hz), 7,11 (d, 1H, J=6.0 Hz), 7,51 (DD, 1H, J=7,8, and 1.6 Hz), 7,87 (d, 1H, J=8.6 Hz), to 7.99 (DD, 1H, J=4,9, 1,6 Hz).

Similarly, a 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methylthiopyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.54 (s, 3H), of 3.73 (s, 3H), 4,01 (s, 2H), 6,33 (s, 1H), between 7.0 and 7.1 (m, 2H), 7,18 (DD, 1H, J=7,8, 1.3 Hz), 7,92 (d, 1H, J=8.5 Hz), of 8.28 (DD, 1H, J=4,4, 1.3 Hz).

Similarly, a 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(etoxycarbonyl)methylthiopyridine.

Sixth stage

To a mixture of 0.3 g of iron powder, 3 ml of acetic acid and 0.3 ml of water is added dropwise a solution of 0.30 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine [connection 9-45 of the present invention] in 2 ml of acetic acid, maintaining the temperature of the reaction solution at 35°With or below. After complete addition, the mixture is stirred for 2 hours, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to column chromatography on silica gel and n is to obtain 0.24 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): to 3.52 (s, 3H), 3,74 (s, 3H), 4,29 (USS, 2H), 5,00 (s, 2H), 6.30-in (s, 1H), is 6.61 (d, 1H, J=11.3 Hz), 6,76 (d, 1H, J=6,8 Hz)6,86 (DD, 1H, J=7,8, 5.0 Hz), 7,22 (DD, 1H, J=7,8, 1.1 Hz), 7,82 (DD, 1H, J=5.0 and 1.1 Hz).

Similarly receive 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methylthiopyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.53 (s, 3H), of 3.75 (s, 3H), was 4.02 (s, 2H), 4,18 (USS, 2H), 6,32 (s, 1H), 6,66 (d, 1H, J=10,7 Hz), PC 6.82 (d, 1H, J=6,7 Hz), to 6.95 (DD, 1H, J=8,4, a 4.9 Hz), 7,03 (DD, 1H, J=8,4, and 1.4 Hz), 8,14 (DD, 1H, J=4,9, 1,4 Hz).

The seventh stage

To a mixture of 0.24 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 99 mg of copper chloride(I), 0.20 g of copper chloride(II) and 2.5 ml of acetonitrile at room temperature is added dropwise 88 mg isoamylamine and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.21 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention]. TPL 52,2°C.

1H-NMR (CDCl3/300 MHz) 4 (ppm): 3,50 (K, 3H, J=1.0 Hz), 3,70 (s, 3H), of 4.90 (d, 1H, J=15,8 Hz), equal to 4.97 (d, 1H, J=15,8 Hz), of 6.29 (s, 1H), 6,9-7,0 (m, 2H), 7,32 (DD, 1H, J=7,7, 1.9 Hz), 7,37 (d, 1H, J=8.7 Hz), 7,92 (DD, 1H, J=4,9, 1,9 Hz).

Similarly receive 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methylthiopyridine [connection 7-27 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.54 (s, 3H), of 3.75 (s, 3H), 4,01 (s, 2H), 6,33 (s, 1H), 6,9-7,0 (m, 3H), 7,42 (d, 1H, J=9.0 Hz), to 8.20 (DD, 1H, J=4,1, 2,2 Hz).

Similarly receive 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methylthiopyridine [connection 7-28 of the present invention].

Example of getting a 14. Getting connection 4-85 of the present invention

The first stage

To a mixture of 0.4 g of 5-benzyloxy-4-chloro-2-methylpyrimidine, 0.17 g of methylglycol and 3.4 ml of tetrahydrofuran at 0°With added 68 mg of sodium hydride. The mixture is stirred at room temperature for 1 hour and then the reaction solution is stirred for 30 minutes at 90°C. To the mixture of 18 mg of methylglucose and the mixture is stirred for 30 minutes at 90°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated brine, drying is over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.21 g of 5-benzyloxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 2.49 USD (s, 3H), of 3.78 (s, 3H), free 5.01 (s, 2H), 5,17 (s, 2H), 7,2-7,5 (m, 5H), to 7.99 (s, 1H).

The second stage

A mixture of 0.21 g of 5-benzyloxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 16 mg of 10% palladium-on-coal and 1.5 ml of ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and obtain 0.15 g of 5-hydroxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 2.51 (s, 3H), 3,81 (s, 3H), of 5.00 (s, 2H), 8,10 (s, 1H).

The third stage

To a mixture of 0.15 g of 5-hydroxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 0.16 g of 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 2 ml of N,N-dimethylformamide added 74 mg potassium carbonate and the mixture is stirred for 1 hour at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.20 g of 5-{4-fluoro-5-[3-is ethyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine. TPL of 149.5°C.

The fourth stage

The mixture is 0.19 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 5 mg of platinum oxide, 2 ml ethanol and 2 ml of ethyl acetate is stirred for 1.5 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and obtain 0.17 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl] phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.

1H-NMR (CDCl3/300 MHz) δ (ppm): to 2.55 (s, 3H), 3,51 (s, 3H), of 3.75 (s, 3H), 4,9-5,1 (m, 2H), 6.30-in (s, 1H), to 6.67 (d, 1H, J=6.3 Hz), 6,83 (USS, 1H), 7,15 (d, 1H, J=11,0 Hz), 7,42 (USS, 1H), 8,18 (s, 1H).

Fifth stage

To a mixture of 0.17 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 67 mg of copper chloride(I), 137 mg of copper chloride(II) and 2 ml of acetonitrile at room temperature is added dropwise 60 mg isoamylamine and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and ucaut 20 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine [connection 4-85 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 2.57 m (s, 3H), 3,51 (K, 3H, J=l,1 Hz), 3,71 (s, 3H), of 4.90 (d, 1H, J=15.7 Hz), 5,00 (d, 1H, J=15.7 Hz), of 6.29 (s, 1H), 6.89 in (d, 1H, J=6.4 Hz), 7,37 (d, 1H, J=9.0 Hz), compared to 8.26 (s, 1H).

Example of receipt 15. Getting connection 4-76 present invention

The first stage

To a mixture of 5-benzyloxy-4-chloro-2-methylpyrimidine, metallichica and tetrahydrofuran at 0°add sodium hydride. The mixture is stirred at room temperature for 1 hour and then at 90°C for 30 minutes. The reaction solution is cooled to room temperature, poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidin.

The second stage

A mixture of 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, 10% palladium-on-coal and ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and receive 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidin.

The third stage

To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrene the ina, 2.5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide add the potassium carbonate and the mixture is stirred for 1 hour at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidin.

The fourth stage

A mixture of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, platinum oxide, ethanol and ethyl acetate is stirred for 1.5 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and receive 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidin.

Fifth stage

To a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyran the Dean, chloride copper(I)chloride copper(II) and acetonitrile at room temperature is added dropwise to soliditet and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidin [connection 4-76 of the present invention].

Example of 16. Getting connection 7-2 of the present invention

The first stage

To the mixture 3,17 g of 2-chloro-3-nitropyridine, 2,19 g metallichica and 20 ml of 1,4-dioxane at 10°add 0.8 g of sodium hydride. The mixture is stirred at room temperature for 1.5 hours, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get a 3.3 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,70 (d, 3H, J=7.0 Hz), 3,74 (s, 3H), 5,46 (K, 1H, J=7,0 Hz), 7,07 (DD, 1H, J=7,8, 5.0 Hz), 8,2-8,4 (m, 2H).

The second stage

A mixture of 1.7 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine, 102 mg oxide PL is Tina and 7.5 ml of ethanol is stirred for 3.5 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get to 1.16 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): and 1.63 (d, 3H, J=6, 8 Hz), 3,74 (s, 3H), 3,84 (USS, 2H), 5,38 (d, 1H, J=6,8 Hz), 6,72 (DD, 1H, J=7,7, 5.0 Hz), 6.90 to (DD, 1H, J=7,7, 1,4 Hz), 7,40 (DD, 1H, J=5.0 and 1.4 Hz).

The third stage

To a mixture of 1.1 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyridine, 3 ml of 1,2-dimethoxyethane and 1 ml of dichloromethane at -10°With added dropwise 1.5 ml of titlefirst of boron TRIFLUORIDE. After stirring for 10 minutes at the same temperature to the reaction solution at -5°or lesser temperature is added dropwise a solution of 0.80 ml of tert-butylnitrite in 1 ml of 1,2-dimethoxyethane. After stirring for 30 minutes at the same temperature in the mixture pour in n-pentane. The bottom layer of the two divided layers are dissolved in 5 ml of acetic anhydride and the mixture is stirred for 1 hour at 70°C. the Solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and obtain 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,60 (d, 1H, J=7,0 Hz), of 2.33 (s, 3H), of 3.73 (s, 3H), 5,34 (K, 1H, J=7,0 Hz)6,91 (DD, 1H, J=7,6, 5.0 Hz), was 7.36 (DD, 1H, J=7,6, 1.5 Hz), of 7.97 (DD, 1H, J=5.0 and 1.5 Hz).

The fourth stud is I

A mixture of 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.11 g of potassium carbonate and 2 ml of methanol is stirred for 1 hour at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 190 mg of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,64 (d, 1H, J=7,0 Hz in), 3.75 (s, 3H), of 5.45 (K, 1H, J=7,0 Hz), 6,0-6,2 (USS, 1H), 6,83 (DD, 1H, J=7,7, 5.0 Hz), to 7.15 (DD, 1H, J=7,7, 1.5 Hz), 7,63 (DD, 1H, J=5.0 and 1.5 Hz).

Fifth stage

To a mixture of 0.18 g of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0,19 g 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 2.0 ml of N,N-dimethylformamide add 91 mg of potassium carbonate and the mixture is stirred for 3 hours at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.21 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine [compound 9-42 this image is placed] (in the form of a mixture of two diastereoisomers).

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,45 (d, 3/2N, J=7,1 Hz)of 1.46 (d, 3/2N, J=7,1 Hz), 3,49 (s, 3/2H), 3,51 (s, 3/2H), 3,66 (s, 3H), from 5.29 (K, 1/2H, J=7,1 Hz), 5,31 (K, 1/2H, J=7,1 Hz), 6,28 (s, 1/2H), 6,30 (s, 1/2H), 6,9-7,0 (m, 1H), 7,10 (d, 1/2H, J=6,1 Hz), 7,17 (d, 1/2H, J=6,1 Hz), 7,4-7,6 (m, 1H), 7,8-7,9 (m, 1H), from 7.9 to 8.0 (m, 1H).

Sixth stage

To a mixture of 0.21 g of iron powder, 3 ml of acetic acid and 0.3 ml of water is added dropwise a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine [compound 9-42 present invention] 1.2 ml of acetic acid, maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the reaction the mixture is stirred for 1 hour, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and obtain 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine (in the form of a mixture of two diastereoisomers).

1H-NMR (CDCl3/300 MHz) δ (ppm): to 1.61 (d, 3H, J=7,1 Hz), 3,52 (s, 3H), and 3.72 (s, 3H), 4,28 (USS, 2H), 5.40 to (K, 1/2H, J=7,1 Hz), 5,41 (K, 1/2H, J=7,1 Hz), 6.30-in (s, 1H), 6,62 (d, 1H, J=10,9 Hz), 6,7-6,8 (m,1H), 6.8 or 6.9 (m, 1H), 7,2-7,3 (m, 1H), 7,7-7,9 (m, 1H).

The seventh stage

To a mixture of 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine, 63 mg of copper chloride(I), 129 mg of copper chloride(II) and 1.5 ml of acetonitrile at 0°With added dropwise 18 mg isoamylamine and the mixture is stirred for 10 minutes at the same temperature, and then at room temperature for 1 hour. This reaction solution was poured into a mixture of 1N hydrochloric acid with ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.12 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine (in the form of a mixture of two diastereoisomers) [7-2 connection of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): is 1.51 (d, 3/2H, J=7.0 Hz), of 1.52 (d, 3/2H, J=7.0 Hz), 3,50 (s, 3H), to 3.67 (s, 3H), from 5.29 (K, 1/2H, J=7,0 Hz), and 5.30 (K, 1/2H, J=7.0 Hz), 6,28 (s, 1/2H), 6,29 (s, 1/2H), 6,8-7,0 (m, 2H), 7.3 to 7.4 (m, 2H), 7,8-7,9 (m, 1H).

Example of receipt 17. Obtaining compounds 4-7 of the present invention

The first stage

To the mixture 0,297 g of sodium hydride and N,N-dimethylformamide add 0,668 g methylglucose and stirred at room temperature for 1 hour. ZAT is m to the mixture of 5-benzyloxy-4-chloropyrimidine (obtained in the following way: a mixture of 1.5 g of 5-benzyloxy-4-methylpyrimidine and 30 ml of phosphorylchloride stirred for 30 minutes at boiling under reflux, the mixture is then cooled to room temperature and concentrated; the residue is added a mixture of ice water, extracted with ether and concentrated) and the mixture is stirred for 3 hours at room temperature. The mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,934 g of 5-benzyloxy-4-(methoxycarbonyl)methoxypyridine. TPL 78,7°C.

The second stage

A mixture of 0.9 g of 5-benzyloxy-4-(methoxycarbonyl)methoxypyridine, 10% palladium-on-coal and ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and receive 0,574 g of 5-hydroxy-4-(methoxycarbonyl)methoxypyridine. TPL 105,5°C.

The third stage

To a mixture of 42 mg of sodium hydride and N,N-dimethylformamide add 0,184 g of 5-hydroxy-4-(methoxycarbonyl)methoxypyridine and stirred at room temperature for 1 hour. Then added to the mixture of 0.35 g of 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and stirred for 2 hours at to matnog temperature, and then 1 hour at 50°C. the Mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,448 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxypyridine. TPL 55,7°C.

The fourth stage

To a mixture of 0.4 g of iron powder, 2 ml of acetic acid and 0.2 ml of water is added dropwise a solution of 0,393 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxypyridine in 1 ml of acetic acid and 2 ml of ethyl acetate. Upon completion of the addition the mixture is stirred for 1 hour at room temperature and for 2 hours at 30-40°C. To the mixture, water is added, then the mixture is filtered through celite and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Then the obtained residue is subjected to chromatography on silica gel and get 0,315 g 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy is rimidine. TPL 71,2°C.

Fifth stage

To the mixture 0,315 g 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine, 0,129 g of copper chloride(I), 0,262 g of copper chloride(II) and acetonitrile at room temperature is added dropwise a solution of 0,228 g isoamylamine in acetonitrile and the mixture is stirred for 3 hours. The mixture is concentrated, diluted with ethyl acetate and filtered through celite. To the filtrate add water and then extracted with ethyl acetate. The organic layer was washed with 1% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine [connection 4-7 of the present invention]. TPL 52,5°C.

Example obtain 18. Getting connection 4-2 of the present invention

The first stage

To a mixture of 5-benzyloxy-4-chloropyrimidine, metallichica and tetrahydrofuran at 0°add sodium hydride. The mixture is stirred at room temperature for 1 hour and then stirred for 30 minutes at 90°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organization is a mini layer was washed with diluted hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.

The second stage

A mixture of 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, 10% palladium-on-coal and ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and receive 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.

The third stage

To a mixture of 5-hydroxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide add the potassium carbonate and the mixture is stirred for 1 hour at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.

The fourth stage

A mixture of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tet is hydropyridine-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, of platinum oxide, ethanol and ethyl acetate is stirred for 1.5 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and receive 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.

Fifth stage

To a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, chloride, copper(I)chloride copper (II) and acetonitrile at room temperature is added dropwise to soliditet and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and the mixture is concentrated, diluted with ethyl acetate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [compound 4-2 of the present invention].

Example obtain 19. Getting connection 7-42 of the present invention

The first stage

To the mixture 0,385 g of sodium hydride and dimethyl sulfoxide at room temperaturedisplay a solution of 1.04 g of benzyl alcohol in dimethyl sulfoxide. The mixture is then stirred for 30 minutes at 50°and cooled to room temperature. To the mixture add a solution of 1.7 g of 4-bromo-3-methoxypyridine (obtained by the method described in Tetrahedron, 12745-12774 (1998)) in dimethyl sulfoxide and the mixture is stirred for 2 hours at 50-60°C. the Mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive a 4-benzyloxy-3-methoxypiperidine. TPL 71,2°C.

The second stage

A mixture of 0.7 g of 4-benzyloxy-3-methoxypiperidine and 1N hydrochloric acid is stirred for 2 hours at 60°C. the Mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and receive 0,547 g of 4-benzyloxy-3-hydroxypyridine. TPL 173, 0mm°C.

The third stage

To a mixture of 57 mg of sodium hydride and N,N-dimethylformamide at room temperature add 0,286 g of 4-benzyloxy-3-hydroxypyridine and stirred for 30 minutes. Then added to the mixture of 0.5 g of 1, 5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and the mixture is stirred for 1 hour at on the th temperature, and then for 1 hour at 50-60°C. the Mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,548 g of 4-benzyloxy-3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}pyridine. nD23,71,5497.

The fourth stage

To a mixture of 0.55 g of iron powder, 3 ml of acetic acid and 0.3 ml of water is added dropwise a solution of 0,548 g of 4-benzyloxy-3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2, 3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}pyridine in 0.5 ml of acetic acid and 3 ml of ethyl acetate. Upon completion of the addition the mixture is stirred for 3 hours at 40-50°C. the Mixture was poured into water, the mixture is then filtered through celite and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrate, get 0,438 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-benzyloxypyridine. TPL 69,3°C.

Fifth stage

To the mixture 0,438 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin--yl]phenoxy}-4-benzyloxypyridine, 0,173 g of copper chloride(I), 0,352 g of copper chloride (II) and acetonitrile at room temperature is added dropwise a solution of 0,307 g isoamylamine in acetonitrile and the mixture is stirred for 1 hour. The next day, the mixture is concentrated, diluted with water and ethyl acetate and filtered through celite. The filtrate is extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,362 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine. TPL 55,0°C.

Sixth stage

The mixture 0,356 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine, 10% palladium-on-coal and ethyl acetate is stirred for 8 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite, the filtrate concentrated and obtain 0.32 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxypyridine. TPL 196,1°C.

The seventh stage

To a mixture of 30 mg of sodium hydride and N,N-dimethylformamide at room temperature is added 0.31 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-Tetra-hydropyridine the-1-yl]phenoxy}-4-hydroxypyridine and stirred for 1 hour. Then added to the mixture 0,114 g methylpropanoate and stirred for 8 hours at room temperature. The mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 27 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine [connection 7-42 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm ): 3,51 (K, 3H, J=1.2 Hz), 3,74 (s, 3H), 4,71 (s, 2H), 6,29 (s, 1H), 6,7-6,8 (m, 2H), 7,37 (d, 1H, J=8,8 Hz), 8,35 (d, 1H, J=5.5 Hz), of 8.37 (s, 1H).

An example of obtaining 20. Getting connection 2-45 of the present invention

The first stage

To the mixture 9,65 g of 2,6-dichloro-3-nitropyridine, of 4.95 g of methylglycol and 100 ml of tetrahydrofuran at 0°add 2.0 g of sodium hydride. The mixture was stirred at 0°C for 4 hours. The reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 10,86 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.

1H-NMR (CDCl3 /300 MHz) δ (ppm): of 3.80 (s, 3H), 5,09 (s, 2H), 7,11 (d, 1H, J=8,4 Hz), a 8.34 (d, 1H, J=8,4 Hz).

The second stage

A mixture of 1.0 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine, of 1.37 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, of 0.67 g of potassium carbonate and 5 ml of N,N-dimethylformamide is stirred for 1 hour at room temperature and then for 30 minutes at 50°C. the resulting mixture was poured into a mixture of ice water and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 2.25 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl )methoxy-3-nitropyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.56 (s, 3H), of 3.64 (s, 3H), to 4.81 (s, 2H), 6,36 (s, 1H), 6.75 in (d, 1H, J=8.6 Hz), 7,14 (d, 1H, J=6.6 Hz), 7,41 (d, 1H, J=8,9 Hz), charged 8.52 (d, 1H, J=8.6 Hz).

The third stage

A mixture of 2.25 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxy-3-nitropyridine, 0.3 g of 10% palladium-on-coal, and 40 ml of ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The remainder of the paragraph will gorhaut column chromatography on silica gel and get to 1.38 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-phenoxy}-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.54 (s, 3H), 3,6-3,7 (ush, 2H), to 3.67 (s, 3H), amounts to 4.76 (s, 2H), 6,33 (s, 1H), 6,47 (d, 1H, J=8.1 Hz), to 7.0, and 7.1 (m, 2H), 7,35 (d, 1H, J=8,9 Hz).

The fourth stage

To a mixture of 1.28 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 3 ml of 1,2-dimethoxyethane and 1 ml of dichloromethane at -7°With added dropwise to 0.72 g of the complex of diethyl ether and boron TRIFLUORIDE. The mixture is stirred for 10 minutes at the same temperature and then the reaction solution at -5°or lesser temperature is added dropwise 0.31 g of tert-butylnitrite. The mixture is stirred for 1 hour at the same temperature and the mixture pour in n-pentane. The solvent is removed by decantation, to the residue, add 7 ml of ethanol and 1.2 g of zinc (dust) and the mixture is boiled with stirring under reflux for 1.5 hours. The reaction solution is filtered through celite, the solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and obtain 0.73 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-(methoxycarbonyl)methoxypyridine [connection 2-45 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,55 (s, 3H), 3,66 (s, 3H), of 4.67 (s, 2H), 6,34 (s, 1H), 6,5-6,6 (m, 1H), 7,1-7,2 (m, 1H), 7.3 to 7.4 (m, 1H), about 7.6 to 7.7 (m, 1H).

Example of getting a 21. aluchemie connection 7-95 of the present invention

The first stage

To a mixture of 2,6-dichloro-3-nitropyridine, methylglucose and 1,4-dioxane at 10°add sodium hydride. The mixture is stirred at room temperature for 2 hours, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.

The second stage

A mixture of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine, platinum oxide and ethanol is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get 3-amino-6-chloro-2-(methoxycarbonyl)methoxypyridine.

The third stage

To a mixture of 3-amino-6-chloro-2-(methoxycarbonyl)methoxypyridine, 1,2-dimethoxyethane and dichloromethane at -10°With added dropwise diethylether of boron TRIFLUORIDE. After stirring for 10 minutes at the same temperature to the reaction solution at -5°or lesser temperature is added dropwise a solution of tert-butylnitrite in 1,2-dimethoxyethane. After stirring for 30 minutes at the same temperature in the mixture pour in n-pentane. N the life layer of the two divided layers are dissolved in acetic anhydride and the mixture is stirred for 1 hour at 80° C. the Solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and get 3-acetoxy-6-chloro-2-(methoxycarbonyl)methoxypyridine.

The fourth stage

A mixture of 3-acetoxy-6-chloro-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 6-chloro-3-hydroxy-2-(methoxycarbonyl)methoxypyridine.

Fifth stage

To a mixture of 6-chloro-3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 2.5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide add the potassium carbonate and the mixture is stirred for 2 hours at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine.

Sixth stage

To a mixture of p is Roshka iron, acetic acid and water is added dropwise a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine, maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the addition the mixture is stirred for 2 hours, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and get 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine.

The seventh stage

To a mixture of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine, chloride, copper(I)chloride copper(II) and acetonitrile at room temperature is added dropwise to soliditet and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column of chromatogra the AI on silica gel and get 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-(methoxycarbonyl)methoxypyridine [connection 7-95 of the present invention].

Example of getting a 22. Getting connection 7-109 of the present invention

The first stage

To a mixture of 2-chloro-6-methoxy-3-nitropyridine, methylglucose and 1,4-dioxane at 10°add sodium hydride. The mixture is stirred at room temperature for 2 hours, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 6-methoxy-2-(methoxycarbonyl)methoxy-3-nitropyridine.

The second stage

A mixture of 6-methoxy-2-(methoxycarbonyl)methoxy-3-nitropyridine, platinum oxide and ethanol is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get 3-amino-6-methoxy-2-(methoxycarbonyl)methoxypyridine.

The third stage

To a mixture of 3-amino-6-methoxy-2-(methoxycarbonyl)methoxypyridine, 1,2-dimethoxyethane and dichloromethane at -10°With added dropwise diethylether of boron TRIFLUORIDE. After stirring for 10 minutes at the same temperature to the reaction solution at -5°or lesser temperature is added dropwise a solution of tert-butylnitrite 1.2-dimetoxy is not. After stirring for 30 minutes at the same temperature in the mixture pour in n-pentane. The bottom layer of the two divided layers are dissolved in acetic anhydride and the mixture is stirred for 1 hour at 80°C. the Solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and get 3-acetoxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine.

The fourth stage

A mixture of 3-acetoxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine.

Fifth stage

To a mixture of 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, 2.5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide add the potassium carbonate and the mixture is stirred for 2 hours at 70°C. the Reaction solution is cooled to room temperature, then poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The remainder under the will eraut column chromatography on silica gel and get 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.

Sixth stage

To a mixture of iron powder, acetic acid and water is added dropwise a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine, maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the addition the mixture is stirred for 2 hours, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and get 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.

The seventh stage

To a mixture of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine, chloride, copper(I)chloride copper(II) and acetonitrile at room temperature is added dropwise to soliditet and the mixture is stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and to the center. The residue is subjected to column chromatography on silica gel and get 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine [connection 7-109 of the present invention].

An example of retrieving 23. Getting connection 7-8 of the present invention

A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention], 0,13 g of sodium carbonate and 7.0 ml of ethanol is refluxed for 2 hours. The mixture is cooled to room temperature, then the solvent is distilled off under reduced pressure and the resulting residue is subjected to chromatography on silica gel, to obtain 0.55 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)labels-dipyridine [connection 7-8 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm): a 1.25 (t, 3H, J=7,1 Hz), 3,50 (K, 3H, J=1.2 Hz), 4.16 the (K, 2H, J=7,1 Hz), 4,88 (d, 1H, J=15,9 Hz), 4,96 (d, 1H, J=15,9 Hz), of 6.29 (s, 1H), 6,9-7,0 (m, 2H), 7.3 to 7.4 (m, 2H), 7,9-8,0 (m, 1H).

Example of getting 24. Getting connection 7-48 present invention

A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of this image is the shadow], of 0.13 g of sodium carbonate and 7.0 ml of n-propanol is refluxed for 2 hours. The mixture is cooled to room temperature, then the solvent is distilled off under reduced pressure, the obtained residue is subjected to chromatography on silica gel and get to 0.62 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(n-propoxycarbonyl)methoxypyridine [connection 7-48 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): to 0.89 (t, 3H, J=7,3 Hz), and 1.63 (CT, 2H, J=7,3, 6.5 Hz), 3,50 (K, 3H, J=0.8 Hz), 4,06 (t, 2H, J=6.5 Hz), 4,89 (d, 1H, J=16.0 Hz), equal to 4.97 (d, 1H, J=16.0 Hz), 6,28 (s, 1H), 6,91 (DD, 1H, J=7,8, 5.0 Hz), 6,93 (d, 1H, J=6.5 Hz), 7,31 (DD, 1H, J=7,8, and 1.6 Hz), was 7.36 (d, 1H, J=8,9 Hz), to $ 7.91 (DD, 1H, J=5.0 and 1.6 Hz).

An example of obtaining 25. Getting connection 7-50 present invention

A mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention], 0.06 g of sodium carbonate and 3.0 ml of n-pentanol stirred for 1.5 hours at 100°C. the Reaction solution is cooled to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.07 g of 3-{2-chloro-4-fluoro-5-[3-methyl-26 dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(n-pentyloxybenzoyl)methoxypyridine [connection 7-50 present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 0,88 (t, 3H, J=6.6 Hz), 1,2-1,4 (m, 4H), of 1.5-1.7 (m, 2H), 3,50 (K, 3H, J=1.0 Hz), 4,0-4,2 (m, 2H), 4,8-5,1 (m, 2H), 6,29 (s, 1H), 6,9-7,0 (m, 2H), 7,28 (DD, 1H, J=7,9, 1,4 Hz), 7,37 (d, 1H, J=9.0 Hz), to $ 7.91 (DD, 1H, J=4,9, 1,4 Hz).

Example 7 to obtain the intermediate compounds. Obtain 3-amino-2-(methoxycarbonyl)methoxypyridine used in the example of obtaining 13, the third stage

A mixture of 55.9 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine, 8,64 g of 10% palladium-on-coal and 600 ml of ethyl acetate is stirred for 2 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get 46,76 g 3-amino-2-(methoxycarbonyl)methoxypyridine.

Example 8 to obtain the intermediate compounds. Obtain 3-acetoxy-2-(methoxycarbonyl)methoxypyridine used in the example of obtaining 13, the fourth stage

To a mixture of 0.5 g of 3-amino-2-(methoxycarbonyl)methoxypyridine, 1.5 ml 1,2-dimethoxyethane and 0.5 ml of dichloromethane at -10°With added dropwise 0,41 g triftormetilfullerenov acid. The mixture is stirred for 10 minutes at the same temperature, then, to the reaction solution at -5°or lesser temperature is added dropwise a solution of 0.34 g of tert-butylnitrite in 0.5 ml of 1,2-dimethoxyethane. The mixture peremeci is up within 1 hour at the same temperature and then the mixture pour in n-pentane. The bottom layer of the two divided layers are dissolved in 1.5 ml of acetic anhydride and the mixture is stirred for 30 minutes at 60°C. the Reaction solution is cooled to room temperature, then poured into water and extracted with tert-butylmethylamine ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to chromatography on silica gel and get to 0.30 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine.

Example of receipt 26. Getting connections 7-17 of the present invention

The first stage

To a mixture of 5.0 g of 2-chloro-5-nitropyridine, 3.13 g of methylglycol and 50 ml of tetrahydrofuran at 0°With added 1.26 g of sodium hydride. The mixture was stirred at 0°C for 15 minutes and then at room temperature for 1 hour. The reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 5,18 g of 2-(methoxycarbonyl)methoxy-5-nitropyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,79 (s, 3H), free 5.01 (s, 2H), 6,99 (d, 1H, J=9.1 Hz), to 8.41 (DD, 1H, J=9,1, 2,8 Hz), 9,03 (d, 1H, J=2,8 Hz).

The second stage

The mixture is 5.18 g of 2-(methoxycarbonyl)methoxy-5-nitropyridine, 0.8 g of 10% Pallady is-on-coal and 50 ml of ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and receive of 4.45 g of 5-amino-2-(methoxycarbonyl)-methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,3-3,5 (USS, 2H), 3,76 (s, 3H), 4,82 (s, 2H), 6,72 (d, 1H, J=8.6 Hz),? 7.04 baby mortality (DD, 1H, J=8,6, 2,9 Hz), 7,58 (DD, 1H, J=2, 9 Hz).

The third stage

To a mixture of 3.0 g of 5-amino-2-(methoxycarbonyl)methoxypyridine, 9 ml of 1,2-dimethoxyethane and 3 ml of dichloromethane at -10°With added dropwise a 1.46 ml triftormetilfullerenov acid. The mixture is stirred for 10 minutes at the same temperature, then, to the reaction solution at -10°or lesser temperature is added dropwise to 2.35 ml solution of tert-butylnitrite in 1 ml of 1,2-dimethoxyethane. To this mixture 1,2-dimethoxyethane and stirred for 20 minutes at the same temperature, then the mixture pour in n-pentane. Precipitated precipitated solid is washed with n-pentane, then it is dissolved in 18 ml of acetic anhydride and the mixture is stirred for 2 hours at 80°C. the Mixture is then poured into a mixture of ice water and extracted with tert-butylmethylamine ether. The organic layer is concentrated and then diluted with tert-butylmethylamine ether. The resulting mixture was washed with saturated aqueous sodium bicarbonate, then saturated brine, dried to the anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 1.4 g of 5-acetoxy-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 2,30 (s, 3H), of 3.77 (s, 3H), 4,89 (s, 2H), to 6.88 (d, 1H, J=8,8 Hz), 7,40 (DD, 1H, J=8,8, 2,8 Hz), 7,89 (DD, 1H, J=2,8 Hz).

The fourth stage

A mixture of 1.4 g of 5-acetoxy-2-(methoxycarbonyl)methoxypyridine, of 0.47 g of potassium carbonate and 10 ml of methanol is stirred for 4.5 hours at room temperature. The solvent is distilled off under reduced pressure, to the residue water is added and the mixture is then neutralized with hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 1.0 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.78 (s, 3H), 4,84 (s, 2H), of 5.92 (USS, 1H), 6,72 (d, 1H, J=8,9 Hz), 7,12 (DD, 1H, J=8,9, 2,9 Hz), a 7.62 (d, 1H, J=2,9 Hz).

Fifth stage

To a mixture of 0.5 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0,80 g 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 5 ml of N,N-dimethylformamide added 0.35 g of potassium carbonate and the mixture is stirred for 1.5 hours at 50°C. the Solution is cooled to room temperature, poured into a mixture of water, hydrochloric acid and brine and e is stragiht with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,54 (K, 3H, J=1.2 Hz), 3,79 (s, 3H), 4,89 (s, 2H), 6,34 (s, 1H), 6,8-7,0 (m, 2H), 7,42 (DD, 1H, J=9,2, 2,9 Hz), 7,88 (d, 1H, J=8.5 Hz), of 7.96 (d, 1H, J=2,9 Hz).

Sixth stage

To a mixture of 1.2 g of iron powder, 5 ml of acetic acid and 0.5 ml of water is added dropwise a solution of 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl] -2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine in 4 ml of acetic acid, maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the addition the mixture is stirred for 2 hours, then filtered through celite and concentrated. The residue is diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. Then the obtained residue is subjected to chromatography on silica gel and get 0,83 g 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)detoxified is on.

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,52 (K, 3H, J=1.2 Hz), of 3.78 (s, 3H), 4,16 (USS, 2H), to 4.87 (s, 2H), of 6.31 (s, 1H), to 6.57 (d, 1H, J=6,8 Hz), only 6.64 (d, 1H, J=10,8 Hz), 6,85 (DD, 1H, J=8,9, 0.5 Hz), 7,35 (DD, 1H, J=8,9, 3.1 Hz), of 7.90 (DD, 1H, J=3.1 and 0.5 Hz).

The seventh stage

To a mixture of 0.83 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl}-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 0.34 g of copper chloride(I), 0,69 g of copper chloride(II) and 3 ml of acetonitrile at room temperature is added dropwise 0.3 g isoamylamine and the mixture is stirred for 1 hour. Add to a mixture of 0.3 g of isoamylamine and the mixture is stirred for 20 minutes. This reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.52 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-Tetra-hydropyridine-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [Saedinenie 7-17 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm): 3,53 (K, 3H, J=1.3 Hz), of 3.78 (s, 3H), 4,88 (s, 2H), 6,33 (s, 1H), 6,76 (d, 1H, J=6.5 Hz), to 6.88 (d, 1H, J=8,9 Hz), 7.3 to 7.4 (m, 1H), 7,39 (d, 1H, J=8,9 Hz), 7,8-7,9 (m, 1H).

Example of getting 27. Obtaining compounds 7-12 of the present invention

The first stage

A mixture of 0.08 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(triform the Teal)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-17 connection of the present invention] and 1 ml of 48% Hydrobromic acid is stirred at the boil under reflux for 3 hours. The mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated, to obtain 0.06 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,51 (s, 3H), of 6.31 (s, 1H), return of 6.58 (d, 1H, J=9.8 Hz), 6,79 (d, 1H, J=6.5 Hz), 7,24 (d, 1H, J=3.0 Hz), 7.3 to 7.4 (m, 2H).

The second stage

To a mixture of 60 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone, 1.0 ml of tetrahydrofuran, 25 mg metallichica and 64 mg of triphenylphosphine added 123 mg of a 40% solution of diisopropylcarbodiimide in toluene and the mixture is stirred for 2 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive 20 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(meloxicam-bonyl)ethoxy}pyridine [compound 7-12 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,60 (d, 3H, J=7.0 Hz), 3,53 (s, 3H), of 3.75 (s, 3H), 5,28 (K, 1H, J=7,0 Hz), 6,32 (s, 1/2H), 6,33 (s, 1/2H), 6,7-6,8 (m, 1H), at 6.84 (d, 1H, J=9.1 Hz), 7.3 to 7.4 (m, 1H), 7,38 (d, 1H, J=8,8 Hz), 7,8-7,9 (m, 1 is).

Example of getting 28. Obtaining compounds 1-45 of the present invention

The first stage

To a mixture of 1.59 g of 4-chloro-6-methoxy-5-nitropyrimidine, and 0.98 g of methylglycol and 10 ml of N,N-dimethylformamide at 0°add 0.4 g of sodium hydride. The mixture is stirred at room temperature for 5 hours, then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine.

1H-NMR (CDCl3/250 MHz) δ (ppm): 2,48 (s, 3H), of 3.77 (s, 3H), 3,93 (s, 3H), 4,88 (s, 2H), by 5.87 (s, 1H).

The second stage

To a solution of 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine in 10 ml of chloroform at 0°add 2,59 g 3-chloroperoxybenzoic acid. The mixture is stirred at room temperature for 3 hours and then added to the mixture of 30 ml of a saturated aqueous solution of sodium thiosulfate. The mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and get to 1.32 g of 6-methoxy-4-(methoxycarbonyl)m the toxi-2-methylsulfonylamino.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,26 (s, 3H), of 3.78 (s, 3H), 4,06 (s, 3H), equal to 4.97 (s, 2H), 6,34 (s, 1H).

The third stage

To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 359 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylamino and 3 ml of N,N-dimethylformamide added 196 mg of potassium carbonate and the mixture is stirred for 1 hour at 80°C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 620 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-(methoxycarbonyl)methoxypyridine [connection 1-45 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,55 (s, 3H), 3,71 (s, 3H), a 3.87 (s, 3H), 4,78 (s, 2H), 5,95 (s, 1H), 6,34 (s, 1H), 7,1-7,2 (m, 1H), 7,37 (d, 1H, J=9.1 Hz).

TPL 60,3°C.

Example get 29. Obtaining compounds 1-42 of the present invention

The first stage

To a solution of 3.9 g of 4,6-dichloro-2-methylthiopyrimidine in 20 ml of N,N-dimethylformamide at 0°add 3,86 g of a 28% solution of sodium methoxide in methanol. Then the mixture is stirred at room temperature for 7 hours the century To the mixture are added 20 g of ice, then dropped into the sediment white substance is collected by filtration with suction, and this solid is washed with water. The solid is dissolved in ethyl acetate, the solution washed with saturated brine, dried over anhydrous magnesium sulfate and concentrate, get 3,18 g of 4-chloro-6-methoxy-2-methylthiopyrimidine.

1H-NMR (CDCl3/300 MHz) δ (ppm): to 2.55 (s, 3H), 3,98 (s, 3H), 6,41 (s, 1H).

The second stage

To a mixture of 1.59 g of 4-chloro-6-methoxy-5-methylthiopyrimidine, 1.13 g of metallichica and 10 ml of N,N-dimethylformamide at 0°add 0.4 g of sodium hydride. The mixture is stirred at room temperature for 5 hours, then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 1.5 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylthiopyrimidine.

1H-NMR (CDCl3/250 MHz) δ (ppm): was 1.58 (d, 3H, J=7.0 Hz), the 2.46 (s, 3H), of 3.73 (s, 3H), 3,92 (s, 3H), 5,33 (K, 1H, J=7,0 Hz), of 5.83 (s, 1H).

The third stage

To a solution of 1.40 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylthiopyrimidine in 13 ml of chloroform at 0°add 2,81 g 3-chloroperoxybenzoic acid. The mixture is stirred at room temperature for 3 hours and then to the mixture add the keys 30 ml of a saturated aqueous solution of sodium thiosulfate. The mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to chromatography on silica gel and gain of 1.62 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylamino.

1H-NMR (CDCl3/250 MHz) δ (ppm): and 1.63 (d, 3H, J=7,0 Hz)at 3.25 (s, 3H), of 3.75 (s, 3H), 4,06 (s, 3H), are 5.36 (K, 1H, J=7,0 Hz), 6.30-in (s, 1H).

The fourth stage

To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 377 mg of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylamino and 3 ml of N,N-dimethylformamide added 196 mg of potassium carbonate and the mixture is stirred for 1 hour at 80°C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 630 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl] phenoxy}-6-methoxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [compound 1-42 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.52 (d, 3H, J=6.8 Hz), 3,55 (s, 3H), 367 (, 3H), a 3.87 (s, 3H), 5,2-5,3 (m, 1H), 5,91 (s, 1H), 6.35mm (s, 1H), 7,16 (d, 1H, J=6,7 Hz), 7,37 (d, 1H, J=9.1 Hz).

TPL 71,2°C.

Example 30. Getting connection 7-82 present invention

A mixture of 0.60 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [7-7 connection of the present invention], 0,13 g of sodium carbonate, 0.39 g of benzyl alcohol, and 2.4 ml of warm toluene at 90°C for 2 hours and then refluxed for 2 hours. The mixture is cooled to room temperature, then the solvent is distilled off, the obtained residue is subjected to chromatography on silica gel and obtain 0.24 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(benzyloxycarbonyl)methoxypyridine [connection 7-82 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,47 (s, 3H), of 5.15 (s, 2H), and 6.25 (s, 1H), 6,8-7,0 (m, 2H), 7,2-7,4 (m, 7H), 7,89 (DD, 1H, J=4,9, 1.3 Hz).

Example of getting 31. Getting connection 7-6 of the present invention

A mixture of 0.24 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(benzyloxycarbonyl)methoxypyridine [connection 7-82 of the present invention], 10 mg of 10% palladium-on-coal and 1 ml of ethyl acetate is stirred for 1.5 hours at room temperature in a hydrogen atmosphere. The reaction system p is duvaut nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-carboxyphenoxypropane [connection 7-6 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,50 (s, 3H), 4.92 in (s, 2H), 6,32 (s, 1H), 6,80 (d, 1H, J=6.4 Hz), to 6.95 (DD, 1H, J=7,7, a 4.9 Hz), 7,35 (DD, 1H, J=7,7, 1.2 Hz), 7,37 (d, 1H, J=6.0 Hz), to 7.93 (DD, 1H, J=4,9, 1.2 Hz).

Example get 32. Getting connection 7-84 present invention

To a mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-carboxyphenoxypropane [connection 7-6 of the present invention] and 56 mg of the hydrochloride of O-methylhydroxylamine, 68 mg of triethylamine and 2 ml of N,N-dimethylformamide at room temperature type of 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and stirred for 2 hours. The mixture is then poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive 90 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-phenoxy}-2-[(methoxyaminomethyl)methoxy]pyridine [compound 7-84 of the present invention].

1H-NMR (CDCl3/300 is Hz) δ (ppm): to 3.52 (s, 3H), 3,74 (s, 3H), to 4.87 (s, 2H), 6,32 (s, 1H), of 6.71 (d, 1H, J=6.0 Hz), of 6.99 (DD, 1H, J=7,6, 5.0 Hz), 7,38 (DD, 1H, J=7,6, 1.7 Hz), 7,44 (d, 1H, J=8.7 Hz), 8,00 (DD, 1H, J=5.0 and 1.7 Hz), 8,7-9,0 (USS, 1H).

An example of obtaining 33. Getting connection 7-119 of the present invention

To a mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-carboxyphenoxypropane [connection 7-6 of the present invention], 60 mg of methylglucose and 2 ml of N,N-dimethylformamide at room temperature type of 0.13 g of the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and stirred for 1.5 hours. The mixture is then poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.18 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-[(methoxycarbonyl)ethoxycarbonylmethoxy]pyridine [compound 7-119 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,50 (s, 3H), 3,74 (s, 3H)and 4.65 (s, 2H), free 5.01 (d, 1H, J=16.2 Hz), 5,09 (d, 1H, J=16.2 Hz), 6,28 (s, 1H), to 6.88 (d, 1H, J=6,7 Hz), 6,93 (DD, 1H, J=7,8, and 4.9 Hz), 7,32 (DD, 1H, J=7,8, the 1.4 Hz), 7,37 (d, 1H, J=9.0 Hz), to 7.93 (DD, 1H, J=4,9, 1,4 Hz).

An example of retrieving 34. Getting connection 7-118 of the present invention

To a mixture of 0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,C,6-tetrahydropyrimidin-yl]phenoxy}-2-carboxyphenoxypropane [connection 7-6 of the present invention], 49 mg acetoxy and 2 ml of N,N-dimethylformamide at room temperature type of 0.13 g of the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and stirred for 2 hours. The mixture is then poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-isopropylidenedicyclohexanol [connection 7-118 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,94 (s, 3H), a 2.01 (s, 3H), 3,49 (s, 3H), 5,0-5,2 (m, 2H), 6,27 (s, 1H), 6,92 (DD, 1H, J=7,8, and 4.9 Hz), 6,98 (d, 1H, J=6, 5 Hz), 7.3 to 7.4 (m, 2H), 7,92 (d, 1H, J=4,9 Hz).

Example of getting 35. Getting connection 9-7 present invention

To the mixture is 0.22 g of copper bromide(I), 0.05 g of copper bromide(II) and 1 ml of acetonitrile at 0°add a solution of 0.5 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine in 1.5 ml of acetonitrile. To the mixture is added dropwise during 30 minutes a solution of 0.18 g of tert-butylnitrite in 1 ml of acetonitrile and the mixture is then stirred at room temperature overnight. This reaction solution was poured into hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with nassen the m brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.28 g of 3-{2-bromo-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [connection 9-7 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,50 (K, 3H, J=l,2 Hz), 3,70 (s, 3H), 4,8-5,0 (m, 2H), 6,29 (s, 1H), to 6.88 (d, 1H, J=6.4 Hz), 6,93 (DD, 1H, J=7,8, 5.0 Hz), 7,32 (d, 1H, J=7.8 Hz), 7,53 (d, 1H, J=8.5 Hz), 7,92 (d, 1H, J=5.0 Hz).

Example obtain 36. Getting connection 9-27 present invention

A mixture of 0.23 g of 3-{2-bromo-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [connection 9-7 of the present invention], 75 mg of copper cyanide and 2 ml of N-methyl-2-pyrrolidone was stirred at 160°C for 2 hours. The reaction mixture is cooled to room temperature, add water to the mixture and the resulting mixture extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.16 g of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [connection 9-27 of the present invention]. TPL 173,1°C.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,49 (s, 3H), to 3.67 (s, 3H), 4,8-5, (m, 2H), 6,28 (s, 1H), of 6.96 (d, 1H, J=5.7 Hz), 7,00 (DD, 1H, J=7,8, 5.0 Hz), 7,50 (d, 1H, J=8,4 Hz), 7,54 (d, 1H, J=7.8 Hz), 8,01 (d, 1H, J=5.0 Hz).

Example of getting 37. Getting connection 2-42 of the present invention

The first stage

To the mixture 9,65 g of 2,6-dichloro-3-nitropyridine, 5,41 g of benzyl alcohol and 30 ml of tetrahydrofuran at 0°add 2.0 g of sodium hydride. The mixture was stirred at 0°C for 1.5 hours and then at room temperature for 1.5 hours. The reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and receive of 10.93 g of 6-chloro-2-benzyloxy-3-nitropyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): is 5.18 (s, 2H), 7,05 (d, 1H, J=8,3 Hz), and 7.3 and 7.6 (m, 5H), of 8.28 (d, 1H, J=8,3 Hz).

The second stage

A mixture of 5.29 g of 6-chloro-2-benzyloxy-3-nitropyridine, 6,77 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, of 3.32 g of potassium carbonate and 30 ml of N,N-dimethylformamide is stirred for 30 minutes at room temperature and then for 2.5 hours at 50°C. the resulting residue is added to a mixture of ice water and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The remainder of Perekrest lizovyvatj of ethyl acetate and hexane and get 9,11 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxy-3-nitropyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.56 (s, 3H), from 5.29 (s, 2H), 6,37 (s, 1H), of 6.68 (d, 1H, J=8.6 Hz), and 7.1 to 7.4 (m, 6N), 7,37 (d, 1H, J=8,8 Hz), of 8.47 (d, 1H, J=8.6 Hz).

The third stage

To a mixture of 3.0 g of iron powder, 15 ml of acetic acid and 1.5 ml of water is added dropwise a solution of 3.0 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxy-3-nitropyridine in 10 ml of acetic acid and 10 ml of ethyl acetate, while maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the addition the mixture is stirred overnight, then filtered through celite and remove the solvent under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to chromatography on silica gel and get to 2.55 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,51 (s, 3H), 3,60 (USS, 2H), 5,1-5,3 (m, 2H), 6,33 (s, 1H), 6.42 per (d, 1H, J=7.9 Hz), of 6.99 (d, 1H, J=8,2 Hz), was 7.08 (d, 1H, J=6,7 Hz), 7,2-7,4 (m, 6N).

The fourth stage

To a mixture of 2.55 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxypyridine, 6 ml of 1,2-dimetho is sitana and 2 ml of dichloromethane at -5° With added dropwise to 1.38 g of the complex of diethyl ether and boron TRIFLUORIDE. The mixture is stirred for 15 minutes at the same temperature, then, to the reaction solution at -5°With added dropwise 0,59 g of tert-butylnitrite. The mixture is stirred for 1 hour at the same temperature and then the mixture pour in n-pentane. The solvent is removed by decantation, the residue is added 15 ml of ethanol and 2.3 g of zinc (dust) and the mixture is stirred at the boil under reflux for 1.5 hours. The reaction solution is filtered through celite, the solvent is distilled off, and then the obtained residue is subjected to chromatography on silica gel and obtain 0.75 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-benzyloxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): to 3.52 (s, 3H), 5,0-5,2 (m, 2H), 6,34 (s, 1H), 6,5-6,6 (m, 2H), and 7.1 to 7.4 (m, 6N), 7,34 (d, 1H, J=9.1 Hz), and 7.5 to 7.7 (m, 1H).

Fifth stage

A mixture of 0.90 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-benzyloxypyridine, 0.1 g of 10% palladium-on-coal and 5 ml of ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get 0,60g 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 3.54 (s, 3H), 6,11 (d, 1H, J=7.9 Hz), 6,33 (s, 1H), 6,44 (d, 1H, J=7.8 Hz), to 7.09 (d, 1H, J=6,7 Hz), 7,37 (d, 1H, J=8,9 Hz), 7,55 (DD, 1H, J=7,9, 7,8 Hz).

Sixth stage

To a mixture of 50 mg of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone, 21 mg, 2-bromopropionate and 1 ml of N,N-dimethylformamide added 21 mg of potassium carbonate and the mixture is stirred for 1 hour at 50°C. the Solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 72 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-{1-(methoxycarbonyl)ethoxy}pyridine [compound 2-42 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): to 1.48 (d, 3H, J=6.9 Hz), 3,55 (s, 3H), of 3.60 (s, 3/2H), 3,61 (s, 3/2H), 5,10 (K, 1H, J=6.9 Hz), 5,12 (K, 1H, J=6, 9 Hz), 6,34 (s, 1H), 6,55 (d, 1H, J=8.0 Hz), 6,56 (DD, 1H, J=7,9, 2,9 Hz), 7,14 (DD, 1H, J=6,9, 2,9 Hz), 7,37 (d, 1H, J=9.0 Hz), a 7.62 (DD, 1H, J=7,9, 6,9 Hz).

Example of getting 38. Getting connection 1-67 of the present invention

To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 360 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylamino and 2 ml of N,N-Dimethylol the amide type 196 mg of potassium carbonate and the mixture is stirred for 5 hours at 80° C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 98 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylamino}-6-methoxy-4-(methoxycarbonyl)methoxypyridine [compound 1-67 of the present invention].

1H-NMR (CDCl3/250 MHz) δ (ppm): only 3.57 (s, 3H), of 3.65 (s, 3H), 3,91 (s, 3H), 4,7-4,9 (m, 2H), of 5.75 (s, 1H), 6,38 (s, 1H), 7,32 (d, 1H, J=8,8 Hz), 7,37 (USS, 1H), of 8.37 (d, 1H, J=7,3 Hz).

TPL 155,6°C.

An example of retrieving 39. Getting connection 2-52 of the present invention

A mixture of 1 g of 3-amino-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine and of 1.16 g of 2-bromopropionate stirred for 30 minutes at 60°and then for 4 hours at 80°C. the Mixture is subjected to column chromatography on silica gel and obtain 0.4 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-{1-(methoxycarbonyl)ethylamino}pyridine [compound 2-52 of the present invention].

TPL 66,4°C.

Example of getting 40. Getting connection 7-8 of the present invention

The first stage

To the mixture 39,63 g 2-PI is the p-3-nitropyridine, 31,23 g ethylglycol, 250 ml of tetrahydrofuran and 20 ml of N,N-dimethylformamide at 0°add 11 g of sodium hydride. The mixture is stirred at room temperature for 5 hours, then the reaction solution is poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get to 48.3 g of 2-(etoxycarbonyl)methoxy-3-nitropyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 1.26 in (t, 3H, J=7,1 Hz), 4,23 (K, 2H, J=7,1 Hz), is 5.06 (s, 2H), 7,0-7,2 (m, 1H), 8,3 an 8.4 (m, 2H).

The second stage

The mixture was 48.3 g of 2-(etoxycarbonyl)methoxy-3-nitropyridine, and 7.8 g of 10% palladium-on-coal and 540 ml of ethyl acetate is stirred for 3 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get to 37.1 g of 3-amino-2-(etoxycarbonyl)-methoxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 1.27 (t, 3H, J=7,1 Hz), 3,8-3,9 (ush, 2H), 4,24 (K, 2H, J=7,1 Hz), is 4.93 (s, 2H), 6,7-6,8 (m, 1H), 6,8-7,0 (m, 1H), 7,4-7,6 (m, 1H).

The third stage

To a mixture of 12 g of 3-amino-2-(etoxycarbonyl)methoxypyridine, 36 ml of 1,2-dimethoxyethane and 12 ml of dichloromethane at -5°With added dropwise 9,18 g triftormetilfullerenov acid. A mixture of TRANS who mesilat for 10 minutes at the same temperature and then the reaction solution at -5° With or lower temperature is added dropwise a solution of EUR 7.57 g of tert-butylnitrite in 3 ml of 1,2-dimethoxyethane. The mixture is stirred for 30 minutes at the same temperature and then the mixture pour in n-pentane. The bottom layer of the two divided layers are dissolved in 12 ml of acetic anhydride and the mixture is stirred for 2.5 hours at 50°C. the Reaction solution is poured into a mixture of ice water and extracted with tert-butylmethylamine ether. The organic layer was washed with saturated aqueous sodium bicarbonate, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is subjected to chromatography on silica gel and get to 4.2 g of 3-acetoxy-2-(etoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/300 MHz) δ (ppm): 1.26 in (t, 3H, J=7,1 Hz), was 2.34 (s, 3H), 4,22 (K, 2H, J=7,1 Hz), the 4.90 (s, 2H), 6,94 (DD, 1H, J=7,8, 5.0 Hz), 7,38 (DD, 1H, J=7,8, 1.5 Hz), of 7.97 (DD, 1H, J=5.0 and 1.5 Hz).

The fourth stage

A mixture of 13.8 g of 3-acetoxy-2-(etoxycarbonyl)methoxypyridine, of 4.38 g of potassium carbonate and 60 ml of ethanol is stirred over night at room temperature. The reaction solution is poured into a mixture of water, sodium chloride and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 10,45 g 3-is hydroxy-2-(etoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 1.28 (t, 3H, J=7,1 Hz), 4,25 (K, 2H, J=7,1 Hz), equal to 4.97 (s, 2H), to 5.93 (s, 1H), 6,86 (DD, 1H, J=7,7, a 4.9 Hz), 7,17 (DD, 1H, J=7,7, 1,6 Hz), the 7.65 (DD, 1H, J=4,9, 1,6 Hz).

Fifth stage

To the mixture 10,45 g of 3-hydroxy-2-(etoxycarbonyl)methoxypyridine, 16,92 g 2,5-debtor-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 100 ml of N,N-dimethylformamide add to 7.32 g of potassium carbonate and the mixture is stirred for 2 hours at 70°C. the Solution is cooled to room temperature, poured into a mixture of ice water, sodium chloride and hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 17,28 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(etoxycarbonyl)methoxypyridine [connection 9-46 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): a 1.25 (t, 3H, J=7,3 Hz), 3,50 (s, 3H), 4,12 (K, 2H, J=7,3 Hz), is 4.85 (d, 1H, J=15,9 Hz), of 4.95 (d, 1H, J=15,GC), 6,28 (s, 1H), 6,98 (DD, 1H, J=7,8, 5.0 Hz), 7,13 (d, 1H, J=6,1 Hz), to 7.50 (DD, 1H, J=7,8, and 1.4 Hz), 7,87 (d, 1H, J=8.6 Hz), to 7.99 (DD, 1H, J=5.0 and 1.4 Hz).

Sixth stage

To a mixture of 17 g of iron powder, 30 ml of acetic acid and 3 ml of water is added dropwise a solution 17,28 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydrate-rimidine-1-yl] - nitrophenoxy}-2-(etoxycarbonyl)methoxypyridine [connection 9-46 present invention] in 20 ml of acetic acid, maintaining the temperature of the reaction solution at 35°With or below. Upon completion of the addition the mixture is stirred for 1 hour at room temperature and for 3 hours at 40°C, then the reaction solution is filtered through celite and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Then the obtained residue is subjected to column chromatography on silica gel and get 15,46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methoxypyridine.

1H-NMR (CDCl3/250 MHz) δ (ppm): of 1.27 (t, 3H, J=7,1 Hz), 3,52 (K, 3H, J=1.2 Hz), 4,21 (K, 2H, J=7,1 Hz), 4,27 (USS, 2H), 4,9-5,1 (m, 2H), of 6.31 (s, 1H), 6,63 (d, 1H, J=10,9 Hz), 6,79 (d, 1H, J=6.9 Hz), 6,86 (DD, 1H, J=7,8, and 4.9 Hz), 7.23 percent (DD, 1H, J=7,8, 1.5 Hz), 7,83 (DD, 1H, J=4,9, 1.5 Hz).

The seventh stage

To the mixture 15,46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4- (trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methoxypyridine, to 6.19 g of copper chloride(I)was 12.61 g of copper chloride (II) and 120 ml of acetonitrile at room temperature is added dropwise a solution of 10,99 g isoamylamine in 10 ml of acetonitrile and the mixture is stirred for 3 hours. This reaction solution was poured into a mixture of ice and hydrochloric acid and extracted with atilas what tatom. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 13,16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methoxypyridine [connection 7-8 of the present invention].

Example 9 to obtain the intermediate compounds. Obtain 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine

The first stage

To a solution of 227 mg triphosgene in 8 ml of ethyl acetate at 0°add a solution of 155 mg of triethylamine and 250 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline in 8 ml of ethyl acetate. The mixture is stirred for 30 minutes at the same temperature and then for 2 hours at the boil under reflux. The reaction solution is filtered while hot, the solvent is distilled off under reduced pressure and obtain 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenylisocyanate. TPL 113,8°C.

1H-NMR (CDCl3/300 MHz) δ (ppm): 3,76 (s, 3H), 4,96 (s, 2H), 6,69 (d, 1H, J=7,1 Hz), 6,93 (DD, 1H, J=7,8, 5.0 Hz), 7,2-7,3 (m, 2H), 7,94 (DD, 1H, J=5.0 and 1.4 Hz).

Similarly receive the following connections:

4-chloro-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}phenylisocyanate,

4-chloro-2-the top 5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]phenylisocyanate,

4-chloro-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]phenylisocyanate.

The second stage

To a mixture of 1 ml of N,N-dimethylformamide and 26 mg of sodium hydride add a solution of 126 mg of ethyl-3-amino-4,4,4-trifurcation in 1 ml N,N-dimethylformamide and the mixture is stirred at 0°C. Then the reaction mixture at the same temperature, add the mixture of 266 mg of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenylisocyanate and 1 ml of N,N-dimethylformamide and the mixture is stirred over night at room temperature. The reaction solution is poured into a mixture of hydrochloric acid and ice-water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.

An example of retrieving 41. The connection is 10-2 of the present invention

The first stage

To a mixture of 24 g of sodium hydride and 500 ml of tetrahydrofuran at room temperature is added dropwise 65 g of benzyl alcohol. The mixture is stirred as long as you do not stop the production of hydrogen, its cool to -50°and then to the mixture was added 100 g of 3,4-dichloro-1,2,5-thiadiazole. The mixture is stirred over night at room temperature and for 3 hours while boiling under reflux. The mixture is concentrated and then poured into dilute hydrochloric acid and extracted with tert-butylmethylamine ether. The organic layer is washed with water, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 33 g of 4-benzyloxy-3-chloro-1,2,5-thiadiazole (purity 72%).

1H-NMR (CDCl3/300 MHz) δ (ppm): 5,43 (s, 2H), 7,2-7,5 (m, 5H).

The second stage

To a solution of 0.60 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 0.50 g of 4-benzyloxy-3-chloro-1,2,5-thiadiazole in 8 ml of dimethyl sulfoxide add 0.25 g of potassium carbonate and the mixture is stirred for 30 minutes at 50°and then for 3 hours at 100°C. the Reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.27 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-1,2,5-thiadiazole (purity, 44%).

The third stage

A solution of 2.5 g of the crude 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-1,2,5-thiadiazole in 20 ml of triperoxonane stirred over night at room temperature. The solution is concentrated and the residue is subjected to column chromatography on silica gel, to obtain 0.50 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl) -1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole.

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.56 (s, 3H), 6,38 (s, 1H), and 7.3-7.5 (m, 2H).

The fourth stage

In 10 ml of N,N-dimethylformamide is dissolved 200 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg of 2-bromopropionate, to this solution was added 100 mg of potassium carbonate and the mixture is stirred for 3 hours at room temperature. This reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.17 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-[1-(methoxycarbonyl)ethoxy]-1,2,5-thiadiazole [compound 10-2 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,70 (d, 3H, J=6.9 Hz), 3,55 (s, 3H), 3,79 (s, 3H), 5,31 (K, 1H, J=6.9 Hz), 6,36 (s, 1H), and 7.3-7.5 (m, 2H).

Example get 42. Getting connection 10-7 of the present invention

In 10 ml of N,N-dimethylformamide is dissolved 200 mg of 3-{2-chloro-4-fluoro-5-[3-meth is l-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg methylpropanoate, to this solution was added 100 mg of potassium carbonate and the mixture is stirred for 3 hours at room temperature. This reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, then saturated brine, dried over anhydrous magnesium sulfate and concentrated. Then the obtained residue was washed with hexane and obtain 0.18 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-1,2,5-thiadiazole [compound 10-7 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.56 (s, 3H), 3,81 (s, 3H), free 5.01 (s, 2H), 6,36 (s, 1H), and 7.3-7.5 (m, 2H).

An example of retrieving 43. Getting connection 3-52 present invention

The first stage

To the mixture 0,098 g of sodium hydride and N,N-dimethylformamide add 0,829 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and the mixture is stirred at room temperature for 2 hours. Then added to the mixture of 5-benzyloxy-4-chloropyrimidine (obtained in the following way: a mixture of 0,495 g of 5-benzyloxy-4-pyrimidinone and 10 ml of phosphorylchloride stirred for 30 minutes at boiling under reflux, the mixture is then cooled to room temperature and concentrated; the residue is added a mixture of ice water, extracted with ether and the conc is t), and the mixture is stirred for 1 hour at room temperature and for 1 hour at 60-70° C. the Mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride, water, 20% aqueous potassium carbonate solution, water, dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0.959 g of 5-benzyloxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine. TPL 58,6°C.

The second stage

A mixture of 0.959 g of 5-benzyloxy-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine, 10% palladium-on-coal and ethyl acetate is stirred for 8 hours at room temperature in a hydrogen atmosphere. The reaction system is rinsed with nitrogen, then the reaction solution is filtered through celite and the filtrate concentrated. The residue is subjected to column chromatography on silica gel and get 0,824 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-hydroxypyrimidine. TPL 190,7°C.

The third stage

To a mixture of 32 mg of sodium hydride and N,N-dimethylformamide added 0.35 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-hydroxypyrimidine and stirred at room tempera what ur in for 1 hour. Then to the mixture is 0.135 g of methyl 2-bromopropionate and the mixture is stirred for 2 hours at room temperature and then for 1 hour at 50°C. the Mixture is then poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,319 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-{1-(methoxycarbonyl)ethoxy}pyrimidine [compound 3-52 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): 1,71 (d, 3H, J=6.8 Hz), 3,57 (d, 3H, J=0.9 Hz), of 3.78 (s, 3H), 5,01 (K, 1H, J=6,8 Hz), 6,37 (s, 1H), 7,24 (d, 1H, J=6,7 Hz), 7,42 (d, 1H, J=8.7 Hz), 8,32 (s, 1H), 8,40 (s, 1H).

An example of retrieving 44. Getting connection 3-57 of the present invention

To a mixture of 32 mg of sodium hydride and N,N-dimethylformamide added 0.35 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-hydroxypyrimidine and stirred at room temperature for 1 hour. Then added to the mixture 0,124 of methylpropanoate and the mixture is stirred for 2 hours at room temperature and then for 1 hour at 50°C. the Mixture is then poured into a saturated solution of ammonium chloride and extracted with ethylacetophenone layer was washed with a saturated solution of ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and get 0,328 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-(methoxycarbonyl)methoxypyridine [connection 3-57 of the present invention]. TPL 62,5°C.

An example of retrieving 45. Obtaining compounds 1-7 of the present invention

The first stage

In 20 ml of N,N-dimethylformamide was dissolved 2.6 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 1.7 g of 4-benzyloxy-2-chloropyrimidine, to this solution was added 1.07 g of potassium carbonate and the mixture is stirred for 2 hours at 80°C. the Reaction solution is cooled to room temperature, then the reaction solution was poured into a mixture of ice water and extracted with ethyl acetate. The organic layer is washed with 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and concentrated, to obtain 1.6 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl) -1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine.

The second stage

A solution of 1 g of 4-benzyloxy-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyrimidine in triperoxonane acid is stirred for 2 hours at 70°C. This reaction solution was cooled to whom atoi temperature, then poured into water and filtered, to obtain 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl] phenoxy}-4-hydroxypyrimidine.

The third stage

To a mixture of 0.3 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxypyrimidine, 127 mg of methylpropanoate and N,N-dimethylformamide at 0°add 30 mg of sodium hydride and the mixture is then stirred at room temperature. The solution is poured into a mixture of hydrochloric acid and ice-water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel and obtain 0.2 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine [connection 1-7 of the present invention].

1H-NMR (CDCl3/300 MHz) δ (ppm): of 3.56 (d, 3H, J=1.1 Hz), to 3.73 (s, 3H), around 4.85 (s, 2H), 6.35mm (s, 1H), 6,63 (d, 1H, J=5.6 Hz), 7,18 (d, 1H, J=6.9 Hz), 7,38 (d, 1H, J=9.1 Hz), 8,30 (d, 1H, J=5.7 Hz).

Forth in tables 1-10 are examples of some compounds of the present invention with the number of connections, but the scope of the present invention, these examples are not limited.

The following are examples of compositions with the compounds of the present invention. In these examples, the connection is the link specified as the connection number, shown in tables 1-10, and "part (s)" is given as "mass (mass) part (s)".

EXAMPLE COMPOSITIONS 1

Thoroughly pulverized and mixed with 50 parts of each of compounds of the present invention 1-1 - 1-67, 2-1 - 2-106, 3-1 - 3-90, 4-1 - 4-94, 5-1 - 5-75, 6-1 - 6-60, 7-1 - 7-125, 8-1 - 8-42, 9-1 - 9-50 and 10-1 - 10-22, 3 parts ligninsulfonate calcium, 2 parts of sodium lauryl and 45 parts of synthetic hydrated silicon dioxide and receive wettable powders based on each connection.

EXAMPLE COMPOSITION 2

Mix 10 parts of each of compounds of the present invention 1-1 - 1-67, 2-1 - 2-106, 3-1 - 3-90, 4-1 - 4-94, 5-1 - 5-75, 6-1 - 6-60, 7-1 - 7-125, 8-1 - 8-42, 9-1 - 9-50 and 10-1 - 10-22, 14 parts polyoxyethyleneglycol ether, 6 parts of dodecylbenzenesulfonate calcium, 35 parts of xylene and 35 parts of cyclohexanone and receive concentrates of emulsions based on each connection.

An EXAMPLE of the COMPOSITION 3

Thoroughly pulverized and mixed 2 parts of each of compounds of the present invention 1-1 - 1-67, 2-1 - 2-106, 3-1 - 3-90, 4-1 - 4-94, 5-1 - 5-75, 6-1 - 6-60, 7-1 - 7-125, 8-1 - 8-42, 9-1 - 9-50 and 10-1 - 10-22, 2 parts of synthetic hydrated silicon dioxide, 2 parts ligninsulfonate calcium, 30 parts of bentonite and 64 parts of kaolin clay, and after adding water and mixing the resulting mixture granularit and dried, and receive granules based on each connection.

An example of a COMPOSITION

Mix 25 parts of each of compounds of the present invention 1-1 - 1-67, 2-1 - 2-106, 3-1 - 3-90, 4-1 - 4-94, 5-1 - 5-75, 6-1 - 6-60, 7-1 - 7-125, 8-1 - 8-42, 9-1 - 9-50 and 10-1 - 10-22, 50 parts of 10% aqueous solution of polyvinyl alcohol and 25 parts of water, crushed in a wet state until particles with an average diameter of 5 μm or less and receive flowable powders based on each connection.

An EXAMPLE of the COMPOSITION 5

To 40 parts of 10% aqueous solution of polyvinyl alcohol is added 5 parts of each of compounds of the present invention 1-1 - 1-67, 2-1 - 2-106, 3-1 - 3-90, 4-1 - 4-94, 5-1 - 5-75, 6-1 - 6-60, 7-1 - 7-125, 8-1 - 8-42, 9-1 - 9-50 and 10-1 - 10-22 and mix with a homogenizer was used emuleret and dispersed to particles with an average diameter of 10 μm or less. Then to the resulting mixture add 55 parts of water and get concentrated emulsions based on each connection.

Example test 1. Test during the processing of the leaves as in the field

Cylindrical plastic pot with a diameter of 10 cm and a depth of 10 cm filled with earth and then sow the morning glory plumeliau (Ipomoea hederacea) and canetic Theophrastus (Abutilon theophrasti). These pilot plants are grown in a greenhouse for 10 days. Then prepare concentrates of emulsions on the basis of each of compounds 1-2, 1-42, 1-45, 1-48, 2-2, 2-7, 2-42, 2-45, 3-2, 3-12, 4-7, 4-85, 5-12-R, 5-12-S, 5-17, 6-2, 7-2, 7-6, 7-8, 7-12, 7-48, 7-50, 7-84, 7-118, 7-119, 7-125, 9-7, 9-27 and 9-45 in accordance with the example composition 2, the eat dilute them to a preset quantity of water, contains a substance that increases the wetting ability, and diluted preparations by means of a spray evenly sprayed on the leaves of the experimental plants at the rate of 1000 liters per hectare. After administration of preparations of the experimental plants grown in a greenhouse for 16 days and determine herbicide activity. As a result, the growth of ipomea plumeleteer and cantica Theophrastus was suppressed completely when using compounds 1-2, 1-42, 1-45, 1-48, 2-2, 2-7, 2-42, 2-45, 3-2, 3-12, 4-7, 4-85, 5-12-R, 5-12-S, 5-17, 6-2, 7-2, 7-6, 7-8, 7-12, 7-48, 7-50, 7-84, 7-118, 7-119, 7-125, 9-7, 9-27 and 9-45, respectively, at a dose of 125 g/ha

Example of test 2. Test soil in field conditions

Cylindrical plastic pot with a diameter of 10 cm and a depth of 10 cm filled with earth and then sow the morning glory plumeliau (Ipomoea hederacea) and canetic Theophrastus (Abutilon theophrasti). Then prepare concentrates of emulsions on the basis of each of compounds 1-2, 1-42, 1-48, 2-2, 2-7, 2-42, 2-45, 3-2, 3-12, 4-7, 4-85, 5-12-R, 5-12-S, 5-17, 6-2, 7-2, 7-6, 7-8, 7-12, 7-48, 7-50, 7-84, 7-118, 7-119, 7-125, 9-7, 9-27 and 9-45 in accordance with the example composition 2, then dilute them to a pre-set amount of water and diluted preparations by means of a spray evenly sprinkle on the soil surface at the rate of 1000 liters per hectare. After administration of preparations of the experimental plants grown in the greenhouse for 19 days and check the herbicide activity. Growth ipomea plumeleteer and cantica Theophrastus was suppressed completely when using compounds 1-2, 1-42, 1-48, 2-2, 2-7, 2-42, 2-45, 3-2, 3-12, 4-7, 4-85, 5-12-R, 5-12-S, 5-17, 6-2, 7-2, 7-6, 7-8, 7-12, 7-48, 7-50, 7-84, 7-118, 7-119, 7-125, 9-7, 9-27 and 9-45 at the dosage of 500 g/ha, respectively.

Example of test 3. Test during the processing of the leaves as in the field

Plastic box with a length of 27 cm, width 20 cm and a depth of 7.5 cm filled with earth and then sow the morning glory plumeliau (Ipomoea hederacea) and cocklebur (Xanthium pensylvanicum). These pilot plants are grown in a greenhouse for 10 days. Then to them transplanted white pigweed (Chenopodium album), Amaranthus spiked and the results of the analysis (Setaria faberi), who sowed in advance and were grown in a greenhouse for 14 days. Experimental plants grown in the greenhouse for 8 days. After that prepare emulsifiable concentrate based compounds 1-12 of the present invention in accordance with example composition 2, then dilute it to a preset quantity of water that contains a substance that increases the wetting ability, and dissolved drug by means of a spray evenly sprayed over the leaves of the experimental plants at the rate of 1000 liters per hectare. After preparation of the experimental plants grown in the greenhouse for 25 days and check herbicide activity. As a result, the growth of ipomea plumeliau, is urnine, Marie white, amaranth spiked and results of the analysis were suppressed completely when using compounds 1-12 at a dose of 16 g/ha

Example of test 4. Test soil in field conditions

Plastic box with a length of 32 cm, width 22 cm and a depth of 8 cm filled with earth and then sow sesbania (Sesbania exaltata), black nightshade (Solanum nigrum), canetic Theophrastus (Abutilon theophrasti), knotweed (Polygonum lapathifolium), white pigweed (Chenopodium album) and the results of the analysis (Setaria faberi). Then prepare emulsifiable concentrate based compounds 1-12 of the present invention in accordance with example composition 2, then dilute it to a preset amount of water and dissolved drug by means of a spray evenly sprayed on the soil surface at the rate of 1000 liters per hectare. After preparation of the experimental plants grown in the greenhouse for 25 days and check herbicide activity. The growth of sesbania, black nightshade, cantica Theophrastus, mountaineer, Marie white and spickle was suppressed completely when using compounds 1-12 at the dosage of 250 g/ha

Example of test 5. Test during the processing of the leaves as in the field

Plastic box with a length of 27 cm, width 20 cm and a depth of 7.5 cm filled with earth and then sow the morning glory plumeliau (Ipomoea hederacea) and cocklebur (Xanthium pens-ylvanicum). After 3 days in the same drawer sow plushie millet (Echinochloa crugalli) and plants grown in the greenhouse for 7 days. Then to them transplanted white pigweed (Chenopodium album), Amaranthus spiked and the results of the analysis (Setaria faberi), who sowed in advance and were grown in a greenhouse for 14 days. Experimental plants grown in the greenhouse for 8 days. After that prepare emulsifiable concentrate based on connections 7-7 of the present invention in accordance with example composition 2 and then dilute it to a preset quantity of water that contains a substance that increases the wetting ability, and dissolved drug by means of a spray evenly sprayed over the leaves of the experimental plants at the rate of 1000 liters per hectare. After preparation of the experimental plants grown in the greenhouse for 6 days and check herbicide activity. As a result, the growth of ipomea plumeliau, cocklebur, batoshevo millet, Marie white, amaranth spiked and results of the analysis were suppressed completely when using connections 7-7 at a dose of 16 g/ha

In the following examples, the tests were evaluated herbicide activity in 11 levels on a scale from 0 to 10, i.e. digital signs"0", "1", "2", "3", "4", "5", "6", "7", "8", "9" and "10"where "0" means that differences in the degree of germination or growth between treated and untreated experimental plants are absent or small, and "10" means that the treated experimental plants Pogue is whether all or germination or growth is completely suppressed.

Table 11
Connection # StructureNote
AWO 92/11244
BUSP 4859229
CWO 98/41093

Example test 6

Plastic box with a length of 27 cm, width 19 cm and a depth of 7 cm filled with earth and then seeded creeping weed (Digitaria sanguinalis) and the results of the analysis (Setaria faberi). After 9 days in the same drawer sow plushie millet (Echinochloa crus-galli), and plants grown in the greenhouse for 15 days. Then fill with ground plastic box with a length of 16.5 cm, width 12 cm, depth 7 cm, and then sow a wild oat (Avena fatua) and grown in the greenhouse for 18 days. Then prepare concentrates of emulsions on the basis of each of the compounds 1-67 of the present invention and in accordance with the example compositions 2 and then diluted them doziranje prescribed amount with water containing a substance that increases the wetting ability, and diluted preparations by means of a spray evenly sprayed on the leaves of the experimental plants at the rate of 1000 liters per hectare. After administration of the preparations of the experiment the performance communications plants grown in the greenhouse for 4 days and check herbicide activity. The results are shown in the following table 12 (table 12 experimental plants are indicated as follows: - millet plushie, LC - creeping weed, GF - spickle, W - oat).

Table 12
Connection # Dosage (g/ha)Herbicide activity
InLCGFW
1-67125109109
32109108
And1254853
324642

Example test 7

Plastic box with a length of 27 cm, width 19 cm and a depth of 7 cm filled with earth and then seeded creeping weed (Digitaria sanguinalis) and the results of the analysis (Setaria faberi). After 9 days in the same drawer sow plushie millet (Echinochloa crus-galli) and plants grown in the greenhouse for 15 days. Then fill with ground plastic box with a length of 16.5 cm, width 12 cm, depth 7 cm, and then sow a wild oat (Avena fatua) and grown in the greenhouse for 18 days. Then prepare concentration is s emulsion on the basis of each of the compounds 1-45 of the present invention and in accordance with the example composition 2, then dilute them to a preset quantity of water that contains a substance that increases the wetting ability, and diluted preparations by means of a spray evenly sprayed over the leaves of the experimental plants at the rate of 1000 liters per hectare. After administration of preparations of the experimental plants grown in the greenhouse for 4 days and check herbicide activity. The results are shown in the following table 13 (table 13 experimental plants are indicated as follows: - millet plushie, LC - creeping weed, GF - spickle, W - oat).

Table 13
Connection # Dosage (g/ha)Herbicide activity
InLCGFW
1-451251010109
321010109
In1258889
326866

Example test 8

Plastic box with a length of 16.5 cm, width 12 cm, and CH is Bina 7 cm filled with earth and then seeded creeping weed (Digitaria sanguinalis), spickle (Setaria faberi) and jonssonova grass (Sorghum halepense). These experimental plants grown in the greenhouse for 25 days. Then prepare concentrates of emulsions on the basis of each of the compounds 2-52 of the present invention and in accordance with the example composition 2, then dilute them to a preset quantity of water that contains a substance that increases the wetting ability, and diluted preparations by means of a spray evenly sprayed over the leaves of the experimental plants at the rate 373 litres per hectare. After administration of preparations of the experimental plants grown in the greenhouse for 4 days and check herbicide activity. The results are shown in the following table 14 (table 14 experimental plants are indicated as follows: LC - creeping weed, GF - spickle, J - jonssonova grass).

Table 14
Connection # Dosage (g/ha)Herbicide activity
LCGFJ
2-52125101010
329910
1259 910
32768

Thus, by applying the compounds of the present invention can obtain an excellent herbicide action.

Extra example tests 9. Test during the processing of the leaves as in the field

Cylindrical plastic pot with a diameter of 10 cm and a depth of 10 cm filled with earth and then sow the morning glory plumeliau (Ipomoea hederacea) and canetic Theophrastus (Abutilon theophrasti). These pilot plants are grown in a greenhouse for 10 days. Then prepare emulsifiable concentrate based on connection example get 2 and then dilute them to a preset quantity of water containing the spray agent, and dissolved drug by means of a spray evenly sprayed on the leaves of the experimental plants at the rate of 1000 liters per hectare. After applying the experimental plants grown in a greenhouse for 16 days and determine herbicide activity. As a result, the growth of ipomea plumeleteer and cantica Theophrastus was suppressed completely when using compounds at dose levels of 125 g/ha

1. A derivative of uracil of the formula [I]

where Q-R3is an R3substituted group 5-membered or 6-membered heterocyclic what about the rings with one or two nitrogen atoms, selected from groups represented by the following formula

where the specified heterocyclic ring may be substituted by at least one Deputy species selected from the group comprising halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy),

Y represents oxygen, sulfur, imino or (C1-C3)-alkylamino,

R1is (C1-C3-halogenated,

R2is (C1-C3)-alkyl,

R3is OR7, SR8or N(R9R10,

X1represents halogen, cyano, thiocarbamoyl the l or nitro,

X2represents halogen,

where each of R7, R8and R10represents, independently, carboxy-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl, (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C1-C8-alkylaminocarbonyl-(C1-C6)-alkyl, phenoxycarbonyl-(C1-C6)-alkyl which may be substituted, phenyl-(C1-C4-alkoxycarbonyl-(C1-C6)-alkyl which may be substituted, (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, ((C1-C6)-alkoxy)(C1-C3-alkylaminocarbonyl-(C1-C6)-alkyl, (C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, ((C1-C6)-alkyl)(C1-C6-alkylaminocarbonyl-(C1-C6)-alkyl, phenylenecarbonyl-(C1-C6)-alkyl which may be substituted, or phenyl-(C1-C4-alkylaminocarbonyl-(C1-C6)-alkyl which may be substituted, and

R9represents hydrogen or (C1-C6)-alkyl.

2. A derivative of uracil n is 1, where the heterocyclic ring may be substituted at least by a Deputy selected from the group comprising halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy,

R3is a OR7, SR8or N(R9R10{where each of R7, R8and R10represents, independently, carboxy-(C1-C6)-alkyl, (C1-C6-alkoxycarbonyl-(C1-C4)-alkyl, (C3-C6-alkenylacyl-(C1-C4)-alkyl, phenoxycarbonyl-(C1-C4)-alkyl which may be substituted, phenyl-(C1-C4-alkoxycarbonyl-(C1-C4)-alkyl which may be substituted, (C1-C6-alkoxycarbonyl-(C1-C4)-alkyl, ((C1-C6)-alkoxy)(C1-C3-alkylaminocarbonyl-(C1-C4)-alkyl, (C1-C6-alkylaminocarbonyl-(C1-C4)-alkyl, ((C1-C6)-alkyl)(C1-C6-alkylaminocarbonyl-(C1-C4)-alkyl, phenylenecarbonyl-(C1-C4)-alkyl which may be substituted, or phenyl-(C1-C4-alkylaminocarbonyl-(C1-C4)-alkyl which may be substituted, and R9represents hydrogen or (C1-C6)-alkyl.

3. A derivative of uracil according to claim 1 or 2 wherein the group represented by Q-R3p is ecstasy any group, selected from groups represented by the following formula:

where R3matter specified in claims 1 or 2, each Z 1and Z2is, independently, hydrogen, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy.

4. A derivative of uracil according to any one of claims 1 to 3, where X1represents a halogen.

5. A derivative of uracil according to any one of claims 1 to 3, where X1represents nitro.

6. A derivative of uracil according to any one of claims 1 to 3, where X1represents chlorine.

7. A derivative of uracil according to any one of claims 1 to 6, where X2represents fluorine.

8. A derivative of uracil according to any one of claims 1 to 3, where X1represents chlorine, and X2represents fluorine.

9. A derivative of uracil according to any one of claims 1 to 8, wherein R1is a CF3.

10. A derivative of uracil according to any one of claims 1 to 9, where R2represents methyl.

11. A derivative of uracil according to any one of claims 1 to 10, where Y represents oxygen or sulphur.

12. A derivative of uracil according to any one of claims 1 to 10, where Y represents the oxygen.

13. A derivative of uracil according to any one of claims 1 to 12, where R3

is a OR7, SR8or N(R9R10, R7, R8and R10are (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl or (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl.

14. Derived from the acyl according to any one of claims 1 to 12, where R3is a OR7, SR8or N(R9R10and R7, R8and R10are (C1-C6-alkoxycarbonyl-(C1-C3)-alkyl or (C3-C8-cycloalkylcarbonyl-(C1-C3)-alkyl.

15. A derivative of uracil according to any one of claims 1 to 12, where R3is a OR7or SR8and R7and R8are (C1-C6-alkoxycarbonylmethyl or 1-{((C1-C6)-alkoxy)carbonyl}ethyl.

16. A derivative of uracil according to any one of claims 1 to 12, where R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

17. A derivative of uracil according to any one of claims 1 to 16, where the group represented by Q-R3represents a group of the formula

where Z1, Z2and R3have the values listed in item 3.

18. A derivative of uracil according to any one of claims 1 to 16, where the group represented by Q-R3represents any group selected from the group consisting of groups of the formula

or

where Z1, Z2and R3have the values listed in item 3.

19. A derivative of uracil by any who have one of claims 1 to 16, where the group represented by Q-R3represents a group of the formula

where Z1, Z2and R3have the values listed in item 3.

20. Herbicide composition containing as active ingredient a derivative of uracil according to any one of claims 1 to 19, and an inert carrier or diluent.

21. Method of controlling weeds comprising applying an effective amount of uracil derivative according to any one of claims 1 to 19 to the weeds or to the place where the weeds grow or will grow.

22. A derivative of uracil according to any one of claims 1 to 19 as a herbicide.

23. The compound of the formula [XXXI]

where X1X2, R1, Q-R3and Y have the meanings indicated in claim 1.

24. Connection item 23, where the group represented by Q-R3represents any group selected from formulas

where X1represents halogen, cyano or nitro, X2represents halogen, Y represents oxygen or sulfur, R1is a (C1-C3-halogenated, R3is a OR7, SR8or N(R9R10, R7, R8and R10are (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl or (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, and Z1and Z2have the values listed in item 3.

25. Connection item 23, where X1represents chlorine, X2represents fluorine, Y is oxygen, Q-R3matter specified in clause 3, Z1and Z2represent hydrogen, R1represents trifluoromethyl, R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

26. The connection point 24, where X1represents chlorine, X2represents fluorine, Y is oxygen, Z1and Z2represent hydrogen, R1represents trifluoromethyl, R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

27. The compound of the formula [XXXXXI]

where the 1X2, Y and Q-R3have the meanings indicated in claim 1.

28. Connection item 27, where the group represented by Q-R3represents any group selected from groups of the formula

where X1represents halogen, cyano or nitro, X2represents halogen, Y represents oxygen or sulfur, R3is a OR7, SR8or N(R9R10, R7, R8and R10are (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl or (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, and Z1and Z2have the values listed in item 3.

29. Connection item 27, where X1represents chlorine, X2represents fluorine, Y is oxygen, Q-R3matter specified in clause 3, Z1and Z2represent hydrogen, R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl the l)ethyl or 1-(etoxycarbonyl)ethyl.

30. Connection p, where X1represents chlorine, X2represents fluorine, Y is oxygen, Z1and Z2represent hydrogen, R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

31. Connection item 27, which is chosen from the group which consists of

4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline,

4-chloro-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}aniline,

4-chloro-2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]aniline,

4-chloro-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]aniline,

4-chloro-2-fluoro-5-[4-(methoxycarbonyl)methoxy-2-pyrimidinone]aniline,

4-chloro-2-fluoro-5-[4-(etoxycarbonyl)methoxy-2-pyrimidinone]aniline,

4-chloro-2-fluoro-5-[4-{1-(methoxycarbonyl)ethoxy}-2-pyrimidinone]aniline and

4-chloro-2-fluoro-5-[4-{1-(etoxycarbonyl)ethoxy}-2-pyrimidinone]aniline.

32. The compound of the formula [XXXXXIII]

where X1X2, Y and Q-R3have the meanings indicated in claim 1.

33. Connection p, where the group represented by Q-R3represents any group selected from groups of the formula

where X1represents halogen, cyano or nitro, X2represents halogen, Y represents oxygen or sulfur, R3is a OR7, SR8or N(R9R10, R7, R8and R10are (C1-C6-alkoxycarbonyl-(C1-C6)-alkyl, (C3-C6-alkenylacyl-(C1-C6)-alkyl, or (C3-C8-cycloalkylcarbonyl-(C1-C6)-alkyl, and Z1and Z2have the values listed in item 3.

34. Connection p, where X1represents chlorine, X2represents fluorine, Y is oxygen, Q-R3matter specified in clause 3, Z1and Z2represent hydrogen, R3is a OR7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

35. Connection p, where X1represents chlorine, X2represents fluorine, Y is oxygen, Z1and Z2represent hydrogen, R3is the Wallpaper OR 7or SR8and R7and R8are methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-(methoxycarbonyl)ethyl or 1-(etoxycarbonyl)ethyl.

36. Connection p selected from the group including

4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenylisocyanate,

4-chloro-2-fluoro-5-{2-(etoxycarbonyl)methoxy-3-pyridyloxy}phenylisocyanate,

4-chloro-2-fluoro-5-[2-{1-(methoxycarbonyl)ethoxy}-3-pyridyloxy]phenylisocyanate,

4-chloro-2-fluoro-5-[2-{1-(etoxycarbonyl)ethoxy}-3-pyridyloxy]phenylisocyanate,

4-chloro-2-fluoro-5-[4-(methoxycarbonyl)methoxy-2-pyrimidinone]phenylisocyanate,

4-chloro-2-fluoro-5-[4-(etoxycarbonyl)methoxy-2-pyrimidinone]phenylisocyanate,

4-chloro-2-fluoro-5-[4-{1-(methoxycarbonyl)ethoxy}-2-pyrimidinone]phenylisocyanate and

4-chloro-2-fluoro-5-[4-{1-(etoxycarbonyl)ethoxy}-2-pyrimidinone]phenylisocyanate.

37. The compound according to claim 1, which is selected from the group

3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine,

3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methoxypyridine,

3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl the l)ethoxy}pyridine,

3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(etoxycarbonyl)ethoxy}pyridine,

2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxypyridine,

2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(etoxycarbonyl)methoxypyridine,

2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine and

2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(etoxycarbonyl)ethoxy}pyrimidine.

38. Connection item 23, which is chosen from the group which consists of

3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine,

3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(etoxycarbonyl)methoxypyridine,

3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine,

3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(etoxycarbonyl)ethoxy}pyridine,

2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]f is noxy}-4-(methoxycarbonyl)methoxypyridine,

2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(etoxycarbonyl)methoxypyridine,

2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}pyrimidine, and

2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(etoxycarbonyl)ethoxy}pyrimidine.

39. The compound of the formula

where R7matter specified in claim 1.

40. Connection § 39, which is chosen from the group which consists of

2-(methoxycarbonyl)methoxy-3-hydroxypyridine, 2-(etoxycarbonyl)methoxy-3-hydroxypyridine, 2-{1-(methoxycarbonyl)ethoxy}-3-hydroxypyridine and 2-{1-(etoxycarbonyl)ethoxy}-3-hydroxypyridine.

41. The compound of the formula

where R34is a (C1-C6-alkoxycarbonylmethyl, 1-((C1-C6-alkoxycarbonyl)ethyl, (C3-C8-cycloalkylcarbonyl, 1-((C3-C8-cycloalkylcarbonyl)ethyl.



 

Same patents:

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

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

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to compounds represented by the formula (Ia) and compositions used in treatment of gastroenteric diseases based on thereof and their complexes being optionally in combination with compounds of the formula (Ib) . Also, invention describes pharmaceutical preparations and methods for their preparing these compounds. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

28 cl, 115 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to methods for stabilizing compounds based on benzimidazole or its physiologically acceptable salt. One variant of a method involves incorporation of crospovidone having small diameter of particles and at least one compound taken among sodium hydroxide and potassium hydroxide into benzimidazole-base compound represented by the formula (1):

wherein Het1 means:

Het2 means:

R1 and R2 are similar or different and taken among hydrogen atom, methoxy- and difluoromethoxy-group; R3 is taken among hydrogen and sodium atom; R4, R5 and R6 are similar or different and taken among group comprising hydrogen atom, methyl, methoxy-, methoxypropoxy- and trifluoroethoxy-group, or its physiologically acceptable salt. Other variants involve applying at least one compounds taken among sodium hydroxide and potassium hydroxide on core formed by incorporation of crospovidone into benzimidazole-base compound represented by the formula (1) or its physiologically acceptable salt, enteric soluble coating, or intermediate coating and the following applying additional enteric soluble coating on it. Also, invention relates to a method for prevention of the benzimidazole-base compound color change or its physiologically acceptable salts and this method involves incorporation of crospovidone and at least one compound taken among sodium hydroxide and potassium hydroxide into benzimidazole-base compound by cl. 1, or its physiologically acceptable salt.

EFFECT: improved stabilizing method.

7 cl, 2 tbl, 8 ex

The invention relates to a method for producing 6-substituted derivatives of 2-(alkylsulfanyl)-4(3H)-pyrimidinone General formula (I), which are used as intermediates for the synthesis of pharmaceuticals and as self-medication
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