Substituted heterocyclic compounds, methods for their preparation, intermediate compounds, the method of controlling undesirable plants

 

(57) Abstract:

Substituted heterocyclic compounds of the formula I where E is oxygen or sulfur, A is CR3or N, R3is hydrogen or lower alkyl; D completes a 5 - or 6 - membered non-aromatic heterocyclic ring which optionally contains additional heteroatoms selected from oxygen, nitrogen or sulfur, possibly substituted C1-C10-alkyl or phenyl; R1and R2is hydrogen, alkyl, alkenyl, quinil, cyclopropyl, cyclopropylmethyl, cyclohexyl, substituted, phenyl or pyridyl, or R1and R2together with the nitrogen atom to which they are attached, form morpholino ring; Z is halogen, cyano, NHOH, SF5acylamino, COOR7, NR13R14, dibenzylidineacetone or Z - alkyl, alkenyl, alkoxy, phenoxy, alkylthio, alkylsulfonyl or CO-alkyl, each of which may be substituted with halogen or C1-6-alkoxy; R7- C1-10-alkyl; R13and R14is hydrogen or SO2-alkyl; m = 0, 1 or 2. The compounds of formula I are active against a wide range of weed species, including monocotyledonous and dicotyledonous weeds.

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5 C. and 10 C.p. f-crystals, 9 Il., 17 table.

This invention against whom Azizian and how to use them.

Herbicide compounds with carbonyl-substituted nitrogen-containing heterocyclic rings are known, e.g. from British patent N 1345159 and DE OS 2212558.

Applicants have discovered a group of compounds that have special nature of substituents and are active as herbicides.

According to the present invention are provided compounds of formula (I):

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in which

E represents oxygen or sulfur;

A is CR3or N, where R3represents hydrogen or hydrocarbon;

D completes a 5 - or 6-membered non-aromatic heterocyclic ring which optionally contains additional heteroatoms selected from oxygen, nitrogen or sulfur and which is optionally substituted lower hydrocarbonyl group, or optionally substituted heteroaryl group;

R1and R2are each independently hydrogen, optionally substituted lower hydrocarbon, or optionally substituted heteroaryl, or R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring;

Z represents halogen, optionally substituted lower hydrocarbon, optional Zam is idrocarburanti, cyano, nitro, CHO, NHOH, ONR7'R7", SF5, CO /optional substituted lower hydrocarbon/, acylamino, COOR7, SO2NR8R9, CONR10R11, OR12or NR13R14where R7, R7', R7", R8, R9, R10and R11are independently H or lower hydrocarbon; R12represents hydrogen, SO2lower hydrocarbon or COR15; R13and R14independently represent lower hydrocarbon, lower hydrocarbonate or group, R12; R15is OR16, NR17R18hydrogen or lower hydrocarbon; R16represents the lower hydrocarbon, R17and R18independently represent hydrogen or lower hydrocarbon, provided that, when there are two or more substituents Z, they may be the same or different;

m represents 0 or an integer from 1 to 5.

D completes a saturated or unsaturated heterocyclic fragment. Preferably D completes a saturated heterocyclic ring.

Particular examples of compounds of formula I are the compounds of formula (II), where A, E, R1, R2, Z and m have the meanings defined in relation to formula (I), and W, X and Y independently you the performance of selected from hydrogen, optionally substituted lower hydrocarbide, or optionally substituted heteroaryl, or R4and R5together with the carbon atom to which they are attached, may form a carbocyclic ring; and n represents 0 or 1, provided that not more than two of A, W, X and Y include heteroatoms in the ring; and when more than one of W, X and Y represents CR4R5, R4and R5may be the same or different; and when more than one of W, X and Y represents NR6each R6may be the same or different.

The expression lower hydrocarbon in previous definitions, regardless of whether you use it by itself or as part of a larger moiety, such as, for example, lower hydrocarbonate, is designed to enable hydrocarbonrich (hydrocarbon) radicals, for example, with the number of carbon atoms up to 10. Subclasses such hydrocarbonrich radicals include radicals containing up to 4 or up to 6 carbon atoms. Expression hydrocarbonyl includes aliphatic, alicyclic and aromatic gidrolabilna or hydrocarbon groups, and combinations thereof. This definition includes, for example, alkyl, alkenyl and alkyline radika the performance communications radicals.

When the lower gidrolabilna group is substituted, the substituents may include, for example, halogen (e.g. chlorine, bromine, fluorine or iodine), cyano, nitro, amino, mono - and dialkylamino, in which the alkyl groups have from 1 to 6 or more carbon atoms, acylamino, (1-6)alkoxy, (1-6)C haloalkoxy, (1-6)C alkylthio, (1-6)C alkylsulfonyl, (1-6)C alkylsulfonyl, carboxy, carboxamide in which the group attached to the N atom, can represent hydrogen or optionally substituted lower hydrocarbon; alkoxycarbonyl, in which the alkoxy group may have from 1 to 6 or more carbon atoms, and aryl, such as phenyl.

Expression heteroaryl in the above definition includes such radicals as pyridyl, triazinyl, thienyl, furyl and thiazolyl. When the heteroaryl radical is substituted, the substituents may include the radicals listed above for substituted lower hydrocarbide.

Specific examples of values for R4and R5include hydrogen, methyl, ethyl, propyl and butyl. When R4and R5together with the carbon atom to which they are attached, form a carbocyclic ring, the ring may be, for example, cyclobutyl, cyclopentyl or tsiklogeksilnogo ring.

3)2C=CH, C(CH3)2CH= CH2C(CH3)2CN, altematively, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 1-methyl-cyclohexyl, 1-methylcyclopentene, 1-methyl-cyclobutyl, 1-methylcyclopropyl, 1-cyano-cyclohexyl, 1-cyano-cyclopentyl, 1-cyano-cyclobutyl, 1-cyano-cyclopropyl, 1-ethynylcyclohexanol, 1-ethinyl, cyclopentyl, 1-ethinyl-cyclobutyl, 1-ethinyl-cyclopropyl, phenyl, p-chlorophenyl and benzyl. When R1and R2together with the nitrogen atom to which they are attached, form a heterocyclic ring, the ring may be, for example, pyrrolidino, piperidino, thiomorpholine or morpholine ring, each of which may be substituted, for example, one or more methyl groups.

Examples of specific values of Z include methyl, ethyl, n-propyl, ISO-propyl, trifluoromethyl, deformity, pentafluoroethyl, trichloromethyl, ethoxyphenyl, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, n-propoxy, ISO-propoxy, triptoreline, tetrafluoroethoxy, cyano, nitro, amino, mono - or dialkylamino in which each alkyl group may have from 1 to 6 or more carbon atoms, hydroxylamino, acyl (n is sulfinyl, trifloromethyl, sulphonamido, carboxy, alkoxycarbonyl, in which the alkoxy group may have from 1 to 6 or more carbon atoms, carboxamide, in which the groups attached to the nitrogen atom may be hydrogen or optionally substituted lower hydrocarbon; or acylamino (e.g., acetamido). When there is more than one Deputy Z, the substituents may be the same or different.

Examples of heterocyclic ring containing W, X and Y are ring podhorany /I/ that include groups of formula (a) - (o) in which R3, R4, R5and R6have the meanings defined above, and R4'and R4"and R5'and R5"have the meanings defined above, respectively, for R4and R5.

Specific examples of compounds of formula I are compounds in which D completes thiazolidinone ring of formula (a), E represents O, R3represents the group CH; m, p, R1, R2, R4and R5have the meanings defined above, and Z represents halogen, optionally substituted lower hydrocarbon, optionally substituted lower hydrocarbonate, optional unsubstituted lower hydrocarbon-thio, -sulfinil, or sulfonyl, cyano, who them and the same of different.

A is preferably CR3especially CH.

Preferably a group of the formula (I) is thiazolidinone group of formula (a) or pyrrolidinone group of formula (b).

E preferably represents oxygen.

The preferred values for Z are CF3"THAT OCF3, OCHF2, CHF2, OMe, F, Cl, Br, I, NH2, NO2CN, (1-4)alkoxy, CO(1-4)alkyl, NHCO(1-4)alkyl, SO2(1-4)alkyl, OCF2CHF2, CF2CF3and SO2NR8R9.

Especially preferred values for Z are CF3, OCF3, OCH3, F, Cl, Br and iodine.

m preferably represents 1, 2 or 3.

Preferred character substitution for Z groups is a replacement for one Z group at the 3-position; or two Z groups in the 3,4 - and 3,5-positions; three Z groups at the 3-, 4 - and 5-positions; moreover, the group Z in the 4-position represents halogen, especially fluorine.

R1is preferably ISO-propyl, sec-butyl, tert-butyl, C(CH3)2C CH or 3 - to 6-membered cycloalkyl, optionally substituted by a group CH3or C CH in the alpha position cycloalkyl rings.

R2preferably represents hydrogen or (1-4)C is SUP>, R4'and R4"preferably represent hydrogen or (1-4 C alkyl.

R5, R5'and R5"are preferably hydrogen or (1-4 C alkyl.

R6is preferably (1-4)C alkyl, especially methyl.

Formula I, above, include tautomeric forms presents patterns, as well as physically, various modifications of the compounds. which may occur, for example, due to the different ways in which molecules are rearranged in the crystal lattice, or the inability of parts of the molecule to rotate freely relative to other parts, or due to geometrical isomerism, or intra-molecular or inter-molecular hydrogen bond, or due to other factors.

Some of the compounds of the invention can exist in enantiomeric or diastereomeric forms. This invention covers all individual isomers and mixtures thereof in all ratios.

Specific examples of the compounds of the invention are listed in Tables I-XV.

The compounds of formula I are obtained in a suitable manner using a wide variety of processes.

In particular, the compounds of formula I can Bnei formula (I): with a compound of the formula /IV/ or when R2represents hydrogen, the compound of the formula /V/, in which R1has the values defined for formula I, and R19imagine going back or delete the group, in the presence of a base.

Suitable bases include weak bases such as triethylamine, pyridine or N-ethyl-N,N-Diisopropylamine.

Suitable to be deleted group, R19include halogen, such as chlorine.

The reaction is carried out suitably in an organic solvent, such as dichloromethane, trichloromethane, tetrahydrofuran or diethyl ether, at temperatures from 0 to 80oC, preferably at ambient temperature.

Some compounds of formula (III are novel and as such form a further aspect of the invention. The compounds of formula /IV/ and /V/ are known compounds or can be obtained from known compounds by conventional methods. The compounds of formula /V/ can be obtained and used in place using standard techniques.

Using the same reaction NCO group of the compounds (V) can be replaced by NCS group. If necessary, NCS group can be formed on site using studenti formula (III lies in the interaction of the compounds of formula (III connection with ClC(O)OCH(Cl)CCl3in the presence of a base, giving the compound of the formula /XIII/, where Z, D, A and m have the meanings defined above in respect to formula I). The reaction is suitably carried out at temperatures from -10 to 10oC, in the presence of a solvent. Suitable bases are heteroaromatic nitrogen bases, such as pyridine. Suitable solvents are dichloromethane or chloroform. The compounds of formula /XIII/ then subjected to reaction with an amine of the formula /VIII/ HNR1R2where R1and R2have the meanings given in relation to formula (I), giving the compounds of formula (I). The reaction is suitably carried out at a temperature of from -10 to 30oC, in the presence of base and solvent. Suitable bases are pyridine and triethylamine. Suitable solvents are dichloromethane and chloroform. The compounds of formula /XIII/ no need to allocate, and may be subjected to reaction with the compound of the formula /VIII/.

Instead of ClC(O)OCH(Cl)CCl3the compounds of formula (III can undergo reaction with phosgene, giving the compounds of formula /XIV/, where Z, A, D and m have the meanings defined in relation to formula (I). The compounds of formula /XIV/ then subjected to interaction of tsetse at a temperature of from -20 to 50oC in the presence of base and solvent.

Suitable bases are pyridine or triethylamine. Suitable solvents are chloroform, dichloromethane or tetrahydrofuran. The connection formula /XIV/ do not need to stand out, and may bust on the site of reaction with the compound of the formula /VIII/.

Some compounds of formula (III in which Y is sulfur and A is CR3, appropriately obtained through reaction of compounds of formula /VI/, where Z, D and m have the meanings defined in relation to formula (I), and R20represents a removable group, such as halogen, especially chlorine; with water in the presence of a base and mix with the water solvent.

Suitable bases include weak inorganic bases such as sodium bicarbonate.

The reaction is carried out suitably in a solvent such as tetrahydrofuran or dioxane: at temperatures from 0 to 50oC.

Some compounds of formula (III, in which A, D, Z and m have the meanings defined in relation to formula (I), are obtained through hydrolysis of compounds of formula /VI/, where A, D, Z and m have the meanings defined in relation to formula (I), ethanol, and silica gel.

A suitable group, R21is trifluoromethyl. The reaction is appropriately carried out in a solvent such as dichloromethane, at temperatures from 0 to 50oC, preferably at ambient temperature.

Some compounds of the formula /VI/, where Y is sulfur and A is CR3, a D, Z and m have the meanings defined in relation to formula (I), and R20is halogen, can be obtained by using haloiding compounds of the formula /X/ palodiruyut agent. Suitable Ganoderma agents include sulfurylchloride or chlorine.

The reaction is suitably carried out in an organic solvent such as dichloromethane or chloroform, at temperatures from 0 to 50oC, preferably at ambient temperature.

Some compounds of formula (III can be obtained by oxidation of compounds of formula /X/, in which A, D, Z and m have the meanings defined in connection with formula I, with a strong base such as LiN(SiMe3)2or LiN(SORG)2with subsequent reaction with the compound of the formula /XVII/.

The reaction is appropriately carried out in a solvent such as tetrahydrofuran, at a temperature which follows the p-taillow group, and Ar' is suitably phenyl.

Some compounds of formula (III, particularly compounds in which A represents N, D, Z and m have the meanings defined in relation to formula (I), a suitable image is obtained by hydrogenolysis of compounds of formula /VI/, where R20is OCH2Ph, and Z, D and m have the meanings defined in relation to formula /I/.

The reaction is appropriately carried out in proton solvent such as alcohol (e.g. methanol) in the presence of a catalyst. A suitable catalyst is palladium on coal. The reaction is suitably carried out at temperatures from 0 to 50oC, preferably at ambient temperature.

Compounds of the formula /X/ can be obtained using a variety of methods, depending on the specific nature of the ring completed by group D.

This is possible when the substituents Z are the nature and distribution, allowing to activate the phenyl ring for nucleophilic substitution, to be combined with the compound of the formula /XI/; where Z and m have the meanings defined above, and R22is the deleted group, with the compound of the formula /XII/; when A is CR3and D is zaklyuchayut halogen, such as fluorine.

Suitable bases include strong bases such as potassium hydroxide or sodium hydroxide.

The reaction is suitably carried out in an organic solvent, such as dimethylsulfoxide or dimethylformamide, at temperatures from 0 to 90oC.

Examples of suitable compounds of the formula /XI/ include 3,4-debtor-5-chloro-, , -triptorelin and 3,4,5-Cryptor-, , - triptorelin.

An alternative and generally more acceptable way of obtaining compounds of the formula /III/, /VI/ and /X/ includes introduction of an appropriate side chain in the appropriately substituted phenyl derivative and the cyclization of the side chain with the formation of the desired heterocyclic fragment. For example, isoxazolidinone ring and dihydro-1,2-oxazinone ring system can be obtained from compounds of the formula /XV/, in which Z and m have the meanings defined in relation to formula /I/.

Through reaction with ClCO(CH2)2Br the compounds of formula /XV/ may be transformed into compounds of formula /XVI/ in which Z and m have the meanings defined in relation to formula (I). The reaction is suitably carried out at a temperature of from -20 to 40oC, preferably at 0 - 25oC, p solvents are tetrahydrofuran or dichloromethane. The compounds of formula /XVI/ may be transformed into compounds of formula /III/, where D completes isoxazolidinone ring and Z and m have the meanings defined in relation to formula (I), by reaction with a strong base followed by reaction with the compound of the formula /XVII/ in which Ar is p-tolyl, and Ar' is phenyl. The reaction is suitably carried out at a temperature of from -80 to 10oC in the presence of a solvent. Suitable bases are hexamethyldisilazide lithium or diisopropylamide lithium. A suitable solvent is tetrahydrofuran.

Through reaction with ClC(O)CH(Br)CH2CH2Br the compounds of formula /XV/ may be transformed into compounds of formula /XVIII/ in which Z and m have the meanings defined in relation to formula (I). The reaction is appropriately carried out in a solvent, in the presence of a base, at a temperature of from -20 to 40oC, preferably at 0-25oC. Suitable bases are tertiary amines, such as triethylamine, and suitable solvents are ethers, such as tetrahydrofuran. The group chlorine and bromine can turn in the iodine group by reaction with sodium iodide at temperatures from 0 to 80oC, the solvent is hydroxy)iodine) benzene in the solvent. Suitably the reaction is carried out at a temperature of from 0 to 30oC, preferably at ambient temperature. Suitable solvents are chlorinated hydrocarbons, such as methylenechloride. Group OCOCF3can turn into OH groups, i.e. the compounds of formula /III/, where D completes dihydro-1,2-oxazinone ring and Z and m have the meanings defined in relation to formula (I), by treatment with methanol at a temperature from 0 to 80oC, preferably at ambient temperature, in the presence of silica gel and solvent. Suitable solvents are chlorinated hydrocarbons, such as methylenechloride.

The compounds of formula /XV/ are known or can be obtained from known compounds by conventional methods.

Through reaction with ClC(O)CH2Cl compounds of formula (XXX), in which Z and m have the meanings given for formula I, may be transformed into compounds of formula /XIX/ in which Z and m have the meanings defined in relation to formula (I). The reaction is suitably carried out at temperatures from 0 to 50oC preferably in a solvent, in the presence of a base. Suitable bases are the formulas /XIX/ may be transformed into compounds of formula (III, that completes dihydro-1,4-oxazine ring, in which Z and m have the meanings defined in relation to formula (I), through reaction with LiN(SiMe3)2in a solvent such as tetrahydrofuran, at temperatures from -80 to 20oC, preferably at 0oC, followed by treatment of the compound of the formula /XVII/ (in which Ar and Ar' have the meanings given above) at a temperature of from 0 to 30oC, in a solvent such as tetrahydrofuran.

The compounds of formula /XXX/ are known or can be obtained from known compounds by conventional methods.

Compounds of the formula /X/, where D completes dihydro-1,4-1,4-diazinone ring and in which Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /XXVIII/ in which Z and m have the meanings defined in relation to formula (I), by heating in a solvent such as xylene or toluene, at a temperature of reflux distilled in the presence of p-toluensulfonate acid. The compounds of formula /XXVIII/ can be obtained from compounds of the formula /XXIX/ in which Z and m have the meanings defined in relation to formula (I), by processing aterciopelados in the presence of a strong base, such CNAS at ambient temperature. The compounds of formula /XXIX/ can be obtained from compounds of the formula/XXX/, in which Z and m have the meanings defined in relation to formula (I), through reaction with brainwashin agent, preferably with tetrabromophenol, and triphenylphosphine at temperatures from 0 to 50oC, preferably at ambient temperature, in the basic solvent such as pyridine.

The compounds of formula /III/, where D completes a 2-imidazolidinone ring and in which Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /XX/ through reaction with hydrogen in the presence of palladium catalyst on coal in an appropriate solvent, such as methanol, at temperatures from 0 to 30oC, preferably at ambient temperature.

The compounds of formula /XX/, in which Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /XXI/ in which Z and m have the meanings defined in relation to formula (I), by reaction with Br(CH2)2Br, in the presence of a base, in a solvent. Suitable bases are strong bases such as sodium hydride, in a suitable solvent is dimethylformamide, and reakciaya environment. The compounds of formula /XXI/ in which Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /XXII/ in which Z and m have the meanings defined in relation to formula (I), through reaction with C6H5CH2ONH2at temperatures from 0 to 50oC, preferably at ambient temperature.

The compounds of formula /XXII/ are known compounds or can be obtained from known compounds by conventional methods.

The compounds of formula /III/, where D completes a saturated 2-pyrimidinone ring, and where Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /XXI/ similarly using Br(CH2)3Br instead of Br(CH2)2Br.

The compounds of formula /III/, where D completes a 2-piperazinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /X/), where D completes a 2-piperazinone ring and Z and m have the meanings defined in relation to formula (I), by reaction with a strong base such as LiN(SiMe3)2with the subsequent reaction with the compound of the formula /XVII/ /in which Ar is the solvent. A suitable solvent is tetrahydrofuran.

Piperazinone compounds of the formula /X/ can be obtained from compounds of the formula /XXIII/ in which Z and m have the meanings defined in relation to formula (I), at temperatures from 0 to 80oC, preferably 25 to 60oC, in a solvent in the presence of a base. Suitable bases are strong bases such as sodium hydride. A suitable solvent is dimethylformamide. The compounds of formula /XXIII/ can be obtained from compounds of the formula /XXIV/ in which Z and m have the meanings defined in relation to formula (I), through interaction with ClC(O)(CH2)3Cl at ambient temperature.

The compounds of formula /XXIV/ are known or can be obtained from known compounds by conventional methods.

The compounds of formula /III/, where D completes a 2-pyrrolidinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /X/), where D completes pyrrolidinone ring and Z and m have the meanings defined in relation to formula (I), by interaction with a strong base such as LiN(SiMe3)2with further interaction ri 0oC, in a solvent. A suitable solvent is tetrahydrofuran. Pyrolidine compounds of the formula /X/ can be obtained by using heat and decarboxylation of compounds of formula /XXV/ in which Z and m have the meanings defined in relation to formula (I). The compounds of formula /XXV/ can be obtained by reaction of compounds of formula /XXIV/ in which Z and m have the meanings defined in relation to formula I, with a compound of the formula /XXXI/ obtained according to the method described in Organic Synthesis, volume 60, pages 66 - 68.

Compounds of the formula /X/), where D completes thiazolidinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained from anilines of formula /XXIV/ in which Z and m have the meanings defined in relation to formula (I), through reaction with thioglycolic acid or timelocal acid, and carbonyl compound R4R5CO, giving thiazolidinone /XXVI/ in which Z and m have the meanings defined in relation to formula (I), R3represents H or methyl. The reaction is preferably carried out in a solvent or diluent and sometimes carried out in the presence of a strong base such as n-toluensulfonate. The preferred solvent is the applicant, which forms with water azeotropic mixture has a boiling point in the range from 100 to 150oC, for example, toluene or xylene. Conveniently the reaction may be carried out by heating the reaction mixture under conditions of reflux distilled, and the collection of water is carried out in delegateuser solvent using a suitable device (for example, traps, Dean-stark). Heating under conditions of reflux distilled may be interrupted when the amount of water collected indicates that the reaction proceeded to the desired degree. The product can stand out in the usual way, by evaporation of the solvent (for example, under reduced pressure, giving crude 4-thiazolidinone as residue. This substance can be purified, if necessary, using conventional methods, for example, by recrystallization or by chromatography.

The reaction can be varied by introducing into the reaction of aniline of the formula /XXIV/ in which Z and m have the meanings defined in relation to formula (I), and thioglycolic in a solvent such as toluene or xylene, at temperatures of 100 - 150oC, giving a compound of the formula /XXXVI/, in which Z and m have the meanings defined in relation to formula (I). The reaction may be carried out in the presence of acid catalysts of the new ring, and Z and m have the meanings defined in relation to formula (I) can then be obtained through reaction of compounds of formula /XXXVI/, in which Z and m have the meanings defined in relation to formula (I) with a carbonyl compound R4R5CO. The reaction is preferably carried out in a solvent such as toluene or xylene, at temperatures from 100 to 150oC. the Reaction can kataliziruetsa the addition of minor amounts of a strong acid, such as p-toluensulfonate acid.

Alternative, thiazolidinone formula /X/), where D completes a 4-thiazolidinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained through reaction of compounds of formula /XXXVI/, in which Z and m have the meanings defined in relation to formula (I), 1,1-digitalcanon, such as diiodomethane, in the presence of a strong base and solvent. Suitable bases are inorganic bases such as sodium hydroxide or potassium hydroxide. Suitable solvents are ethers, such as trageriemen or acetone. The reaction is carried out at temperatures of about 30 - 100oC, preferably at a temperature of reflux distilled solvent.

Alternate the I in the connection formula /XXVI/, in which Z and m have the meanings defined in relation to formula (I), and R3is H, by reaction with thioglycolic acid and a carbonyl compound R4R5CO in a solvent such as ethanol, at temperatures from 0 to 50oC, preferably at ambient temperature, followed by treatment with thionyl chloride in an organic solvent such as methylene chloride.

The reaction is suitably carried out at temperatures from 0 to 50oC, preferably at ambient temperature, in the presence of an organic base such as triethylamine.

4 thiazolidinone /XXVI/ processed gloriouse agent /for example, sulfurylchloride/ to convert it into the corresponding chlorine compound /XXVII/ in which Z and m have the meanings given to share the formula /I/. Conveniently the reaction is carried out in a solvent, e.g. a chlorinated hydrocarbon solvent (e.g. dichloromethane, chloroform or tetrachlorophenol) at low temperature (for example, at a temperature in the range from 0 to 10oC). The reaction is usually exothermic and requires cooling (for example, in an ice bath to maintain the temperature in prenom pressure), leaving a moist chlorine compound in the form of residue. Untreated or raw product /XXVII/ can be purified if desired using conventional methods, for example by recrystallization/ or be used directly in the next stage.

Chlorine-connection /XXVII/ converted into the corresponding hydroxy-connection /III/, where D completes a 4-thiazolidinone ring and Z and m have the meanings defined for the formula /I/ using hydrolysis under mild conditions (for example, when the ambient temperature is, for example, at 15 - 25oC, and at moderate pH values, for example, at pH 8 - 9/. The reaction is conveniently carried out in a solvent. The solvent may be, for example, mixed with water, the solvent (e.g. tetrahydrofuran) or a mixture of such solvent with water. The hydrolysis can be carried out, for example, by processing chlorine-compounds in solution with aqueous sodium bicarbonate at ambient temperature and stirring the mixture until then, until the reaction is substantially completed; this may take up to several days. Hydroxy-connection /III/ may be produced using conventional procedures, for example, by diluting the reaction mixture with water, extracting the mixture is not mesutronic connection in the form of residue. This residue can then be purified, if necessary, using conventional methods (for example, using recrystallization).

The compounds of formula /III/, where D completes a saturated 1,3,4-thiazolidinone ring and Z and m have the meanings given for formula I, can also be obtained from compounds of formula /XXXII/, where D completes a saturated thiazolidinone ring and Z and m have the meanings given for formula I, with the help of the reaction first with sulfurylchloride in dichloromethane solution at 0-25oC, followed by hydrolysis of the intermediate chloro-compounds using aqueous solution of sodium bicarbonate and mixed with water solvent, such as tetrahydrofuran.

The compounds of formula /XXXII/ can be obtained through reaction of compounds of formula /XXXIII/ in which Z and m have the meanings defined in relation to formula I with a strong base such as sodium hydride, followed by treatment of the compound of the formula /XXXIV/ in which R30represents a removable group, such as halogen. The reaction is carried out at 0 - 50oC, preferably at ambient temperature, in a solvent such as dimethylformamide.

The compounds of formula /XXXIII/ can ewu reaction with thioglycolic acid or timelocal acid and a carbonyl compound of the formula COR4R5according to the method similar to the method of producing compounds of the formula /XXVI/.

The compounds of formula /XXV/ or are known compounds or can be obtained from known compounds by conventional methods.

Compounds of the invention, in which p represents 1 or 2, can be obtained by treatment of the corresponding compounds of formula I in which p is 0, an oxidizing agent. The oxidizing agent may be, for example, m-chlormadinone acid. When using this oxidizing agent, the reaction may conveniently be carried out in a solvent, e.g. a chlorinated hydrocarbon solvent. Examples of such solvents include dichloromethane and chloroform. The reaction may be conducted at ambient temperature (e.g., 15-25oC). When using one-molar ratio m-chlormadinone acid compound of the formula I in which p=0, can be transformed into a compound of formula I in which p=0. Similarly, the compound of the formula I in which p= 1, can turn into a compound of formula I in which R=2, by processing one-molar amount of m-chlormadinone acid. Alternatively, the compound of formula I, in which the molar proportions of m-chlormadinone acid.

Compounds of the formula /X/), where D completes a 4-oxazolidinone ring and Z and m have the meanings given for formula I, can be obtained by methods similar to the methods described for preparing compounds of the formula /X/), where D completes a 4-thiazolidinone ring and Z and m have the meanings defined for the formula /I/, but with the use of glycolic acid instead of thioglycolic and lactic acid instead timelocal acid. The compounds of formula /III/, where D completes form 4-oxazolidinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of the formula /X/), where D completes a 4-oxazolidinone ring and Z and m have the meanings defined in relation to formula (I), by methods analogous to the methods described above.

Compounds of the formula /X/), where D completes a 4-imidazolidinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained by methods similar to the methods described for preparing compounds of the formula /X/), where D completes a 4-thiazolidinone ring and Z and m have the meanings defined in relation to formula (I), using alpha-amino acid derivatives instead thioglycolic CIIA, defined for formula I, can be obtained from compounds of the formula /X/), where D completes a 4-imidazolidinone ring and Z and m have the meanings defined in relation to formula (I), by methods similar to those described above.

Compounds of the formula /X/), where D completes a saturated pyrazinone ring and Z and m have the meanings given for formula I, can be obtained by methods similar to the methods described for obtaining the compounds (X) where D completes dihydro-4-diazinone ring and Z and m have the meanings described for formula (I), but using alpha-amino complex ester instead of ethyldiglycol. Properly alpha-amino ester is the ethyl ester of sarcosine.

The compounds of formula /III/, where D completes a saturated pyrazinone ring and Z and m have the meanings given for formula I, can be obtained from compounds of the formula /X/), where D completes a saturated pyrazinone ring and Z and m have the meanings described for formula (I), according to methods similar to the methods described above.

Compounds of the formula /X/), where D completes a 3-pyrazolidinone ring and Z and m have the meanings defined in relation to formula (I), can be polymet values, defined for formula I, and compounds of the formula /X/), where D completes a saturated 1,3,4-thiadiazine ring and Z and m have the meanings defined for the formula /I/, but using the compounds of the formula /XXXV/ in which Z and m have the meanings defined in relation to formula (I), instead of the compounds of formula /XV/, in which Z and m have the meanings defined in relation to formula /I/.

The compounds of formula /III/, where D completes a 3-pyrazolidinone ring and Z and m have the meanings given for formula I, can be obtained from compounds of the formula /X/), where D completes a 3-pyrazolidinone ring and Z and m have the meanings given for formula I, according to methods similar to those described above.

The compounds of formula /VI/, where D completes a 3-pyridazinone ring and Z and m have the meanings given for formula I, and R20is iodine can be obtained by using a combination of methods similar to the methods described for preparing compounds of the formula /XVIII/ in which Z and m have the meanings given for formula I, and compounds of the formula /X/), where D completes a saturated 1,3,4-thiadiazine ring, and X and m have the meanings defined for the formula /I/, but using the compounds of the formula /XXX values, defined in relation to formula /I/.

The compounds of formula /III/, where D completes a saturated pyridazinone ring and Z and m have the meanings defined in relation to formula (I) can be obtained from compounds of formula (I) where D completes a saturated pyridazinone ring and Z and m have the meanings given for formula I, and R20is iodine, according to the method similar to the method described for preparing compounds of the formula /III/, where D completes a saturated 1,2-oxazinone ring and Z and m have the meanings defined for the formula /I/.

Specialists in the art will obvious modifications of the above procedures, as well as alternative methods of producing compounds of the present invention.

The compounds of formula I, above, are active as herbicides, and the invention, therefore, provides in accordance with the following aspect of a strong way of damage or destruction of undesirable plants, which provides the application with regard to the plants or to the environment for plant growth herbicide effective amount of the compounds of formula I, as defined here earlier.

The compounds of formula I are activecontrol selectivity for certain species; they can be used, for example, as selective herbicides in crops of soybeans and corn or maize. The compounds of formula I are applied directly to undesirable plants (post-harvest application), but they are preferably applied to the soil before sprouts appear undesirable plants (preschedule application).

The compounds of formula I can be used by themselves to destroy or inflict heavy damage, unwanted plants, but preferably they are used in the form of compositions comprising a compound of formula I in a mixture with a carrier comprising a solid or liquid diluent.

Compositions containing the compounds of formula (I) include as diluted compositions which are ready for immediate use, and concentrated compositions, which require dilution before use, usually with water. Preferably the compositions contain from 0.01% to 90% by weight of the active ingredient. The diluted compositions ready for use, preferably contain from 0.01 to 2% of active ingredient, while concentrated compositions can contain from 20 to 90% of the active ingredient, although usually predpochtitelnye ingredient is mixed with finely ground solid diluent, for example, kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered dioxide magnesium, fallerovo earth and plaster. They can also be in the form of dispersible powders or granular preparations containing a wetting agent to facilitate dispersion of the powder or grains in the liquid. Solid compositions in powder form can be used for pollination of foliage in the form of Farrukh Dustov.

Liquid compositions can include a solution or suspension of the active ingredient in water, optionally containing a surface-active agent, or they may include a solution or dispersion of the active ingredient is mixed with water, an organic solvent which is dispersed as droplets in water.

Surface-active agents can be cationic, anionic or non-ionic type or a mixture of them. Cationic agents are, for example, Quaternary ammonium compounds /for example, cetyltrimethylammonium bromide/. Suitable anionic agents are Soaps, salts of aliphatic mono-esters of sulfuric acid, for example sodium lauryl sulphate; and salts of sulphonated aromatic compounds, for example, dodecylbenzenesulfonate sodium, sodium lignosulphonate, ka is the acid. Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols, such as alilovic alcohol and cetyl alcohol, or with alkyl phenols such as octyl or nonyl-phenol /for example, Agral 90/ or artilcles. Other non-ionic agents are the partial esters derived from fatty acids with long chain and hexitol-anhydrides, for example, monolaurate sorbitan; condensation products of partial esters with ethylene oxide; lecithins; and a silicone surface-active agents or water-soluble surface-active agents having the skeleton, which includes the siloxane chain (for example, Silwet L 77)). A suitable mixture in mineral oil is Atplus 411F.

Aqueous solutions or dispersions can be prepared by dissolving the active ingredient in water or in an organic solvent optionally containing wetting or dispersing agent/s/, and then, when using organic solvents, adding the thus obtained mixture to water, optionally containing wetting or dispersing agent(s). Suitable organic solvents include, for example, telengard, isopropyl alcohol, propylene glycol, d is output in the form of aqueous solutions or dispersions are usually supplied in the form of a concentrate, containing a high proportion of the active ingredient, and the concentrate is then diluted before use with water. Concentrates are usually required to withstand storage for prolonged periods and after such storage, they must be capable of dilution with water for the formation of aqueous preparations which remain homogeneous for a sufficient time to be able to apply them using conventional spraying equipment. Concentrates conveniently contain 20 to 90%, preferably 20-70%, by weight of the active ingredient (or ingredients). Diluted preparations ready for use may contain different amounts of active ingredient, depending on the purpose for which the drug is intended; are typically used amount of from 0.01 to 10.0% and preferably 0.1 to 2%, by weight of the active ingredient.

The preferred form of a concentrated composition includes an active ingredient finely ground and dispersed in water in the presence of surface-active agent and a suspending agent. Suitable suspendresume agents are hydrophilic colloids, and they include, for example, polyvinylpyrrolidone and carboxymethyloxime agents are agents, which impart thixotropic properties of drugs and increase the viscosity of the concentrate. Examples of preferred suspendida agents include hydrated colloidal silicates, such as montmorillonite, Badelt, nontronite, hectorite, saponite and sauquoit. Especially preferred is bentonite. Other suspendresume agents include cellulose derivatives and polyvinyl alcohol.

The degree of use or the consumption rate of the compounds of this invention depends on a number of factors, including for example, the compound selected for use, type of plants, the growth of which is expected to inhibit, new form is selected for use, and whether the connection to the foliage or root uptake.

However, usually the rate of flow of from 0.001 to 20 kg per hectare is appropriate, however, may be preferred rate from 0.025 to 10 kg /hectare.

The compositions of this invention may include in addition to one or more compounds of the present invention, one or more compounds that are not relevant to the invention, but which possess biological activity. Accordingly, according to another embodiment of the invented is rmula /I/, defined above, with at least one other herbicide.

Another herbicide may be any herbicide that does not have a formula /1/. Usually a herbicide, providing an additional action when a specific application.

Examples of useful additional herbicides include:

A. benzo-2,1,3-thiadiazin-4-one-2,2-dioxides such as bentazon,

B. herbicide hormones, especially phenoxy-alcamovia acid, such as MCPA, MCPA-thioethyl, dichlorprop, 2,4,5-T, MSRV, 2,4-D, 2,4-DV, mecoprop, triclopyr, clopyralid and their derivatives (e.g. salts, esters and amides).

C. 1,3-dimethylpyrazole derivatives, such as paradoxien, pyrazolate, benzefoam,

D. dinitrophenol and their derivatives (e.g., acetates), such as dinoterb, dinoseb and their esters, dinoseb-acetate,

E. dinitroaniline herbicide, such as dinitramine, trifluralin, dataflurry, pendimethalin, oryzalin,

F. kilmacanogue herbicides, such as Diuron, fluometuron, metoxuron, neburon, Isoproturon, chlortoluron, chloroxuron, linuron, monolinuron, chlorbromuron, Diuron, methabenzthiazuron,

G. phenylcarbamoyloxyphenylcarbamate, such as phenmedipham and desmedipham,

H. 2-phenylpyridazin-2-it, such Cazenovia herbicides, such as atrazine, Simazine, isoprotein, cyanazine, prometryn, deltamethrin, simetryn and terbutryn,

K. phosphorotioate herbicides, such as piperophos, bensulide and butamifos.

L. THIOCARBAMATE herbicides, such as cycloate, vernolate, molinet, thiobencarb, butyl, ARTS, three-Allat, di-Allat, asbroker, thiocarbonyl, peridot and timepart,

M. 1,2,4-triazine-5-about herbicides, such as metamitron and metribuzin,

N. Benzoylacetate herbicides such as 2,3,6-TBA, dicamba and chloramben,

O. aniline herbicides, such as pretilachlor, butachlor, Athlon, propachlor, propanil, metazachlor, metolachlor, acetochlor and dimethachlor,

P. dihalogenoalkane herbicides, such as dichlobenil, bromoxynil and ioxynil,

Q. haloalkane herbicides, such as dalapon, TCA and their salts,

R. diphenylamine herbicides, such as lactofen, fluoroglycofen or their salts or esters, nitrogen, bifenox, acifluorfen and its salts and esters, oxilorphan, fomesafen, chlornitrofen and chlorotoxin,

S. phenoxybenzamine herbicides, such as diclofop and its esters, such as methyl ether, fluazifop and its esters, haloxyfop and its esters, quizalofop and its esters and phenoxypropionic, cycloxydim, tralkoxydim, clethodim,

U. sulfonilmocevina herbicides, such as chlorsulfuron, sulfometuron, metsulfuron and its esters, beskulture, and its esters, such as DPX-M, chlorimuron and its esters, such as ethyl ether, primisulfuron and its esters, such as its methyl ester, 2-[3-(4-methoxy-6-methyl-1,3,5-triazine-2-yl)-3-methylpredisolone] benzeneacetate esters, such as methyl ether (DPX-LS300) and pyrazosulfuron,

V. imidazolidinone herbicides, such as imazighen, imazamethabenz, imazapyr and isopropylammonium salt it, imazethapyr,

W. allenylidene herbicides, such as femprep and its esters, benzoylperoxy-ethyl, diflufenican,

X. amino acid herbicides such as glyphosphate and glufosinate and their salts and esters, Alfacam and bialaphos,

Y. michalkaronski herbicides, such as mononitrobenzene /MSMA/,

Z. herbicide amide derivatives, such as napropamide, propyzamide, carbetamide, tabulam, bromated, isoxaben, nitroanilide and naptalam,

AA. additional herbicides, including Atalanta, cinmetacin, difenacoum, and its salts, such as methylsulfate salt, clomazone, oxadiazon, bromophenoxy, Barban, tridiphane, flurochloridone include:

BIPYRIDILIUM herbicides, such as herbicides, in which the active part is paraquat, and herbicides, in which the active part is Diquat,

*These compounds are preferably used in combination with the security agent, such as dichlormid.

This invention is illustrated in the examples. /Intermediate compounds described in Preparative examples and examples Get/. Abbreviations used in the examples have the following meanings:

NMR spectrum: spectrum of nuclear magnetic resonance, which was recorded at 270 or 400 MHz. /This refers to the spectrum of proton magnetic resonance, unless otherwise noted/. The following abbreviations are used to indicate the multiplicity of the peaks in the NMR spectrum:

c. s (singlet), d d (doublet), so t (triplet), square q (Quartet), Queen. quin (quintet), m m (multiplet), Shir. br (broad).

Infrared spectrum: the infrared absorption spectrum.

MS: mass spectrum

GC: gas chromatography

TLC: thin layer chromatography

so PL: melting point, because: boiling point

Preparative example 1

Obtaining 3-(3,4-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(3,4-dichloro)phenyl-4-the acid /of 5.68 g/. After 10 minutes, the solution was treated dropwise 37% aqueous formaldehyde /4,75/ ml, and then p-toluensulfonate acid /10 mg/. The mixture is then heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark after 4 hours the mixture was cooled and extracted with saturated aqueous sodium bicarbonate solution /100 ml. White solid precipitated, was filtered off, dried and precrystallization from a mixture of ethyl acetate/hexane, yielding the target compound as a white crystalline solid, yield 5,70 g, so pl. 151 - 152oC.

1H NMR /CDCl3/: 3,71 /2H, c/, 4,79 /2H, c/, 7,37 /1H, DD,./, 7,47 /1H, D./, of 7.64 /1H, d/.

Stage 2

Obtaining 3-(3,4-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Stir a solution of 3-(3,4-dichloro)phenyl-4-thiazolidinone /obtained as described in stage 1 above/ /4,50 g/ in dichloromethane /130 ml/ was cooled in an ice bath. After the solution was barotiwala a stream of nitrogen, and was added dropwise a solution of sulfurylchloride /2,47 g/ in dichloromethane /5 ml/. After adding the solution was left to warmed to room temperature and stirred for an additional 2 hours while maintaining the flow of nitrogen, the solution after trituration with hexane was dissolved in Tetra who was peremeshivaesh within 2 hours. The organic layer was separated, diluted with ethyl acetate /50 ml were washed with saline /50 ml, then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave the pitch, which was chromatographically on silica gel with elution with mixtures of hexane/ethyl acetate, yielding the target compound in the form of resin which hardened on standing, giving 3,40,

1H NMR /CDCl3/: 4,78 /1H, D./, 5,06 /1H, D./, 5,58 /1H, D./, 6,98 /1H, D./, 7,40 - 7,50 /2H, m,/, 7,80 /1H, D./.

Preparative example 2

Getting 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 3-triptorelin /43,50 g/ toluene /275 ml/ processed thioglycolic acid /of 24.90 g/. After 10 minutes, was added dropwise to a solution of 37% aqueous formaldehyde /20,8 ml/ s followed by addition of p-toluenesulfonic acid /30 mg/. The mixture is then heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark. After going to 23.5 ml of water, the mixture was cooled, extracted with saturated aqueous sodium bicarbonate solution /100 ml and dried /magnesium sulfate/. Evaporation under reduced pressure gave a yellow oil, which gave the P>C.

1H NMR /CDCl3/: 3,76 /2H, S./, 4,85 /2H, S./, 7,47 - 7,58 /2H, M./. 7,68 - 7,76 /2H, M./.

Stage 2

Getting 5-chloro-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as in stage 1 above/ /10,00 g/ in dichloromethane /150 ml/ was cooled in an ice bath. After the solution was barotiwala a stream of nitrogen, and was added dropwise a solution of sulfurylchloride /5,47 g/ in dichloromethane /5 ml/. After adding the solution was left to warmed to room temperature and stirred for a further one hour while maintaining a stream of nitrogen. The solution was evaporated under reduced pressure, leaving the product as a solid residue. This product was used directly in subsequent reactions.

1H NMR /CDCl3/: 4,72 /1H, D./, 5,24 /1H, D./, 5,77 /1H, s/, 7,50 - to 7.61 /2H, m,/, 7,70 - 7,82 /2H, M./.

Stage 3

Getting 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 5-chloro-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained in stage 2 above/ in tetrahydrofuran /100 ml was treated with an aqueous solution of sodium bicarbonate /100 ml, and the mixture is stirred vigorously for 3 hours. The organic layer was separated, diluted Atila under reduced pressure left a resin. Rubbing with hexane gave a yellow-brown solid, which was precrystallization from a mixture of ethyl acetate/hexane, yielding the target compound as a white crystalline solid, yield was 7.08 g, so pl. 87 - 88oC.

1H NMR /CDCl3/: 4,70 /1H, D./, 5,00 /1H, broad, S./, of 5.05 /1H, D./, 5,74 /1H, s/, of 7.48 -7,59 /2H, m/, of 7.64-7,76 /2H, M./.

Preparative example 3

Obtain 3-[3,5-bis(trifluoromethyl)]phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtain 3-[3,5-bis(trifluoromethyl)]phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 1, above, but using 3,5-bis/trifluoromethyl/aniline /10,42 g/, thioglycolic /4,10 g/, 37% aqueous formaldehyde /4,1/ ml and toluene /100 ml/ this compound was obtained as a white solid, yield 10,80 g, so pl. 49 - 51oC.

1H NMR /CDCl3/: 3,78 /2H, S./, 4,90 /2H, S./, 7,73 /1H, s/, 8,00 /2H, S./.

Stage 2

Getting 5-chloro-3-[3,5-bis(trifluoromethyl)]phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 2, above, but using 3-[3,5-bis(trifluoromethyl)]phenyl-4-thiazolidinone /recip is eposredstvenno at stage 3

Stage 3

Getting 5-hydroxy-3-[3,5-bis(trifluoromethyl)]phenyl-4-thiazolidinone

Using a procedure similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-[3,5-bis(trifluoromethyl)] -phenyl-4-thiazolidinone /obtained as in stage 2 of the above target compound was obtained as a white solid, yield 7,10 g, so square 138 - 139oC.

1H NMR /CDCl3/: to 4.41 /1H, D./, 5,16 /1H, D./, 5,65 /1H, D./, 6.42 per /1H, D./, 7,73 /1H, s/, 8,08 /1H, s/.

Preparative example 4

Getting 5-hydroxy-3-(4-trifluoromethyl)phenyl-4-thiazolidinone

Stage 1

Getting 5-chloro-3-(4-trifluoromethyl)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(4-trifluoromethyl)phenyl-4-thiazolidinone /0,78 g/, sulfurylchloride /0.25 ml/ and dichloromethane /5 ml/. This product was used directly in stage 2.

Stage 2

Getting 5-hydroxy-3-(4-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-/4-trifluoromethyl/phenyl-4-thiazolidinone /polyceram was the target compound as a white solid, output 0,22 g, so pl. 100 - 101oC.

1H NMR /CDCl3: 4,47 /1H, broad, S./, 4,73 /1H, D./, of 5.05 /1H, D./, 5,75 /1H, s/, a 7.62 - 7,73 /4H, m/.

Preparative example 5

Obtaining 3-(3-chloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(3-chloro)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using 3-Chloroaniline /30,10 g/, thioglycolic /21,7 g/, 37% aqueous formaldehyde /18.3 ml, toluene /350 ml/ and p-toluenesulfonic acid /30 mg/ and recrystallization of the crude product from a mixture of ethyl acetate/hexane was obtained this compound as a pale yellow solid, yield and 36.80 g, so pl. 79oC.

1H NMR /CDCl3/: 3,72 /2H, S./, 4,80 /2H, S./, 7,22 /1H, m,/, 7,28 - 7,40 /2H, m,/, 7,50 /1H, m,/.

Stage 2

Getting 5-chloro-3-(3-chloro)phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 2 above, but using 3-(3-chloro)phenyl-4-thiazolidinone /obtained as in stage 1 above/ /34,70 g/, sulfurylchloride /13,20 ml and dichloromethane /150 ml/. This product was used directly in stage 3.

Stage 3
the Oh in preparative example 2, stage 3 above, but using 5-chloro-3-(3-chloro)-phenyl-4-thiazolidinone /obtained as in stage 2 above/ tetrahydrofuran /150 ml saturated aqueous sodium bicarbonate solution /150 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane was the target connection, the output 19,90 g, so pl. 112 - 114oC.

1H NMR /CDCl3/: with 4.64 /1H, D./, 5,00 /1H, D./, 5,39 /1H, broad, S./, 5,75 /1H, s/, 7,20 - 7,38 /3H, m/, 7,50 /1H, s/.

Preparative example 6

Obtaining 3-(3,5-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(3,5-dichloro)phenyl-4-thiazolidinone

Using a procedure similar to the procedure described in preparative example 2, step 1 above, but using 3,5-dichloraniline /28.70 g/, thioglycolic /16.30 g/ 37% aqueous formaldehyde /13.7 ml, toluene /350 ml/ p-toluensulfonate acid /30 mg/ and recrystallization of the crude product from a mixture of ethyl acetate/hexane this compound was obtained as a pale yellow solid, yield increased by 28.70,

1H NMR /CDCl3/: 3,72 /2H, S./, 4,78 /2H, S./, 7,21 /1H, T./, 7,45 /2H, D./.

Stage 2

Getting 5-chloro-3-(3,5-dichloro)phenyl-4-thiazolidinone

This loadentitiesbyid 3-(3,5-dichloro)phenyl-4-thiazolidinone /received as described in stage 1 above/ /28.30 g/, sulfurylchloride /9,2/ ml and dichloromethane /100 ml. This product was used directly in stage 3.

Stage 3

Obtaining 3-(3,5-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Using a procedure similar to the procedure described in preparative example 2, step 3, above, but using 5-chloro-3-(3,5-dichloro)phenyl-4-thiazolidinone /obtained as described in stage 2 above, tetrahydrofuran /125 ml and saturated aqueous sodium bicarbonate /125 ml/ and trituration of the crude product with diethyl ether was the target connection, the output 16,70 g, so pl. 107 - 111oC.

1H NMR /CDCl3/: br4.61 /1H, D./, 4,98 /1H, D./, 5,19 /1H, broad, S./, 5,71 /1H, s/, 7,21 /1H, m,/, 7,42 /2H, M./.

Preparative example 7

Obtaining 3-(3-chloro-4-fluoro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(3-chloro-4-fluoro)phenyl-4-thiazolidinone

Using a procedure similar to the procedure described in preparative example 2, step 1 above, but using 3-chloro-4-foranyone /19,46 g/, thioglycolic /12,50 g/, 37% aqueous formaldehyde /10,5 ml of toluene /150 ml/ and trituration of the crude product with a mixture of diethyl ether/hexane was obtained this compound in H, C./, 4,78 /2H, S./, 7,18 /1H, m,/, 7,31 /1H, m,/, 7,55 /1H, m,/.

Stage 2

Getting 5-chloro-3-(3-chloro-4-fluoro)phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 2 above, but using 3-(3-chloro-4-fluoro)phenyl-4-thiazolidinone /obtained as described in stage 1 above/ /20,00 g/, sulfurylchloride /11,2 ml and dichloromethane /100 ml. This product was used directly in stage 3.

1H NMR /CDCl3/: 4,63 /1H, D./, 5,27 /1H, D./, 5,75 /1H, s/, 7,21 /1H, m,/, 7,37 /1H, m/, to 7.61 /1H, m,/.

Stage 3

Obtaining 3-(3-chloro-4-fluoro)-phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a white solid using the procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(3-chloro-4-fluoro)-phenyl-4-thiazolidinone /obtained as described in stage 2 above, tetrahydrofuran (THF /50 ml saturated aqueous sodium bicarbonate /50 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane followed by rubbing with carbon tetrachloride, the output 12,50 g, so pl. 118 - 121oC.

1H NMR /CDCl3/: 4,63 /nucene 3-(2-chloro)-phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(2-chloro)phenyl-4-thiazolidinone

This compound was obtained as a white solid with a yield 5,70 g/ T. pl. 62 - 63oC/ using a procedure similar to the procedure described in preparative example 2, step 1 above, but using 2-Chloroaniline /was 12.75 g/, thioglycolic /9,2 g/, 37% aqueous formaldehyde /7,8/ ml and toluene /100 ml and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane.

1H NMR /CDCl3/: 3,72 /2H, S./, 4,69 /2H, S./, 7,28-7,40 /3H, m/, 7,49 /1H, m,/.

Stage 2

Getting 5-chloro-3-(2-chloro)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(2-chloro)phenyl-4-thiazolidinone /obtained in stage 1 above/ /5.20 g/, sulfurylchloride /2.0 ml,/ and dichloromethane /50 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(2-chloro)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a white solid using a procedure similar to the procedure described in preparative example 2, step 3 above, but with the use of the and saturated aqueous sodium bicarbonate /25 ml/ and recrystallization of the crude product from toluene, yield 3.80 g, so pl. 117 - 119oC.

1H NMR /CDCl3/: 4,58 /1H, d/ of 4.83 /1H, D./, of 5.05 /1H, s/, 5,78 /1H, s/, 7,30 - 7,21 /3H, m/, 7,52 /1H, m,/.

Preparative example 9

Getting 5-hydroxy-3-(4-methoxy)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(4-methoxy)phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 1 above, but using 4-methoxyaniline /8,43 g/, thioglycolic /6,30 g/, 37% aqueous formaldehyde /5,3 ml of toluene /100 ml and recrystallization of the crude product from a mixture of ethyl acetate/hexane, white solid, yield of 7.00 g, so pl. 95 - 97oC.

1H NMR /CDCl3/: 3,72 /2H, S./, 3,80 /3H, s/, 4,77 /2H, S./, 6,90 - of 6.96 /2H, m,/, 7,27 - 7,33 /2H, M./.

Stage 2

Getting 5-chloro-3-(4-methoxy)phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 2 above, but using 3-(4-methoxy)phenyl-4-thiazolidinone /obtained as described in stage 1 above,/, /6.20 g/, sulfurylchloride /2.4 ml/ and dichloromethane /50 ml/. This product was used directly in stage 3.

Stage 3

Getting 5-hydroxy-westva using procedures similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-/4-methoxy/phenyl-4-thiazolidinone /obtained as described in stage 2 above, tetrahydrofuran (THF /30 ml saturated aqueous sodium bicarbonate /60 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane followed by recrystallization from toluene, the output 3,20 g, so pl. 126 - 128oC.

1H NMR /CDCl3/: 3,81 /3H, s/, 4,63 /1H, d/, 4,87 /1H, D./, 4,94 /1H, D./, 5,75 /1H, D./, 6,89-6,97 /2H, m,/, 7,28 was 7.36 /2H, M./.

Preparative example 10

Obtaining 3-(2,3-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(2,3-dichloro)phenyl-4-thiazolidinone

This compound was obtained as a white solid using the procedure analogous to the procedure described in preparative example 2, step 1 above, but using 2,3-dichloraniline /10,00 g/, thioglycolic /of 5.68 g/, 37% aqueous formaldehyde /4,75/ ml, toluene /120 ml and p-toluenesulfonic acid /10 mg/ and trituration of the crude product with a mixture of diethyl ether/hexane, the yield of 1.43 g

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,67 /2H, S./, 7,15-7,32 /2H, m,/, 7,51 /1H, m,/.

Stage 2

Getting 5-CHL is Roy, described in preparative example 2, step 2 above, but using 3-(2,3-dichloro)phenyl-4-thiazolidinone /obtained in stage 1 above/ /1.20 g/, sulfurylchloride /0.65 g/ and dichloromethane /20 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(2,3-dichloro)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a pale yellow solid with a yield 0.66 g using the procedure similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(2,3-dichloro)phenyl-4-thiazolidinone /obtained as described in stage 2 above), tetrahydrofuran (THF /30 ml saturated aqueous sodium bicarbonate /25 ml/ and trituration of the crude product with diethyl ether.

1H NMR /CDCl3/: to 4.52 /1H, D./, 4,85 /1H, D./, the ceiling of 5.60 /1H, D./, 6,99 /1H, D./, 7,30 - 7,40 /2H, m,/, 7,55 /1H, m,/.

Preparative example 11

Getting 5-hydroxy-3-(4-methyl)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(4-methyl)phenyl-4-thiazolidinone

This compound was obtained as a white solid using a procedure similar to the procedure described in preparative example 1, step 1 above, but using 4-methylaniline /14,30 g/, thioglycolic x2">

1H NMR /CDCl3/: 2,34 /3H, s/, 3,72 /2H, S./, 4,79 /2H, S./, 7,15 - 7,32 /4H, m/.

Stage 2

Getting 5-chloro-3-(4-methyl)phenyl-4-thiazolidinone

This compound was obtained using a procedure similar to the procedure described in preparative example 2, step 2 above, but using 3-(4-methyl)phenyl-4-thiazolidinone /obtained as described in stage 1 above/ /9.00 g/, sulfurylchloride /3,8 ml and dichloromethane /100 ml. This product was used directly in stage 3.

Stage 3

Getting 5-hydroxy-3-(4-methyl)phenyl-4-thiazolidinone

The target compound was obtained as a pale yellow solid using a procedure similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(4-methyl)phenyl-4-thiazolidinone /obtained as described in stage 2 above, tetrahydrofuran (THF /75 ml saturated aqueous sodium bicarbonate /100 ml and recrystallization of the crude product from toluene, the yield of 5.00 g, so pl. 137 - 138oC.

1H NMR /CDCl3/: 2,37 /3H, s/, 4,60 /1H, D./, 4,95 /1H, D./, 5,71 /2H, S. + S. broad/, 7,12 - 7,31 /4H, m/.

Preparative example 12

Obtaining 3-(3-chloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(4-chloro)the dryer is illogical procedure, described in preparative example 2, step 1 above, but using 4-Chloroaniline /14,50 g/, thioglycolic /10,50 g/, 37% aqueous formaldehyde /8,9/ ml and toluene /150 ml/ and trituration of the crude product with diethyl ether, the yield 17.0 g, so pl. 96 - 98oC.

1H NMR /CDCl3/: 3,72 /2H, S./, 4,79 /2H, S./, 7,32-7,43 /4H, m/.

Stage 2

Getting 5-chloro-3-(4-chloro)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2, above, but using 3-(4-chloro)phenyl-4-thiazolidinone /obtained as described above in stage 1/ /15,00 g/, sulfurylchloride /5,7/ ml and dichloromethane /150 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(4-chloro)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(4-chloro)phenyl-4-thiazolidinone /obtained in stage 2 above, tetrahydrofuran (THF /50 ml saturated aqueous sodium bicarbonate /50 ml/ and recrystallization of the crude product from toluene, the output 9.80 g, so pl. 118 - 120oC.

1H
Obtaining 3-(2,5-dichloro)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(2,5-dichloro)phenyl-4-thiazolidinone

This connection is taught in the form of a white solid using the procedure analogous to the procedure described in preparative example 2, step 1 above, but using 2,5-dichloraniline /10,00 g/, thioglycolic /of 5.68 g/, 37% aqueous formaldehyde /4,75/ ml, toluene /120 ml and p-toluenesulfonic acid /10 mg/ and trituration of the crude product with a mixture of diethyl ether/hexane, yield 0,78 g

1H NMR /CDCl3/: 3,71 /2H, S./, 4,66 /2H, S./, 7,29 - 7,46 /3H, m/.

Stage 2

Getting 5-chloro-3-(2,5-dichloro)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(2,5-dichloro)phenyl-4-thiazolidinone /received, as described above, stage 1/ /0,68 g/, sulfurylchloride /0,37 g/ and dichloromethane /15 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(2,5-dichloro)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a reddish brown solid using a procedure analogous to the procedure, op is received in stage 2 above/ tetrahydrofuran (THF) /20 ml and saturated aqueous sodium bicarbonate /30 ml/ and trituration of the crude product with diethyl ether, the yield of 0.36 g

1H NMR /CDCl3/: 4,55 /1H, d/, 4,87 /1H, D./, 5,68 /1H, D./, of 6.31 /1H, D./, 7,25 - 7,46 /3H, m/.

Preparative example 14

Getting 4-hydroxy-2-(3-trifluoromethyl)phenyl-3-isoxazolidinone

Stage 1

Obtaining N-(3-trifluoromethyl)phenylhydroxylamine.

Its preparation is described in preparative example 50.

Stage 2

Getting 4-bromo-2-(3-trifluoromethyl)phenyl-3-isoxazolidinone

A solution of N-/3-trifluoromethyl/phenylhydroxylamine /4,69 g/ triethylamine /2,94 g/ dry tetrahydrofuran (THF /5 ml was added dropwise during 30 minutes to a vigorously stirred solution of 2,3-dibromopropionamide /6,63 g/ dry tetrahydrofuran /20 ml) cooled to 0oC. the Mixture was left to heated slowly to room temperature and stand overnight. The mixture was then filtered through Hyflo Supercel, and the filtrate was vigorously mixed with an aqueous solution of sodium carbonate /2 ml, saturated/ over 2 hours. The mixture was left to stand overnight, it was diluted with ethyl acetate, washed with saline, dried over magnesium sulfate and VI dichloromethane-hexane /3,1/, and then dichloromethane as eluents, giving the target compound /2,84 g/ in the form of butter.

1H NMR /CDCl3/: 4,6 /1H, DD,./, 4,75 /1H, DD,./, 4,8 /1H, DD,./, 7,4 /2H, m,/, 7,9 /2H, M./.

M/C: 309 /M+, Br = 79/.

Stage 3

Getting 4-iodine-2-(3-trifluoromethyl)phenyl-3-isoxazolidinone

A mixture of 4-bromo-2-(3-trifluoromethyl)phenyl-3-isoxazolidinone /0.28 g/ and sodium iodide /0.36g/ acetone /10 ml/ mixed in the absence of light for twenty hours at room temperature. Then it was filtered through Hyflo Supercel and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure, giving the target compound /0.28 g/ in the form of a pale yellow oil, essentially pure according to GC.

1H NMR /CDCl3/: 4,6 /1H, DD,./, 4,75 /1H, DD,./, 4,95 /1H, DD,./, 7,5 /2H, m,/, 8,0 /2H, M./.

M/S: 357 /M+/

Stage 4

Getting 2-(3-trifluoromethyl)phenyl-3-isoxazolidinone

A solution of 4-iodine-2-(3-trifluoromethyl)phenyl-3-isoxazolidinone /0.20 g/, anti-hydride /0.16 g/ and-azoisobutyronitrile /0.01 g/ toluene /10 ml was heated under conditions of reflux distilled for two hours. The mixture was evaporated under Polyglactin-hexane /1:3/ as eluents. The target compound was obtained /0,09 g/ in the form of a pale yellow oil.

1H NMR (CDCl3/: 3,05 /2H, t/, 4,6 /2H, so/, 7,5 /2H, m,/, 8,0 /2H, M. /.

M/C: 231 /M+/

This substance can be obtained more conveniently by using a combination of arylhydroxylamine directly with 3-bromopropionitrile. Although treatment is extremely tedious, stage 5 can directly be used partially purified material.

Thus, a solution of N-(3-trifluoromethyl)phenylhydroxylamine /0.50 g/ triethylamine /0,59 g/ dry tetrahydrofuran (THF /5 ml was added dropwise to a stirred solution of 3-bromopropionitrile /0,48 g/ dry tetrahydrofuran /20 ml) cooled to 0oC. the Mixture is stirred at 0oC for 2 hours, was left to warmed to room temperature, it was diluted with ethyl acetate and was washed with an aqueous solution of sodium carbonate and then brine. The extract was dried over magnesium sulfate, supariwala under reduced pressure, and the residue was chromatographically on silica using a mixture of ethyl acetate: hexane /1:3 as eluent, giving a pale yellow oil /0,22 g/. This oil contained approximately 30% of the target compounds according to the1H is ormetal)phenyl-3-isoxazolidinone

Bis/(trimethylsilyl)/lithium amide /0,29 ml, 1M solution in tetrahydrofuran/ added slowly to a stirred solution of pure 2-(3-trifluoromethyl)phenyl-3-isoxazolidinone /0.06 g/ dry tetrahydrofuran (THF /5 ml, the temperature was maintained below -75oC. the Mixture was mixed for ten minutes at -78oC, referred to be heated up to -25oC, re-cooled to -78oC, then processed N-(4-toluensulfonyl)-3 - phenyloxazolidine /0.08 g, obtained as described in J. Org. Chem., 1988, 53, 2087/. The mixture is stirred at -78oC for a further 1 hour, was left to warmed to room temperature, poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The extracts were washed with saline, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographically on silica using as eluents mixture of hexane-ethyl acetate /3:1/, and then ethyl acetate, giving a pale yellow solid matter /0.05 g/, which includes a mixture of target compound and toluene-p-sulfonamida. This material can be directly used for carbamylcholine, and tert-BUTYLCARBAMATE easily separated from the toluene-p-sulfo is, ,5 /2H, m,/, 7,95 /2H, M./.

GC/MS: M+247.

Preparative example 15

Obtaining 3-(2-fluoro-5-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(2-fluoro-5-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using 2-fluoro-5-triptorelin /10,20 g/, thioglycolic /5,80 g/, 37% aqueous formaldehyde /4.8 ml/ toluene /100 ml and distillation Cuellar crude product under reduced pressure was obtained this compound in the form of a colorless oil, which crystallized upon standing, the output 2,80 g, so pl. 40 - 43oC.

1H NMR /CDCl3/: 3,71 /2H, S./, 4,74 /2H, S./, 7,30 /1H, m,/, 7,58 - 7,70 /2H, M./.

Stage 2

Getting 5-chloro-3-(2-fluoro-5-trifluoromethyl)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(2-fluoro-5-trifluoromethyl)phenyl-4-thiazolidinone /obtained in stage 1 above, sulfurylchloride /0,85 ml and dichloromethane /25 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(2-fluoro-5-trift is using the procedures similar to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(2-fluoro-5-trifluoromethyl)phenyl-4-thiazolidinone /obtained in stage 2 above, tetrahydrofuran (THF /30 ml saturated aqueous sodium bicarbonate /50 ml/, recrystallization of the crude product from chloroform, the output of 2.10 g, so pl. 145 - 147oC.

1H NMR /CDCl3/: 4,69 /1H, D./, 4,96 /1H, D./, 5,64 /1H, D./, 6,85 /1H, D./, 7,28 - 7,38 /1H, m/, to 7.61 /1H, m,/, 7,75 /1H, m,/.

Preparative example 16

Obtaining 3-(3-chloro-4-methyl)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(3-chloro-4-methyl)phenyl-4-thiazolidinone

This compound was obtained as crystalline solid using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using 3-chloro-4-methylphenylamine /14,15 g/, thioglycolic /9,20 g/, 37% aqueous formaldehyde /7,88 ml of toluene /120 ml/ and trituration of the crude product with a mixture of diethyl ether/hexane followed by recrystallization from a mixture of ethyl acetate:hexane, the yield of 10.50 g, so pl. 90 - 91oC.

1H NMR /CDCl3/: 2,32 /3H, s/, 3,71 /2H, S./, 4,76 /2H, S./, 7,25 /2H, S./, 7,47 /1H, s/.

Stage 2

Getting 5-chloro-3-(3-chloro-described in preparative example 2, stage 2 above, but using 3-(3-chloro-4-methyl)phenyl-4-thiazolidinone /obtained as in stage 1 above/ /8,80 g/, sulfurylchloride /3,13 ml and dichloromethane /50 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(3-chloro-4-methyl)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a white solid using the procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(3-chloro-4-methyl)phenyl-4-thiazolidinone /obtained as in stage 2 above/ tetrahydrofuran /50 ml saturated aqueous sodium bicarbonate /50 ml/ and recrystallization of the crude product from a mixture of ethyl acetate/hexane to yield 6.20 g, so pl. 91 - 93oC.

1H NMR /CDCl3/: 2,33 /3H, s/, br4.61 /1H, D./, equal to 4.97 /1H, D./, 5,39 /1H, s/, 5,73 /1H, s/, of 7.23 /2H, S./, 7,46 /1H, s/.

Preparative example 17

Getting 5-hydroxy-3-phenyl-4-thiazolidinone

Stage 1

Obtaining 3-phenyl-4-thiazolidinone

This compound was obtained as colorless needles with the release of 0.38 g using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using aniline /4,65 g/, thioglycolic /4,60 g/, 37% vodno is using chromatography on silica gel /elution by chloroform/ followed by recrystallization from a mixture of chloroform/hexane.

1H NMR /CDCl3/: to 3.73 /2H, m,/, 4,81 /2H, m,/, 7,25 /1H, m,/, 7,37-7,47 /2H, M./.

Stage 2

Getting 5-chloro-3-phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-phenyl-4-thiazolidinone /obtained as in stage 1 above/ /0,38 g/, sulfurylchloride /0,29 g/ and dichloromethane /5 ml/. This product was used directly in stage 3.

Stage 3

Getting 5-hydroxy-3-phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-phenyl-4-thiazolidinone /obtained as in stage 2 above/ tetrahydrofuran /10 ml and saturated aqueous sodium bicarbonate /15 ml/ was the target compound in the form of oily solids, the yield of 0.24 g

1H NMR /CDCl3/: to 4.52 /1H, D./, 4,89 /1H, D./, 5,65 /1H, D./, 5,76 /1H, broad, S./, 7,19 /1H, m,/, 7,25-7,34 /4H, m/.

Preparative example 18

Obtaining 3-(4-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-(4-fluoro-3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in prelati /9,20 g/, 37% aqueous formaldehyde /7.7 ml of toluene /110 ml/ and trituration of the crude product with a mixture of diethyl ether/hexane was obtained this compound in the form of a white solid, yield 16,00 g, so pl. 83 - 85oC.

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,80 /2H, S./, 7,25 /1H, m/, of 7.64 - 7,72 /2H, M./.

Stage 2

Getting 5-chloro-3-(4-fluoro-3-trifluoromethyl)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(4-fluoro-3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as in stage 1 above/ /14,00 g/, sulfurylchloride /4,3/ ml and dichloromethane /100 ml. This product was used directly in stage 3.

1H NMR /CDCl3/: 4,68 /1H, D./, a total of 5.21 /1H, D./, 5,77 /1H, s/, 7,29 /1H, m,/, 7,69 - 7,78 /2H, M./.

Stage 3

Obtaining 3-(4-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone

The target compound was obtained as a white solid using the procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(4-fluoro-3 - trifluoromethyl)phenyl-4-thiazolidinone /obtained in stage 2 above, tetrahydrofuran /50 ml and saturated water oC.

1H NMR /CDCl3/: 4,40 /1H, D./, 4,69 /1H, D./, 4,99 /1H, D./, 5,75 /1H, D./, 7,28 /1H, m/, to 7.67 - to 7.77 /2H, M./.

Preparative example 19

Obtaining 3-(3-pentafluoroethyl)phenyl-5-hydroxy-4-thiazolidinone

Stage 1

Obtaining 3-pentafluoroaniline

The powder recovered iron /8,60 g/ was added to a stirred solution of 3-pentafluorothiophenol /2.65 g/ in a mixture of isopropanol /27 ml/ water /6 ml/ and conc. hydrochloric acid /0.3 ml/. The resulting mixture was heated under conditions of reflux distilled for 1 hour and then left to cool slightly before it was filtered through Hyflo. Hiflo the filter was washed with additional portions of isopropanol, and the combined filtrates were evaporated under reduced pressure. The residue was dissolved in a small amount of diethyl ether, and the solution was treated with solid sodium bicarbonate, then dried over magnesium sulfate. After filtration to remove inorganic substances, the solution was evaporated under reduced pressure, and the apparatus Cuellar competed oily residue. The target compound was collected as a colourless oil, so Kip. 110oC /temperature furnace/ 12 mm RT.art., which crystallized p is asolidimage

Using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using pentafluoroaniline /received, as described above, stage 1/ /1,90 g/, thioglycolic /0,80 g/, 37% aqueous formaldehyde /0.7 ml/, toluene /20 ml/ and p-toluenesulfonic acid /2 mg/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane turned out this connection in the form of a white solid, yield 1.45 g, so pl. 48 - 50oC.

1H NMR /CDCl3/: 3,75 /2H, S./, 4,84 /2H, S./, 7,52 /1H, m,/, 7,60 - 7,69 /2H, m,/, 7,89 /1H, m,/.

Stage 3

Getting 5-chloro-3-(3-pentafluoroethyl)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(3-pentafluoroethyl)phenyl-4-thiazolidinone /obtained as described above, stage 2/ /1,14 g/, sulfurylchloride /0.3 ml/ and dichloromethane /10 ml/. This product was used directly in stage 4.

Stage 4.

Obtaining 3-(3-pentafluoroethyl)phenyl-5-hydroxy-4 - thiazolidinone

Using a procedure analogous to the procedure described in preparative who, the AK at stage 3, above/ tetrahydrofuran /20 ml and saturated aqueous sodium bicarbonate /20 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane followed by recrystallization from a mixture of carbon tetrachloride/hexane was obtained target compound as a white solid, yield 1.19 g, so pl. 122 - 124oC.

1H NMR /CDCl3/ 4,70 /1H, D./, 4,92 /1H, s/, 5,03 /1H, D./, 5,73 /1H, s/, 7,51 /1H, m,/, EUR 7.57 - 7.68 per /2H, m,/, 7,89 /1H, m,/.

Preparative example 20

Obtaining 3-(2-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4 - thiazolidinone

Stage 1

Obtaining 3-(2-fluoro-3-trifluoromethyl)phenyl-5-thiazolidinone

The target compound was obtained as a light solid using the procedure analogous to the procedure described in preparative example 2, step 1 above, but using 2-fluoro-3-triptorelin /10,00 g/, thioglycolic /5,14 g/, 37% aqueous solution /4,30 ml/, toluene /110 ml/ and p-toluenesulfonic acid and distillation of the crude product in the apparatus Cuellar under reduced pressure, output, or 10.60

1H NMR /CDCl3/ 3,72 /2H, S./, 4,77 /2H,, 7,32 /1H, m,/, 7,55 - 7,63 /2H, M./.

Stage 2

Getting 5-chloro-3-(2-fluoro-3-trifluoromethyl)FeNi is preparative example 2, stage 2 above, but using 3-(2-fluoro-3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as in stage 1 above/ /9.00 g/, sulfurylchloride /4.59 g/ and dichloromethane /120 ml/. This product was used directly in stage 3.

Stage 3

Obtaining 3-(2-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4 - thiazolidinone

The target compound was obtained as a white solid using the procedure analogous to the procedure described in preparative example 2, step 3 above, but using 5-chloro-3-(2-fluoro-3-trifloromethyl)phenyl-4-thiazolidinone /obtained as described above in stage 2/, tetrahydrofuran /100 ml and saturated aqueous sodium bicarbonate /50 ml/ and recrystallization of the crude product from stage a ethyl acetate/hexane, yield 4,40,

1H NMR /CDCl3/: / 4,58 /1H, D./, 5,00 /1H, D./, 5,63 /1H, D./, 6,86 /1H, D./, 7,32 /1H, m,/, EUR 7.57 - 7,70 /2H, M./.

Preparative example 21

Getting 5-hydroxy-2-phenyl-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone

Stage 1

Getting 2-phenyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Mix a solution of benzaldehyde /5.0 ml/ and 3-triptorelin /6,14 ml/ toluene /100 ml was heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark. JV is provided, that the reaction was only about 50% complete. To the reaction mixture portions was added a small amount of thioglycolic, and the heating continued until until GC analysis showed 99% reaction. The solution was cooled and evaporated under reduced pressure. The oily residue was dissolved in diethyl ether were carefully rinsed with saturated aqueous sodium bicarbonate solution, brine, then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified using chromatography on silica gel, with elution with a mixture of ethyl acetate/hexane, giving a colorless oil, which slowly crystallized upon standing. Rubbing with hexane gave the product as a white crystalline solid, yield of 6.90 g, so pl. 53 - 55oC.

1H NMR /CDCl3/: 3,86 /1H, D./, 3,98 /1H, D./, 6,10 /1H, s/, 7,20 - 7,31 /5H, m/, 7,32 - 7,40 /3H, m/, of 7.48 /1H, m,/.

Stage 2

Getting 5-hydroxy-2-phenyl-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone

Using a procedure analogous to the procedure described in preparative example 1, step 2 above, but using 2-phenyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /received, both at the stage of solution of sodium bicarbonate /50 ml/ and purification using chromatography on silica gel with elution with a mixture of ethyl acetate /hexane was obtained as crude product in the form of a mixture of diastereoisomers, output being 0.036,

1H NMR /CDCl3/: by the way 5,91 /1H, s/, 5,95 /1H, s/, 6,01 /1H, s/, 6,32 /1H, s/.

Preparative example 22

Obtaining 3-(4-chloro-3-trifluoromethyl)phenyl-5-hydroxy-4 - thiazolidinone

Stage 1

Obtaining 3-(4-chloro-3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using 4-chloro-3-triptorelin /19,60 g/, thioglycolic /9,20 g/, 37% aqueous formaldehyde /7,80 ml of toluene /100 ml and recrystallization of the crude product from a mixture of ethyl acetate/hexane, was the target compound in the form of solids, the output 14,80 g, so pl. 94 - 95oC.

1H NMR /CDCl3/: 3,72 /2H, S./, 4,80 /2H, S./, 7,51 /1H, D./, 7,65 /1H, DD,./, 7,80 /1H, D./.

Stage 2

Getting 5-chloro-3-(4-chloro-3-tripometer)phenyl-4-thiazolidinone

This compound was obtained using a procedure analogous to the procedure described in preparative example 2, step 2 above, but using 3-(4-chloro-3-trifluoromethyl)phenyl-4-thiazolidinone /obtained above, as in stage 1/ /12.00 g/, sulfurylchloride /3,50/ ml and dichloromethane /50 ml/. This product was used directly in stage 3.

Stage 3
oC.

1H NMR /CDCl3/: 4,63 /1H, D./, 5,08 /1H, D./, 5,64 /1H, D./, 6,62 /1H, D./, 7,52 /1H, D./, 7,69 /1H, DD,./, of 7.90 /1H, D./.

Preparative example 23

Getting 5-hydroxy-5-methyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stage 1

Getting 5-methyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in preparative example 2, step 1 above, but using 3-triptorelin /16,10 g/, timelocal acid /or 10.60 g/, 37% aqueous formaldehyde /7,50/ ml, toluene /150 ml/ type and p-toluenesulfonic acid /20 mg/ and distillation apparatus Cuellar crude product under reduced pressure was obtained target compound as a pale yellow oil, yield 20,10,

1H NMR /CDCl3/: 1,63 /3H, d/, 3,98 /1H, square/, 4,70 /1H, D./, a 4.86 /1H, D./, 7,45 - 7,58 /2H, D./, 7.68 per - 7,79 /2H, D./.

Stage 2<-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone /received as described above, stage 1/ /2,61 g/ in dichloromethane /65 ml/ was cooled in an ice bath. After the solution was barotraumas stream of nitrogen, and was added dropwise a solution of sulfurylchloride /0,89 ml/. Once added, the solution stirred for an additional 1.5 hours while maintaining the flow of nitrogen. Then, water was added, and the mixture was mixed vigorously for 10 minutes. The organic phase was then separated, washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a yellow oil /3.33 g/. Cleaning 1.63 g of this oil by chromatography on silica gel with elution with mixtures of chloroform and methanol gave the target compound as a pale yellow oil which crystallised on standing, yield 1.18 g, so pl. 98 - 101oC.

1H NMR /CDCl3/: 1,85 /3H, s/, 4,10 /1H, broad, S./, br4.61 /1H, D./, 4,95 /1H, D./, 7,45 - 7,55 /2H, m,/, 7,65 - 7,79 /1H, m,/.

Preparative example 24

Getting 5-hydroxy-3-(2-methoxy)phenyl-4-thiazolidinone

Stage 1

Obtain S-(2-methoxybenzylamine)methylthiophenol acid

Mix a solution of ortho-anisidine /18,00 g/ and thioglycolic /13,40 g/ in ethanol /50 ml/ was treated with 37% aqueous formaldehyde solution /11,4 ml/, and pols dichloromethane. Dichloromethane extracts were washed with 2 M hydrochloric acid /2 x 50 ml) and water, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a colourless oil /13,70 g/. This oil contained the crude product was used directly in the next stage.

Stage 2.

Obtaining 3-(2-methoxy)phenyl-4-thiazolidinone

Mix a solution of triethylamine /8,40 ml and dichloromethane /50 ml/ was cooled to 5oC, and to it was added dropwise thionyl chloride /4,40 ml, followed by adding a solution of crude S-(2-methoxybenzylamine)methylthiophenol acid obtained in stage 1 above/ /13,70 g/ in dichloromethane /50 ml/. The mixture is stirred for a further 2 hours and then left to stand for 18 hours. Added an additional amount of triethylamine /8,40 ml, and the mixture is stirred for 5 hours. Water was added, and the mixture was filtered through Hyflo. The filtrate was collected, and the organic layer was separated, washed with saline and dried /magnesium sulfate/. The solution was evaporated under reduced pressure giving a brown resin, which was purified using chromatography on silica gel with elution with mixtures of ethyl acetate and hexane, giving the product in the form with the CLASS="ptx2">

Stage 3

Getting 5-hydroxy-3-(2-methoxy)phenyl-4-thiazolidinone

Stir a solution of 3-(2-methoxy)phenyl-4-thiazolidinone /received, as described above, stage 2/ /0,73 g/ in dichloromethane /20 ml/ was cooled in an ice bath under nitrogen atmosphere, was added dropwise sulfurylchloride /of 0.28 ml/. After adding the solution was left to slowly heated to room temperature. The solution was evaporated under reduced pressure, giving a red oil, which was dissolved in tetrahydrofuran /10 ml/, and is treated with an aqueous solution of sodium bicarbonate /20 ml/. This mixture was mixed vigorously for 30 minutes and then was extracted with dichloromethane /2 x 50 ml/. The combined organic extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a solid residue. Chromatography on silica gel with elution with mixtures of hexane and ethyl acetate gave specified in the title compound as a white crystalline solid, yield of 0.29 g

1H NMR /CDCl3/: 3,82 /3H, s/, 4,18 /1H, broad D./, 4,60 /1H, D./, 4,80 /1H, DD. /, 5,73 /1H, D./, 6,94? 7.04 baby mortality /2H, m,/, 7,25 /1H, m,/, 7,34 /1H, m,/.

Preparative example 25

Getting 5-hydroxy-3-(3-nitro)phenyl-4-T3-nitroaniline /6,575 g/ toluene /100 ml was processed in thioglycolic acid /3,48 ml/ nitrogen atmosphere. After 15 minutes, the suspension was treated dropwise 37% aqueous formaldehyde /of 4.05 ml, resulting in easy ectothermy /initial temperature rose to 30oC/. The reaction mixture was then heated up to the temperature of reflux distilled water was going into the unit Dean-stark. After 3 hours the mixture was cooled and left to stand at room temperature overnight, during this period, the reaction mixture was separated a small amount of crystals and a dark oil. The toluene was decontrols, and the residue was dissolved in ethyl acetate. The combined organic phases were washed with a saturated solution of sodium bicarbonate /x 2/ and a salt solution. The organic layer was dried /Na2SO4/ and the solvent was removed under reduced pressure giving an orange-brown solid /3,781 g/. This substance was precrystallization using toluene, giving an orange-brown crystals, yield 1,921 g, so pl. 142oC.

1H NMR /CDCl3/: of 3.77 /2H, S./, 4,90 /2H, S./, 7,60 /1H, T./, 7,95 /1H, DD,./, 8,10 /1H, DD,./, 8,31 /1H, T./.

Stage 2

Getting 5-chloro-3-(3-nitro)phenyl-4-thiazolidinone

Stir a solution of 3-(3-nitro)phenyl-4-thiazolidinone /received, as described above, at the stage of the ion mixture became brown, after 15 minutes, TLC showed no starting material. The reaction mixture was concentrated under reduced pressure, and the product was used directly in stage 3.

Stage 3

Getting 5-hydroxy-3-(3-nitrophenyl)-4-thiazolidinone

5-Chloro-3-(3-nitro)phenyl-4-thiazolidinone /received, as described above, in stage 2/ suspenderbelt in mixture /1 : 1/ tetrahydrofuran and saturated aqueous sodium bicarbonate solution /60 ml/ and stirred vigorously at room temperature over night. The tetrahydrofuran was removed under reduced pressure, and added ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate /twice/. The combined organic substances were dried /sodium sulfate, and the solvent was removed under reduced pressure giving an orange solid /2,265 g/. This substance was purified on silica gel using as eluent a mixture of ethyl acetate : hexane /45 - 55% ethyl acetate/, giving the target compound in the form of solids output 1,837 g, so pl. 129 - 131oC.

1H NMR /CDCl3/ /d6DMCO/: 4,72 /1H, D./, 5,15 /1H, D./, 5,65 /1H, D./, 6,89 /1H, D./, to 7.61 /1H, T./, of 7.96 /1H, DD,./, 8,10 /1H, DD,./, 8,45 /1H, T./.

Preparative example 26
is dinona

3-Aminobenzonitrile /recrystallized from a mixture of ethyl acetate and hexane/ /4.6 g/, ethanol /15 ml/ and thioglycolate acid /2,71/ ml were mixed together at room temperature for 30 minutes. Then was added 37% aqueous formaldehyde solution /3,16 ml/, causing a soft ectothermy. Formed solid precipitate and stirring continued over night. Then, water was added, forming an emulsion, and the mixture was extracted with ethyl acetate /three times/. The combined extracts were dried /magnesium sulfate/ and evaporated under reduced pressure giving a residue /9 g/, which was taken in dichloromethane /150 ml/. To this solution was added thionyl chloride /2,85 ml/ and after 45 minutes the triethylamine /5,43 ml/ while cooling in an ice bath. There was a formation of smoke, and after 1 hour the reaction mixture was poured on ice, and the product was extracted with dichloromethane. The organic layer was washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a dark oil /6.4g/, which was chromatographically on silica gel using mixtures of ethyl acetate/hexane. The target compound was obtained as yellow solid, yield 2.3 g, and had the data:

1H NMR /CDCl3/: 3,75 /2H, S./, 4,84 /2H, the-4-thiazolidinone

3-(3-cyano)phenyl-4-thiazolidinone /received, as described above, stage 1/ /1,935 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /21 ml/ sulfurylchloride /0,762 ml/. The target compound was immediately used in stage 3.

1H NMR /CDCl3/: 4,71 /1H, D./, 5,23 /1H, D./, 5,78 /1H, s/, to 7.59 /2H, m/, of 7.82 /1H, m, 7,89 /1H, s/.

Stage 3

Getting 5-hydroxy-3-(3-cyano)phenyl-4-thiazolidinone

5-chloro-(3-cyano)phenyl-4-thiazolidinone /received, as described above, in stage 2/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 3, using a mixture of tetrahydrofuran /6 ml/ and saturated sodium bicarbonate solution /10 ml/. The crude product /1.73 g/ purified on silica gel using a mixture of ethyl acetate: hexane /2: 3 as eluent. The target connection /1,627 g/ had:

1H NMR /CDCl3/ d6-DMCO/: 4,67 /1H, D./, 5,12 /1H, D./, 5,62 /1H, D./, 6,88 /1H, D./, 7,54 /2H, m,/, 7,80 /1H, m,/, 7,97 /1H, broad, S./.

MS: m/e 220 /M+/

Preparative example 27

Getting 5-hydroxy-3-(3-fluoro)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3-fluoro)genioglossal acid /5,85/ ml and 37% aqueous formaldehyde /6,83 ml/ s by using the procedure similar to the procedure described in preparative example 25, step 1. Transparent toluene layer was decenterable besieged with dark oil was washed with a saturated solution of sodium bicarbonate. The organic layer was dried /magnesium sulfate/ and evaporated, yielding the crude product 3.5, This substance was purified using chromatography on silica gel using a mixture of ethyl acetate: hexane /1:3 as eluent, giving a solid which was precrystallization from hot hexane (containing a few drops of chloroform), giving the target compound as a white solid, entrance 0,880 g

1H NMR /CDCl3/: 3,74 /2H, S./, a 4.83 /2H, S./, 6,94 /1H, dt./, 7,19 - 7,42 /3 3H, m/.

Stage 2

Getting 5-chloro-(3-fluoro)phenyl-4-thiazolidinone

3-(3-fluoro)phenyl-4-thiazolidinone /received, as described above, in stage 1/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /10 ml/ sulfurylchloride /0,36 ml/. The target compound was used immediately in stage 3.

1H NMR /CDCl3/: 4,70 /1H, D./, 5,22 /1H, D./, 5,77 /1H, s/, 7,03 /1H, m,/, 7,25 - 7,50 /3H, m/.

Stage 3

Getting 5-hydroxy-3-(prevraschalsya in the target connection using the procedures similar to the procedure similar to the procedure described in preparative example 25, step 3, using a mixture of tetrahydrofuran /5 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /0.75 g/ purified on silica gel using a mixture of etelaat and hexane as eluent /35:65 40:60/. The target connection /0,42 g/ had:

1H NMR /CDCl3/ d6DMCO/: 4,65 /1H, D./, 5,09 /1H, D./, 5,62 /1H, D./, 6,80 /1H, D./, 6,95 /1H, dt./, 7.23 percent - of 7.48 /3H, m/.

Preparative example 28

Getting 5-hydroxy-3-(3-(1,1,2,2-tetrafluoroethoxy))phenyl-4 - thiazolidinone

Stage 1

Obtaining 3-(3-(1,1,2,2-tetrafluoroethoxy))phenyl-4-thiazolidinone

3-(1,1,2,2-tetrafluoroethoxy)aniline /12,095 g/ turned into a target connection using a toluene /140 ml/, thioglycolic /a 4.03 ml and 37% aqueous formaldehyde /4,7 ml/ using a procedure analogous to the procedure described in preparative example 25, step 1. The crude product was purified using chromatography on silica gel using as eluent a mixture of ethyl acetate-hexane/5:95 - 15:85/, giving the target compound, the yield of 3.45 g, which had:

1H NMR /CDCl3/: 3,74 /2H, S./, 4,84 /2H, S./, 5,91 /1H, TT/, 7,11 /1H, m,/, 7,41 /3H, m/.

MS: m/e 295 /M+/

Stage 2

P is non /received as described above, stage 1/ /3,45 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /26 ml/ sulfurylchloride /of 0.94 ml/. The target compound was used immediately in stage 3.

1H NMR /CDCl3/: 4,71 /1H, D./, 5,23 /1H, D./, 5,77 /1H, s/, of 5.92 /1H, TT/, 7,07 /1H, m,/, 7,46 /3H, m/.

Stage 3

Getting 5-hydroxy-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl-4 - thiazolidinone

5-Chloro-3-(3-(1,1,2,2-tetrafluoroethoxy))phenyl-4-thiazolidinone /received, as described above, in stage 2/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 3, using a mixture of tetrahydrofuran /7 ml/ and saturated sodium bicarbonate solution /10 ml/. The crude product /4 g/ chromatographically on silica gel using a mixture of ethyl acetate-hexane /35:65/ as eluent. The target compound was obtained as a Golden oil output 2,942,

1H NMR /CDCl3/: 4,20 /1H, broad, S./, 4,71 /1H, D./, 5,02 /1H, DD,./, 5,72 /1H, s/, of 5.92 /1H, TT/, 7,14 /1H, m,/, 7,44 /3H, m/.

MS: m/e 311 /M+/

Preparative example 29

Getting 5-hydroxy-3-(3-methyl)phenyl-4-thiazolidinone

Study the I in toluene /50 ml and processed thioglycolic acid /7 ml/. The mixture was heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark during the night. The reaction mixture was then cooled and poured into hexane /50 ml/. The product was separated in the form of oil, and solvents were removed under reduced pressure, giving a white solid /17,975 g/. Attempts recrystallization failed, and the residue was chromatographically on silica gel. Product /14,84 g/, still contaminated meta-toluidine, was taken into ethyl acetate and was washed with 2 M hydrochloric acid. The target connection then stood out in the usual manner in the form of a white solid, yield 13,13 g, so pl. 58 - 60oC.

1H NMR /CDCl3/: 2,00 /1H, T., exchanges with D2O/; 2,35 /3H, s/, 3,40 /2H, D./, 6,95 /1H, D./, 7,20 - 7,30 /2H, m,/, 7,35 /1H, D./, 7,40 /1H, s/, 8,4 - 8,55 /1H, broad, S., exchanges with D2O/.

Stage 2

Obtaining 3-(3-methyl)phenyl-4-thiazolidinone

2-Mercapto-N-(3-were)ndimethylacetamide /obtained as described above in stage 1/ /2,0455 g/ dissolved /when heated/ toluene /25 ml, and the solution processed p-toluensulfonate /0,215 g/ and para-formaldehyde /0,339 g/. There was ectothermy, and the resulting thick white suspension. The reaction mixture then was heated to reflux distilled, and the water gathered in apparel was left to cool to room temperature. The toluene was decenterable besieged with reddish oil was evaporated, giving an oil /0,707 g/. This substance was chromatographically on silica gel using a mixture of ethyl acetate-hexane /35:65/, giving the target compound in the form of oil output 0,388,

1H NMR /CDCl3/: 2,38 /3H, s/, 3,75 /2H, S./, 4,81 /2H, S./, 7,08 /1H, D./, 7,15 - 7,35 /3H, m/.

MS: m/e 193 /M+/

Stage 3

Getting 5-chloro-3-(3-methyl)phenyl-4-thiazolidinone

3-(3-Methyl)phenyl-4-thiazolidinone /obtained as described in stage 2/ /0,369 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /5 ml/ sulfurylchloride /0,169 ml/. The target compound was used immediately in stage 4.

1H NMR /CDCl3/: 2,41 /3H, s/, 4,67 /1H, D./, 5,19 /1H, D./, 5,77 /1H, s/, 7,11 /1H, D./, 7,20 - 7,40 /3H, m/.

Stage 4

Getting 5-hydroxy-3-(3-methyl)phenyl-4-thiazolidinone

5-Chloro-3-(3-methyl)phenyl-4-thiazolidinone /received, as described above, at stage 3/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 3, using a mixture of /1 : 1/ tetrahydrofuran and saturated solution of bicarbonate H3/: 2,35 /3H, s/, 4,45 - 4,60 /1H, broad, S./, 4,67 /1H, D./, 4,95 /1H, D./, 5,74 /1H, s/, 7,10 /1H, D./, 7,20 - 7,40 /3H, m/.

Preparative example 30

Getting 5-hydroxy-3-(3-methoxy)phenyl-4-thiazolidinone

Stage 1

Getting 2-mercapto-N-3 - (methoxyphenyl)ndimethylacetamide

Fresh 3-methoxyaniline /7,6615 g/ dissolved in toluene /35 ml/ and processed thioglycolic acid /4,75/ ml. The mixture was heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark during the night. After cooling to room temperature was formed crystals, which were collected using a pump. The target connection /which was sufficiently pure for the next reaction/ was obtained as a white solid, yield 9,233,

1H NMR /CDCl3/: 2,03 /1H, T./, 3,38 /2H, D./, 3,80 /3H, s/, 6,70 /1H, DD,./, 7,00 /1H, D./, 7,20 - 7,34 /2H, m,/, 8,4 - 8,65 /1H, broad, S./.

MS: m/e 197 /M+/

Stage 2

Obtaining 3-(3-methoxy)phenyl-4-thiazolidinone

Dry acetone /250 ml was injected through a tube into a 3-necked flask equipped with condenser, addition funnel and inlet to the membrane. The dropping funnel was loaded with a solution of 2-mercapto-N-(3-methoxyphenyl)ndimethylacetamide /received, as described above, stage 1/ /2,36 g/ and diiodomethane /2 ml/ is by suspension was then placed in an oil bath, pre-heated to 60oC. When the solvent began to deflagrate, for 30 minutes was injected the contents of the dropping funnel. After the addition was completed, the reaction mixture was left to cool to room temperature and filtered through a layer of celite. The solution is then mixed with chloroform and water, and the organic layer was separated. The aqueous layer was extracted with additional portions of chloroform, and the combined organic layers were washed with saline, and then dried /sodium sulfate/. The solvent was removed under reduced pressure giving a brown oil /are 5.36 g/, which was chromatographically on silica gel using mixtures of ethyl acetate and hexane /3:7 - 10:0/ as eluent, yielding the target compound, the output 0,659,

1H NMR /CDCl3/: 3,74 /2H, S./, 3,82 /3H, s/, 4,81 /2H, S./, 6,80 /1H, DD,./, 6,98 /1H, DD,./, 7,08 /1H, T./, 7,31 /1H, T./.

MS: m/e 209 /M+/

Stage 3

Getting 5-chloro-3-(3-methoxy)phenyl-4-thiazolidinone

3-(3-methoxy)phenyl-4-thiazolidinone /received, as described above, stage 2/ /0,629 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichlor the>

Stage 4

Getting 5-hydroxy-3-(3-methoxy)phenyl-4-thiazolidinone

5-Chloro-3-(3-methoxy)phenyl-4-thiazolidinone /received, as described above, at stage 3/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 3, using /1:1/ mixtures of tetrahydrofuran and saturated solution of sodium bicarbonate /20 ml/. The target connection /0,37 g/ had:

1H NMR /CDCl3/: 3,81 /3H, s/, 4,67 /1H, D./, the 4.75 - 4,95 /1H, broad, S./, 4,99 /1H, D./, 5,75 /1H, s/, 6,83 /1H, DD,./, 7,00 /1H, DD,./, 7,09 /1H, T./, 7,35 /1H, m,/.

MS: m/e 225 /M+/

Preparative example 31

Getting 5-hydroxy-3-(3-methoxycarbonyl)phenyl-4 - thiazolidinone

Stage 1

Obtaining 3-(3-methoxycarbonyl)phenyl-4-thiazolidinone

3-Methoxycarbonylamino /5 g/ turned into a target connection using a toluene /125 ml/, thioglycolic /2,3/ ml and 37% aqueous formaldehyde /2,68 ml/ using a procedure analogous to the procedure described in preparative example 25, step 1. The crude product /3,95 g/ precrystallization from a mixture of ethyl acetate and hexane, yielding the target compound as a white solid, yield 3,322 g, so pl. 118 - 119,5oC.

1H NMR /CDCl3/: 3,7 the R-3-(3-methoxycarbonyl)phenyl-4-thiazolidinone

3-(3-Methoxycarbonyl)phenyl-4-thiazolidinone /obtained as described above, stage 1/ /is 3.08 g/ turned into a target compound using a procedure analogous to the procedure. described in preparative example 25, step 2, using dichloromethane /25 ml/ sulfurylchloride /1,04 ml/. The target compound was used immediately in stage 3.

1H NMR /CDCl3/: 3,94 /3H, s/, 4,74 /1H, D./, 5,25 /1H, D./, 5,79 /1H, D./, 7,53 /1H, T./, a 7.85 /1H, DD,./, 7,97 /1H, D./, 8,08 /1H, m,/.

Stage 3

Getting 5-hydroxy-3-(3-methoxycarbonyl)phenyl-4-thiazolidinone

5-Chloro-3-(3-methoxycarbonyl)phenyl-4-thiazolidinone /received, as described above, in stage 2/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 3, using a mixture of tetrahydrofuran /20 ml and saturated solution of sodium bicarbonate /15 ml/. The crude product /2,95 g, red-brown oil was purified on silica gel using a mixture of ethyl acetate: hexane /1:1, then 6:4 as eluent. The target compound was obtained as a sticky orange solid, yield of 2.34 g

1H NMR /CDCl3/: 3,92 /1H, s/, 4,05 /1H, broad, S./, 4,75 /1H, D./, 5,03 /1H, D./, 5,75 /1H, s/, 7,51 /1H, T./, 7,82 /1H, DD,./, of 7.96 /1H, D./, 8,06 /1H, stage 1

Obtaining 3-(3-bromo)phenyl-4-thiazolidinone

3 Bromaniline /13,315 g/ turned into a target connection using a toluene /170 ml/, thioglycolic /5,4/ ml and 37% aqueous formaldehyde /6,24 ml/ using a procedure analogous to the procedure described in preparative example 25, step 1. Toluene layer was decenterable besieged with orange oil and were washed with a saturated solution of sodium bicarbonate. The organic layer was dried /magnesium sulfate/ and evaporated, giving an oil /7,92 g/, which was chromatographically on silica gel using mixtures of ethyl acetate and hexane /15:85/ as eluent. The target connection /3,81 g/ had:

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,80 /2H, S./, 7,24 - 7,45 /3H, m/, 7,65 /1H, m,/.

MS: m/e 257 /M+; Br = 79/

Stage 2

Getting 5-chloro-3-(3-bromo)phenyl-4-thiazolidinone

3-(3-bromo)phenyl-4-thiazolidinone (obtained as described above, in stage 1) /is 3.08 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /25 ml/ sulfurylchloride /to 0.96 ml/. The target compound was used directly in stage 3.

1H NMR /CDCl3/: 4,68 /1H, D./, 5,20 /1H, D./, 5,75 /1H, BR> 5-Chloro-3-(3-bromo)phenyl-4-thiazolidinone /received, as described above, in stage 2/ mixed with a tetrahydrofuran /15 ml and saturated sodium bicarbonate solution /10 ml and stirred at room temperature for 45 minutes. The reaction mixture was processed as in preparative example 25, step 3, but NMR showed incomplete reaction and impurities. The material was chromatographically on silica gel using mixtures of ethyl acetate and hexane /35: 65/ that showed both product and starting material. This substance was subjected to further reaction in tetrahydrofuran /15 ml and saturated sodium bicarbonate solution /10 ml/ during the night, and then processed as in preparative example 25, step 3. Balance /2 g/ chromatographically on silica using as eluent a mixture of /3:7/ ethyl acetate and hexane, yielding the target compound, the output 0,964 g, which had:

1H NMR /CDCl3/: 4,08 /1H, broad, S./, 4,69 /1H, D./, 4,99 /1H, D./, 5,71 /1H, s/, 7.23 percent - of 7.48 /3H, m/, 7,69 /1H, m,/.

Preparative example 33

Getting 5-hydroxy-3-(3-iodine)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3-iodine)phenyl-4-thiazolidinone

3-Iodoaniline /11,757 g/ turned into a target connection with the use of toluene is th procedure described in preparative example 25, step 1. Toluene layer was decenterable besieged with red oil was filtered and 2 M hydrochloric acid, sodium bicarbonate and saline. Toluene layer was dried /magnesium sulfate/ and evaporated giving a residue /6.5 g/, which was chromatographically on silica using a mixture of ethyl acetate:hexane /15:85/ as eluent. The target compound was obtained in the form of not quite white solid, yield of 4.00 g, so pl. 88 - 88.5oC.

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,79 /2H, S./, 7,12 /1H, T./, 7,43 /1H, DD,./, to 7.59 /1H, D./, 7,80 /1H, m,/.

MS: m/e 305 /M+/

Stage 2

Getting 5-chloro-3-(3-iodine)phenyl-4-thiazolidinone

3-(3-Iodine)phenyl-4-thiazolidinone /received, as described above, stage 1/ /2,91 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 25, step 2, using dichloromethane /27 ml/ sulfurylchloride /of 0.77 ml/. The target compound was immediately used in stage 3.

1H NMR /CDCl3/: 4,66 /1H, D./, 5,19 /1H, D./, 5,75 /1H, s/, 7,17 /1H, T./, 7,50 /1H, m/, of 7.64 /1H, D./, 7,98 /1H, m,/.

Stage 3

Getting 5-hydroxy-3-(3-iodine)phenyl-4-thiazolidinone

5-Chloro-3-(3-iodine)phenyl-4-thiazolidinone /pasanau in preparative example 25, stage 3, using a mixture of tetrahydrofuran /7 ml/ and saturated sodium bicarbonate solution /10 ml/. The crude product /3.04 from g/ purified on silica gel using mixtures of ethyl acetate and hexane /35:65/ as eluent. The target compound was obtained as yellow solid, yield 1.85 g, so pl. 141 - 142oC.

1H NMR /CDCl3/: 3,59 /1H, D./, 4,69 /1H, D./, 4,96 /1H, D./, 5,70 /1H, D./, 7,15 /1H, T./, 7,49 /1H, DD,./, 7,63 /1H, D./, 7,84 /1H, m,/.

Preparative example 34

Getting 5-hikkoshi-3-(3-phenoxy)phenyl-4-thiazolidinone

Stage 1

Getting 2-mercapto-N-(3-phenoxyphenyl)ndimethylacetamide

Fresh 3-fenoxedilom /5,94 g/ dissolved in toluene /30 ml/ nitrogen atmosphere and processed thioglycolic acid /2,45 ml/. The mixture was heated under reflux and the water was going over the night in the office of Dean-stark. The solvent was removed under reduced pressure, and the residue was taken into ethyl acetate. This substance was filtered sequentially 2M hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer was processed in the usual way, giving the target compound /which was sufficiently pure for the next reaction/ in the form of a pale yellow oil, in the so/, 7,25 - 7,40 /5H, m/, 8,40 at 8.60 /1H, broad, S./.

Stage 2

Obtaining 3-(3-phenoxy)phenyl-4-thiazolidinone

2-Mercapto-N-(3-phenoxyphenyl)ndimethylacetamide /received, as described above, stage 1/ /3,102 g/ turned into a target compound using a procedure analogous to the procedure described in preparative example 30, step 2, using diiodomethane /2 ml/ and crushed potassium hydroxide /4.0 g/, except that instead of acetone as the solvent used was tetrahydrofuran /350 ml/. The crude product was purified on silica gel using mixtures of ethyl acetate and hexane /15:85/, giving the target compound, the output worn: 0.505,

1H NMR /CDCl3/: 3,72 /2H, S./, 4,80 /2H, S./, 6,87 /1H, DD,./, 7,00 - 7,40 /8H, m/.

Stage 3

Getting 5-chloro-3-(3-phenoxy)phenyl-4-thiazolidinone

3-(3-phenoxy)phenyl-4-thiazolidinone /received, as described above, stage 2/ /0,500 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /5 ml/ sulfurylchloride /0,163 ml/. The target compound was used immediately in stage 4.

Stage 4

Getting 5-hydroxy-3-(3-phenoxy)phenyl-4-thiazolidinone

5-Chloro-3-(3-phenoxy)phenyl-is similar to that described in preparative example 25, stage 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /5 ml/. The target compound was purified on silica gel using as eluent a mixture of ethyl acetate and hexane /35:65/ and was obtained in the form of oil, which slowly crystallized upon standing, the output to 0.263 g

1H NMR /CDCl3/: 4,15-4,30 /1H, broad, S./, 4,67 /1H, D./, 4,96 /1H, D./, 5,70 /1H, s/, 6,90 /1H, DD,./, 7,00-7,40 /8H, m/.

MS: m/e 287 /M+/

Preparative example 35

Getting 5-hydroxy-3-(3-methanesulfonyl)phenyl-4-thiazolidinone

Stage 1

Receive (3-nitro)phenyl-methyl-sulfone

Phenylmethylsulfonyl /4.0 g/ was added in portions to fuming nitric acid, stirred at 0oC. the Reaction mixture was left to warmed to room temperature, stirred for 1 hour and then poured carefully into ice. The solution was carefully kind of balanced out by sodium bicarbonate, and the mixture was filtered using a pump. Going solid, which was rinsed with water and dried under reduced pressure over potassium hydroxide, yielding the target compound as white solids /5,63 g/ in a state of sufficient purity for the next reaction.

1H Antisoliton

(3-Nitro)phenylmethylsulfonyl (obtained above in stage 1) /5,396 g/, reduced iron /7.5 g/ and ammonium chloride /7,18 g/ blended together in a mixture of ethanol and water /2:1/ /150 ml and heated under conditions of reflux distilled for 2 hours. The black solution was filtered through "Celite", and the filter medium was rinsed with ethyl acetate. The solvents were removed under reduced pressure and the residue was taken in a mixture of ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted 3 additional portions of ethyl acetate. The combined organic layers were washed brine, and the solvent was removed under reduced pressure, giving a dark orange oil /3,9275 g/. This oil was chromatographically on silica gel using mixtures of ethyl acetate and hexane 45:55 to 50:50 as eluent, yielding the target compound as an orange oil, yield 3,607,

1H NMR /CDCl3/: 3,02 /3H, s/, 3,8-4,2 /2H, broad, S./, 6,90 /1H, m,/, 7,18 - 7,38 /3H, m/.

Stage 3

Obtaining 3-(3-methanesulfonyl)phenyl-4-thiazolidinone

(3-Amino)phenylmethylsulfonyl (obtained as described above, in stage 2) /3.6 g/ turned into a target connection using a toluene /175 ml/, thioglycolic /a 1.46 ml and 37% water the Crude product was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /1:1/ as eluent. The target compound was obtained as a pale yellow solid, yield 1,105 g, so pl. 92 - 95.5oC.

1H NMR /CDCl3/: is 3.08 /3H, s/, of 3.77 /2H, S./, 4,88 /2H, S./, 7,63 /1H, T./, 7,82 /1H, D./, 7,89 /1H, D./, 7,99 /1H, m,/.

Stage 4

Getting 5-chloro-3-(3-methanesulfonyl)phenyl-4-thiazolidinone

3-(3-methanesulfonyl)phenyl-4-thiazolidinone /received, as described above, at stage 3/ /1 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /10 ml/ sulfurylchloride /0,31 ml/. The target compound was immediately used in stage 5.

Stage 5

Getting 5-hydroxy-3-(3-methanesulfonyl)phenyl-4-thiazolidinone

5-Chloro-3-(3-methoxyphenyl)thiazolidin-4-one (obtained as described above, in stage 4) were converted to the target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /15 ml and saturated sodium bicarbonate solution /5 ml/. The crude product /0,892 g/ was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /3:1/ as eluent. The target compound was obtained in the form of a soft yellow solid, o the,84 /2H, m/, 8,07 /1H, m,/.

Preparative example 36

Getting 5-hydroxy-3-(3,4,5-trichloro)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3,4,5-trichloro)phenyl-4-thiazolidinone

3,4,5-trichloroaniline /5,167 g/ turned into a target connection using a toluene /250 ml/, thioglycolic /2,75 ml and 37% aqueous formaldehyde /2.35 ml/ using a procedure analogous to the procedure described in preparative example 25, step 1. In this reaction were not deposited any oil, but upon cooling formed a little pale brown needles, which were removed by filtration. The filtrate was concentrated, giving a white solid, which was taken in dichloromethane and was washed sequentially 2M hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer was dried /magnesium sulfate/ and evaporated, giving not quite white solid /2.8 g/. The crude product was chromatographically on silica gel using as eluent a mixture of ethyl acetate and hexane /15:85/, giving the target compound as a white solid, yield of 2.27 g, so pl. 161 - 163oC.

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,79 /2H, S./, to 7.61 /2H, S./.

Stage 2

Getting 5-holdem stage 1) /2,00 g/ turned into a target compound using the procedures similar to that described in preparative example 25, step 2, using dichloromethane /20 ml/ sulfurylchloride /0.63 ml/. The target compound was used immediately in stage 3.

Stage 3

Getting 5-hydroxy-3-(3,4,5-trichloro)phenyl-4-thiazolidinone

5-Chloro-3-/3,4,5-trichloro/phenyl-4-thiazolidinone /received, as described above, in stage 2/ turned into a target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /2.15 g/ purified on silica gel using mixtures of ethyl acetate and hexane /35:65/ as eluent. The target compound was obtained as a brown solid /1.3 g/ and had:

1H NMR /CDCl3/ d6DMCO/: 4,63 /1H, D./, of 5.05 /1H, D./, 5,59 /1H, D./, of 6.96 /1H, D./, 7,72 /2H, S./.

Preparative example 37

Getting 5-hydroxy-3-(3-methylthio)phenyl-4-thiazolidinone

Stage 1

Getting 2-mercapto-N-(3-methylthiophenyl)ndimethylacetamide

3-Methylmercaptopurine /5,041 g/ turned into a target compound using a procedure similar to that described in preparative example 34, step 1, using toluene /25 ml/ and thioglycolic is-> 1:3 as eluent. The target compound was obtained in the form of a creamy white solid, yield, 6,55

1H NMR /CDCl3/: 2,03 /1H, T./, 2,50 /3H, s/, 3,40 /2H, D./, 7,02 /1H, m,/, 7,25 /2H, m,/, 7,53 /1H, m,/, 8,50 /1H, broad, S./.

Stage 2

Obtaining 3-(3-methylthio)phenyl-4-thiazolidinone

2-Mercapto-N-(3-methylthiophenyl)ndimethylacetamide /received, as described above, stage 1/ /5 g/ turned into a target compound using a procedure similar to that described in preparative example 30, step 2, using diiodomethane /3,89 ml/ and crushed potassium hydroxide /7,89 g/, except that as a solvent instead of acetone was used tetrahydrofuran /500 ml/. The crude product was purified on silica gel using mixtures of ethyl acetate and hexane /1: 4 as eluent, giving a brown oil /1,302 g/, is still contaminated with a small amount of aniline, which was removed by extraction of an ethyl acetate solution of the material 2M hydrochloric acid. This solution was processed in the usual way, giving the target compound in the form of an orange-brown oil /0.97 g/ in a fairly clean condition for the next stage of the synthesis.

1H NMR /CDCl3/: 2,48 /3H, s/, 3,75 /2H, S./, 4,81 /2H, S./, 7,10 - 7,37 /4H, m/.

obtained, as described above, at stage 3/ /0,97 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /20 ml/ sulfurylchloride /0,35 ml/. The target compound was used immediately in stage 4.

1H NMR /CDCl3/: 2,48 /3H, s/, 4,68 /1H, D./, 5,19 /1H, D./, 5,77 /1H, s/, 7,15 - 7,45 /4H, m/.

Stage 4

Getting 5-hydroxy-3-(3-methylthio)phenyl-4-thiazolidinone

5-Chloro-3-(3-methylthio)phenyl-4-thiazolidinone (obtained as described above, in stage 3) were converted to the target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /20 ml saturated sodium bicarbonate /15 ml/. The crude product was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /1:1/ as eluent. The target compound was obtained as a brown resin, the output 0,578,

1H NMR /CDCl3/: 2,48 /3H, s/, 4,14 /1H, broad, S./, 4,70 /1H, D./, 4,98 /1H, D./, 5,72 /1H/, 7,10-7,40 /4H, m/.

Preparative example 38

Getting 5-hydroxy-3-(3-triptoreline)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3-triptoreline)phenyl-4-thiazolidinone

3-(Thrift is you /2,99 ml and 37% aqueous formaldehyde /2,56 ml/ s by using the procedure similar to that described in preparative example 25, step 1. The crude product /8,583 g/ was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /15:85/ as eluent. The target compound was obtained in the form of rolling a pale yellow oil, yield 3,818,

1H NMR /CDCl3/: to 3.73 /2H, S./, 4,82 /2H, S./, 7,10 /1H, m,/, 7,42 /3H, m/.

MS: m/e 263 /M+/

Stage 2

Getting 5-chloro-3-(3-triptoreline)phenyl-4-thiazolidinone

3-(3-Triptoreline)phenyl-4-thiazolidinone (obtained as described above, in stage 1) /3,468 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /25 ml/ sulfurylchloride /1,06 ml/. The target compound was used immediately in stage 3.

1H NMR /CDCl3/: 4,70 /1H, D./, 5,22 /1H, D./, 5,76 /1H, s/, 7,16 /1H, m/, of 7.48 /3H, m/.

Stage 3

Getting 5-hydroxy-3-(3-triptoreline)phenyl-4-thiazolidinone

5-Chloro-3-(3-triptoreline)phenyl-4-thiazolidinone /received, as described above, in stage 2/ turned into a target compound using a procedure similar to that described in preparative example 25, step 3, using 1: 1 mixture of tetrahydrofuran and is barely using a mixture of ethyl acetate and hexane as eluent. The target compound was obtained as yellow solid, yield 1,514,

1H NMR /CDCl3/: 3,63 /1H, broad, S./, 4,73 /1H, D./, 5,00 /1H, D./, 5,72 /1H, s/, 7,15 /1H, m,/, 7,47 /3H, m/.

Preparative example 39

Getting 5-hydroxy-3-(3-methoxy-5-trifluoromethyl)phenyl-4-thiazolidinone

Stage 1

Obtaining 3-(3-Methoxy-5-trifluoromethyl)phenyl-4-thiazolidinone

5-Methoxy-, , -Cryptor-m-toluidine /5,286 g/ turned into a target connection using a toluene /80 ml/, thioglycolic /2,1/ ml and 37% aqueous formaldehyde /of 2.51 ml/ using a procedure similar to that described in preparative example 25, step 1. Evaporation of the toluene gave yellow solid, which was dissolved in diethyl ether and washed successively 2M hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer was dried /magnesium sulfate and the solvent was removed under reduced pressure giving a residue /4,2 g/, which was chromatographically on silica using a mixture of ethyl acetate-hexane /2: 8 to 25: 75/ as eluent. The target connection /3,459 g/ had:

1H NMR /CDCl3/: 3,75 /2H, S./, a 3.87 /3H, s/, 4,85 /2H, S./, 7,01 /1H, s/, 7,25 /1H, s/, 7,34 /1H, s/.

MS: m/e 277 /Miformity)phenyl-4-thiazolidinone /received as described above, stage 1/ /3,45 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /24 ml/ sulfurylchloride /1,05 ml/. The target compound was used immediately in stage 3.

Stage 3

Getting 5-hydroxy-3-(3-methoxy-5-trifluoromethyl)phenyl-4-thiazolidinone

5-Chloro-3-(3-methoxy-5-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described above, in stage 2) were converted to the target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /3.2 g/ purified on silica gel using a mixture of ethyl acetate-hexane /2:3/ giving the target connection /2,56 g/, which had:

1H NMR /CDCl3/: a 3.87 /3H, s/, 4,15 /1H, broad, S./, 4,72 /1H, D./, 5,01 /1H, D./, 5,71 /1H, s/, 7,03 /1H, s/, 7,27 /1H, D./, of 7.36 /1H, D./.

MS: m/e 293 /M+/

Preparative example 40

Getting 5-hydroxy-3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone

Stage 1

Obtain 3-nitro-5-triptorelin /see J. Med. Chem., 1981, 24, 742/

3,5-Dinitrobenzotrifluoride /10 g/ dissolved in a mixture of methanol /200 ml/ 1,4-di the I acid /30 ml/, and then small portions of the powder recovered iron /9 g/. Precautions: rapid evolution of gas. The reflux was continued for another 1 hour, and the reaction mixture was left to cool to room temperature. The mixture was filtered through celite, and the filter medium was rinsed with dichloromethane. The solvents were removed under reduced pressure giving a residue that was distributed between dichloromethane and water. The organic layer was washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure giving a brown semi-solid substance /8 g/. This substance was chromatographically on silica gel, giving the target compound in the form of a thin Golden crystals, yield to 4.98 g

1H NMR /CDCl3/: 4,10-4,40 /2H, broad, S./, 7,15 /1H, broad, S./, 7,63 /1H, m,/, 7,81 /1H, broad, S./.

Stage 2

Obtaining 3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone

3-Nitro-5-triptorelin (obtained as described above, in stage 1) /to 4.98 g/ turned into a target connection using a toluene /90 ml/, thioglycolic /2,30/ ml and 37% aqueous formaldehyde /2,75 ml/ using procedures similar to those described in preparovanie, and the filtrate was evaporated under reduced pressure, giving semi-solid residue /3,965 g/. The residue was taken into ethyl acetate and washed sequentially with 2 M hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer was dried with magnesium sulfate and evaporated under reduced pressure giving the crude product /2,82 g/. This product was chromatographically on silica gel using mixtures of ethyl acetate and hexane /3:7 as eluent, yielding the target compound, the yield of 1.78 g

1H NMR /CDCl3/: 3,81 /2H, S./, 4,94 /2H, S./, 8,28 /1H, s/, 8.34 per /1H, s/, 8,58 /1H, m,/.

MS: m/e 292 /M+/

Stage 3

Getting 5-chloro-3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone

3-(3-Nitro-5-trifluoromethyl)phenyl-thiazolidin-4-one (obtained as described above in stage 1) /1.78 g/ turned into a target compound using a procedure similar to that described in preparative example 2, step 2, using dichloromethane /20 ml/ sulfurylchloride /0.54 ml/. The target compound was immediately used in stage 4.

Stage 4

Getting 5-hydroxy-3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone

5-Chloro-3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone /received, as described above, the ore 25, stage 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /1,67 g/ purified on silica gel using ethyl acetate and hexane /2:3 as eluent. The target compound was obtained as yellow solid, yield 1,118,

1H NMR /CDCl3/: / 4,78 /1H, D./, a total of 5.21 /1H, D./, 5,65 /1H, D./, 6,94 /1H, D./, 8,33 /2H, S./, 8,67 /1H, m,/.

MS: m/e 308 /M+/

Preparative example 41

Getting 5-hydroxy-3-(3-triftormetilfullerenov)thiazolidin-4-it

Stage 1

Obtaining 3-nitrobenzenesulfonamide

3-Nitrobenzenesulfonamide /10 g/ dissolved in 1,4-dioxane /30 ml and stirred at room temperature. To this solution was added a solution of potassium fluoride /3,9 g/ water /5 ml, and stirring was continued at room temperature for 5 hours. The reaction mixture was left to stand at room temperature overnight and poured into a mixture of ice and water. The product was extracted with dichloromethane, the solvent was dried /magnesium sulfate/ and evaporated under reduced pressure, giving the target compound /8 g/. This material was pure enough for the next stage of the synthesis.

1H NMR /CD /see Synthesis, 1990, 1151/.

3-Nitrobenzenesulfonate (obtained as described above, in stage 1), /6,79 g/ suspenderbelt in petroleum ether /60/80/ /35 ml was mixed at room temperature in a nitrogen atmosphere. To this solution was added Tris/dimethylamine/sulfur/(trimethylsilyl)/differed /0,92 g/, then /a trifluoromethyl/trimethylsilane /9,77 ml/ dissolved in dry tetrahydrofuran /35 ml/. The reaction mixture was stirred at room temperature for 3.5 hours, then the GC analysis found 25% of the source material and 75% of the product. The mixture was then treated with water and the product and neprevyshenie source material was extracted in hexane. The combined organic layers were dried and evaporated giving a residue /4,62 g/, which was treated with a mixture of aqueous ammonia and tetrahydrofuran to turn unchanged sulfonyl fluoride in the corresponding sulfonamide. When TLC showed that all of the sulfonyl fluoride was subjected to the conversion, the mixture was diluted with water, the organic layer was separated, dried /magnesium sulfate/ and evaporated under reduced pressure giving a residue /3.8 g/, which was chromatographically on silica gel using as eluent a mixture of /1:9/ ethyl acetate and hexane. Target with +
/

Stage 3

Obtaining 3-(trifloromethyl)aniline

3-Triftormetilfullerenov (obtained as described above, in stage 2) /3,27 g/ mixed with water /30 ml/ ethanol /60 ml/, ammonium chloride /3,4245 g/ and restored iron /3,584 g/, and the mixture was heated under reflux for 30 minutes. The reaction mixture was left to cool to room temperature and filtered through celite. The filtrate was diluted with water and the product was extracted with dichloromethane /three times/. The combined organic layers were dried and evaporated under reduced pressure giving a residue /2,752 g/, which was merged with a similar remnant from an earlier retrieval using /0.2 g/ 3-triftormetilfullerenov. This substance was chromatographically on silica gel using mixtures of ethyl acetate and hexane /1:4 as eluent, yielding the target compound /2,466 g/, which had:

1H NMR /CDCl3/: 3,90 - 4,20 /2H, broad, S./, 7,05 /1H, m,/, 7,25 /1H, s/, 7,40 /2H, M./.

MS: m/e 225 /M+/

Stage 4

Obtaining 3-(3-trifloromethyl)phenyl-4-thiazolidinone

3-(Trifloromethyl)aniline /received, as described above, at stage 3/ /2,46 g/ turned into a target connected to the power procedure, similar to the procedure described in preparative example 25, step 1. The solvent was removed, giving a Golden colored oil, which was taken into ethyl acetate and was filtered 2M hydrochloric acid, saturated sodium bicarbonate solution and saline. The ethyl acetate was dried and evaporated giving a residue /0.87 g/, which contained the product. Due to poor selection of product attributability the washing water was brought to pH 4 with 2 M hydrochloric acid and was extracted into ethyl acetate. The resulting material was dried /magnesium sulfate/ and evaporated under reduced pressure giving a residue /2,90 g/, which, as it was found, is intermediate acyclic acid, S-(N-(3-(trifloromethyl)phenylamino)methyl)thioglycolic acid. This substance is turned into a target compound using a procedure similar to that described in preparative example 26, step 1, using dichloromethane /50 ml/, thionyl chloride /0,65 ml/ triethylamine /1.25 ml/. This gave an additional sample /2,07 g/ containing the target compound, which was merged with early balance /0.87 g/ and purified on silica gel using mixtures of ethyl acetate and hexane /35:65/ as eluent. The target connection /1,634 g/ n is /1H, D./ 8,05 /1H, s/, 8,15 /1H, D./.

MS: m/e 311 /M+/

Stage 5

Getting 5-chloro-3-(3-trifloromethyl)phenyl-4 - thiazolidinone

3-(3-Trifloromethyl)phenyl-4-thiazolidinone, obtained as described above in stage 4, /1.63 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /20 ml/ sulfurylchloride /0,46/ ml. The target compound was used immediately in stage 6.

Stage 6

Getting 5-hydroxy-3-(3-trifloromethyl)-4-thiazolidinone

5-Chloro-3-(3-trifloromethyl)phenyl-4-thiazolidinone (obtained as described above, at stage 5) were converted to the target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /1,09 g/ purified on silica gel using a mixture of ethyl acetate: hexane /1:1/ as eluent. The target connection /0,47 g/ had:

1H NMR /CDCl3/: 3,64 /1H, broad, S./, 4,79 /1H, d/. 5,10 /1H, D./, 5,75 /1H, s/, 7,76 /1H, T./, 7,93 /1H, D./, 8,18 /2H, M./.

MS: m/e 327 /M+/

Preparative example 42

Obtain 3-hydroxy-1-(3-CryptoMemory

Suspension of 6,6-dimethyl-5,7-dioxaspiro/2.5/octane-4,8-dione /received, as described in Organic Synthesis, volume 60, pages 66 - 68/ /8.00 g/ 3-triptoreline /8,05 g/ stirred at room temperature for 24 hours. The mixture was filtered, and the insoluble solid was rinsed with chloroform. The combined filtrates were washed with 2 M hydrochloric acid, brine, and then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave a brown solid, which was precrystallization from a mixture of chloroform and hexane, giving the product as a white crystalline solid, yield of 4.10 g, so pl. 135 - 136oC /colour / div./.

1H NMR /CDCl3/: 2,47 - 2,67 /2H, m,/, 3,70 /1H, T./, 3,92 - 4,01 /2H, m,/, 7,00 /wide/, 7,45 - 7,60 /2H, m,/, 7,81 - of 7.90 /2H, M./.

Stage 2

Obtain 1-(3-trifluoromethyl)phenyl-2-pyrrolidinone

1-(3-trifluoromethyl)phenyl-2-pyrrolidine-3-carboxylic acid obtained as described above, stage 1/ /of 3.60 g/ heated up to its melting point, and heating continued for as long as you do not stop the rapid evolution of gas /approximately 50 minutes/. The melt was cooled, dissolved in diethyl ether and processed decolorizing charcoal. Coal tfilter who was lisbianas of hexane, giving the product as colorless needles, yield 2.20 g, so pl. 67 - 68oC.

1H NMR /CDCl3/: 2,19 /2H, Quint./, 2,62 /2H, so/, 3,89 /2H, so/, 7,35 - 7,53 /2H, m,/, 7,81 - 7,93 /2H, M./.

MS: m/e 229 /M+/

Stage 3

Obtain 3-hydroxy-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone

Mix a solution of 1-(3-trifluoromethyl)phenyl-2-pyrrolidinone /received, as described above, stage 2/ /1.10 g/ dry tetrahydrofuran (THF /5 ml/ was cooled to -70oC in nitrogen atmosphere, was added dropwise a solution of hexamethyldisilazide lithium in hexane /1,04 M, 4.9 ml/. The resulting pale yellow suspension was then treated with a solution of N-toluensulfonyl-3-phenyloxazolidine /received, as described in Journal of Organic Chemistiy, 1988, 53, 1087/ /2,00 g/ dry tetrahydrofuran (THF /5 ml/. The resulting pale yellow solution was left to warmed to room temperature, and then was extinguished with water and pagkilala to pH 5 with 2 M hydrochloric acid. The mixture was extracted diethyl ether /twice/, and the combined extracts were washed with water, dried /magnesium sulfate/ and evaporated under reduced pressure giving an oil. Purification via chromatography on silica gel, with elution with mixtures of ethyl acetate and hexane, gave the 1H, m/, 2,63 /1H, m,/, 3,72 - 3,90 /2H, m,/, 4,51 /1H, m,/, 7,39 - 7,58 /2H, m/, to 7.77 - 8,02 /2H, M./.

MS: m/e 245 /M+/

Preparative example 43

Obtain 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-hydroxy-2-pyrrolidinone

Stage 1

Obtain 1-(2-chloro-6-fluoro-4-trifluoromethyl-phenyl-2-pyrrolidinone

Stir a suspension of 2-pyrrolidinone /2,60 g/ and finely ground potassium hydroxide /1,80 g/ dry dimethylsulfoxide 40 m/ processed 1-chloro-2,3-debtor-5-triftorperasin /6.50 g/. The mixture is stirred at room temperature for 1 hour, then lightly padillas using 2 M hydrochloric acid. The crystalline precipitate which had formed was filtered off, rinsed with water and dried giving the product as a white crystalline compound, the output 6,30 g, so pl. 115 - 116oC.

1H NMR /CDCl3/: 2,22-2,37 /2H, m,/, 2,56-2,66 /2H, m,/, 3,70 /1H, m,/, 3,79 /1H, m,/, 7,38 /1H, m,/, EUR 7.57 /1H, m,/.

Stage 2

Obtain 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-hydroxy-2-pyrrolidinone

Using a procedure analogous to the procedure described in preparative example 42, step 3, but using 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-2-pyrrolidinone /received, as described above, stage 1/ /11,40 g/ N-toluensulfonyl-3-fenyleenidiamiini lithium in tetrahydrofuran /1.0 M, 41,0 ml/ and purification of the crude product through chromatography on silica gel with elution with mixtures of ethyl acetate and hexane, was the target compound in the form of crystalline solid, yield of 2.40 g, so pl. 102 - 104oC.

1H NMR /CDCl3/: 2,28 /1H, m,/, 2,64 /1H, m,/, 3,52-3,81 /3H, m/, 5,52 /1H, m,/, 7,38 /1H, m/, to 7.59 /1H, m,/.

Preparative example 44

Getting dihydro-2-hydroxy-4-(3-trifluoromethyl)phenyl-4H-1,4-oxazin-3/2H/she

Stage 1

Getting dihydro-4-(3-trifluoromethyl)phenyl-4H-1,4-oxazin-3/2H/she

Mix a solution of N-(3-triptoreline)ethanolamine /8,20 g/ dry tetrahydrofuran /25 ml was treated by adding dropwise chloroacetanilide /4,50 g/. The resulting solution was cooled in an ice bath, and the portions was added sodium hydride /3,20 g, 60% dispersion in mineral oil/. The mixture was then left to warmed to room temperature and stirred for further 5 hours. Water was added, and the mixture was extracted thoroughly with diethyl ether. The combined ether extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure giving a brown oil. Purification via chromatography on silica gel with al, output 2,80 g, so pl. 47 - 48oC.

1H NMR /CDCl3/: 3,79 /2H, m,/, 4,05 /2H, m,/, 4,37 /2H, S./, 7,50 - 7,58 /3H, m/, 7,62 /1H, m,/.

Stage 2

Getting dihydro-2-hydroxy-4-(3-trifluoromethyl)phenyl-4H-1,4-oxazin-3/2H/she

Mix a solution of dihydro-4-(3-trifluoromethyl)phenyl-4H-1,4-oxazin-3/2H/she /received, as described above, stage 1/ /0,49 g/ dry tetrahydrofuran /20 ml/ was cooled to 0oC in nitrogen atmosphere, was added dropwise a solution of hexamethyldisilazide lithium in tetrahydrofuran /1.0 M, and 2.1 ml/. The resulting pale yellow suspension was then added to a solution of N-toluensulfonyl-3-phenyloxazolidine /received, as described in Journal of Organic Chemistry, 1988, 53, 2087/ /1.10 g/ dry tetrahydrofuran /10 ml/. The resulting pale yellow solution was left to warmed to room temperature and stirred for 1 hour before it was extinguished with water and pagkilala to pH 5 with 2 M hydrochloric acid. The mixture was extracted diethyl ether /twice/, and the combined extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure giving an oil. Purification via chromatography on silica gel with elution with mixtures of ethyl acetate and g1H NMR /CDCl3/: 3,59 /1H, m,/, 3,91 - 4,05 /2H, m,/, 4,49 /1H, m,/, 5,04 /1H, broad, S./, 5,43 /1H, s/, 7,50 - 7,63 /4H, m/.

Preparative example 45

Getting dihydro-2-hydroxy-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H-she

Stage 1

Obtaining N-(2-bromacil)-, , -Cryptor-m-toluidine

N-(3-triptoreline)ethanolamine /4,17 g/ and triphenylphosphine /5.50 g/ dissolved in dry pyridine /35 ml and stirred at 0oC. To this solution portions were added chetyrehhloristy carbon /7,08 g/. Stirring is continued for 1 hour and the reaction mixture was left to stand at room temperature over night. Added silent triphenylphosphine /0.20 g/ and, when virtually all of the original alcohol was consumed, the pyridine was removed under reduced pressure giving a brown residue /14,10 g/. This substance was chromatographically on silica gel with elution with a mixture of ethyl acetate and hexane /1:9 as eluent, yielding the target compound as a pale brown oil, yield 3,35,

1H NMR /CDCl3/: to 3.58 /4H, m/, 4,25 /1H, broad, S./, 6,77 /1H, D./, for 6.81 /1H, s/, 6,98 /1H, D./, 7,29 /1H, D./.

Stage 2

Getting ethyl S-(2-(3-triptoreline)ethyl)thioglycolate

A solution of N-(2-bromacil)-, , -Cryptor-m-tolui is it ethyldiglycol /received using ethyldiglycol /1,25 g/ and sodium hydride /1,25 g of 60% dispersion in mineral oil/ dimethylformamide /total volume of 100 ml, and they remained mixed at room temperature for about 2 hours. The reaction mixture was carefully extinguished 5% aqueous solution of ammonium chloride, and the product was extracted in diethyl ether /3 times/. The combined organic layers were washed successively with water /x 2/, and brine, then dried /sodium sulfate/ and evaporated under reduced pressure. Balance /3.00 g/ chromatographically on silica gel with elution with a mixture of ethyl acetate and hexane /15: 85/, giving the target compound in the form of oil output 2,07 g

1H NMR /CDCl3/: 1,36 /3H, T./, 2,92 /2H, so/, 3,25 /2H, S./, 3,40 /1H, square /, 4,29 /2H, square/, 4,39 /1H, broad so/, 6,77 /1H, D./, 6,82 /1H, s/, 6,95 /1H, D./, 7,27 /1H, T./.

MS: m/e 307 /M+/

Stage 3

Getting dihydro-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2/she

Ethyl S-(2-(3-triptoreline)ethyl)thioglycolate (obtained as described above, in stage 2) /2,05 g/ dissolved in xylene /25 ml) was added p-toluensulfonate acid /to 0.127 g/. The solution was heated under mild delegirovano for 28 hours, then cooled, and the solvent was removed under reduced pressure giving a brown oil /1.88 g/. This substance was chromatographically on silica gel with elution with a mixture of these is="ptx2">

1H NMR /CDCl3/: 3,05 /2H, so/, 3,48 /2H, S./, was 4.02 /2H, so/, 7,52 /4H, m/.

MS: m/e 261 /M+/

Stage 4

Getting dihydro-2-chloro-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/she

Dihydro-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/he (obtained as described above, in stage 3) /1,31 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /17 ml/ sulfurylchloride /0,403 ml/. This product was used directly in stage 5.

Stage 5

Getting dihydro-2-hydroxy-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/she

Dihydro-2-chloro-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/he (obtained as described above, in stage 4) were converted to the target compound using a procedure similar to that described in preparative example 25, step 3, using tetrahydrofuran /7 ml/ and saturated sodium bicarbonate solution /10 ml/. The crude product /1,33 g/ was purified using chromatography on silica gel with elution with a mixture of ethyl acetate and hexane /35:65/. The target connection /0,68 g/ had:

1H NMR /CDCl3/: 3,20 /2H, m,/, 4,10 /3H, m/, 5,62 /1H, D./, 7,55 /4H, m/.

MS: m/e 277 /M+/

Preparative example 46

Receiving the l)prilocaine

Hydrochloride 0-benzylhydroxylamine /1,71 g/ suspenderbelt in ethyl acetate, and the mixture was thoroughly washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried /magnesium sulfate/ and evaporated under reduced pressure, giving 0-benzylhydroxylamine in the form of oil. This oil was added dropwise to 3-triftormetilfullerenov /2,00 g/, and the mixture was left standing for 1 hour. The mixture was then dissolved in ethyl acetate and was washed with 2 M hydrochloric acid. The organic layer was separated, dried /magnesium sulfate/ and evaporated under reduced pressure giving the product, the yield of 2.91 in,

1H NMR /CDCl3/: 4,90 /2H, S./, 7,18 - to 7.59 /11H, m/.

Stage 2

Getting 1-benzyloxy-3-(3-trifluoromethyl)phenyl-2-imidazolidinone

Mix a solution of N-benzyloxy-N'-(3-trifluoromethyl)phenylacetone (obtained as described above, in stage 1) /0,815 g/ dimethylformamide /30 ml was treated by adding portions of sodium hydride /0,113 g of a 55% dispersion in mineral oil/. The solution was mixed for 30 minutes, then was added 1,2-dibromethane /0,494 g/. The mixture was mixed for another 30 minutes and then was treated in portions with sodium hydride /0,113 g of a 55% dispersion in mineral oil/. The mixture pereles /magnesium sulfate/ and evaporated under reduced pressure. Purification via chromatography on silica gel with elution with mixtures of ethyl acetate and hexane gave the target compound, the output 0,410,

1H NMR /CDCl3/: 3,43 /2H, so/, 3,70 /2H, so/, of 5.05 /2H, S./, 7,22 - 7,52 /7H, m/, 7,74 - 7,89 /2H, M./.

Stage 3

Obtain 3-hydroxy-1-(3-trifluoromethyl)phenyl-2-imidazolidinone

Mix a solution of 1-benzyloxy-3-(3-trifluoromethyl)phenyl-2-imidazolidinone /received, as described above, stage 2/ /0,223 g/ methanol /30 ml/ gidrirovaniya over 5% palladium catalyst on coal /0.025 g/ in for 1 hour. Then was added an additional amount of catalyst /0.025 g/, and the mixture was gerasoulis for an additional hour. The mixture was filtered through Hyflo were washed with additional methanol, and the combined filtrates were evaporated under reduced pressure, giving the resin. Purification via chromatography on silica gel with elution with mixtures of ethyl acetate and hexane gave the target compound, the output 0,049,

1H NMR /CDCl3/: 3,65 - 3,76 /2H, m,/, 3,76 - a 3.87 /2H, m,/, 7,38 /1H, D./, of 7.48 /1H, T./, 7,75 /1H, s/, 7,80 /1H, D./, 8,72 /1H, broad/.

MS: m/e 246 /M+/

Preparative example 47

Getting tetrahydro-3-hydroxy-1-(3-trifluoromethyl)phenyl-2/1H/-pyrimidinone

Stage 1

the ow is described in preparative example 46, stage 2, but using N-benzyloxy-N'-/3-trifluoromethyl/prilocaine /obtained as described in preparative example 46, step 1 above/ /0,714 g/, dimethylformamide /30 ml, sodium hydride /0,100 g of a 55% dispersion in mineral oil, 1,3-dibromopropane /0,465 g/ and an additional amount of sodium hydride /0,100 g of a 55% dispersion in mineral oil, and with purification of the crude product through chromatography on silica gel with elution with mixtures of ethyl acetate and hexane were obtained target compound, 0,510,

1H NMR /CDCl3/: 2,11 /2H, Quint./, 3,52 /2H, so/, 3,63 /2H, so/, 4,99 /2H, S./, 7,30 - 7,58 /9H, m/.

Stage 2

Getting tetrahydro-3-hydroxy-1-(3-trifluoromethyl)phenyl-2-/1H/-pyrimidinone

Using procedures similar to those described in the prior example 46, step 3 above, but when the hydrogenation tetrahydro-1-benzyloxy-3-/3-trifluoromethyl/phenyl-2/1H/-pyrimidinone /obtained in stage 2 above/ /0.75 g/ over 5% palladium catalyst on coal /0.015 g/ methanol /5 ml/ get the target connection.

1H NMR /CDCl3/: 2,28 /2H, Quint./, 3,74 /4H, T./, 7,40 - 7,53 /4H, m /, /OH, wide - were observed/.

MS: m/e 260 /M+/

Preparative example 48

Obtain 3-hydroxy-1-(3-trifluoromethyl)phenyl/2-piperazinone is the very 3-triptoreline /5,00 g/. The resulting solid mass was dissolved in ethyl acetate, and the solution was washed with 2 M hydrochloric acid, water and saturated sodium bicarbonate solution. The organic layer was dried /magnesium sulfate/ and evaporated under reduced pressure giving the product as an oil, yield of 8.06 g

1H NMR /CDCl3/: 1,78-1,95 /4H, m/, 2,42 /2H, so/, 3,55 /2H, so/, 7,31-7,47 /2H, m/, to 7.59 /1H, broad, S./, 7,71 /1H, D./, 7,82 /1H, s/.

Stage 2

Obtain 1-(3-trifluoromethyl)phenyl-2-piperidino

A solution of N-(3-trifluoromethyl)phenyl-5-chlorpheniramine (obtained as described above, in stage 1) /to $ 7.91 g/ dimethylformamide /100 ml was treated with portions of sodium hydride /1,23 g of a 55% dispersion in mineral oil/. The mixture is stirred at room temperature for 16 hours, then was heated to 60oC for 2 hours. The mixture then was cooled, it was diluted with diethyl ether, and extracted thoroughly with water and the organic phase was then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave the product as a solid substance, the output 3,24,

1H NMR /CDCl3/: 1,88-2,03 /4H, m/, 2,58 /2H, so/, 3,67 /2H, so/, 7,44-7,56 /4H, m/.

Stage 3

Obtain 3-hydroxy-1-(3-trifluoromethyl)phenyl-2-piperidino
<3 g/ tetrahydrofuran /15 ml/ was cooled to 0oC in nitrogen atmosphere, was added dropwise litigationrelated /4,2 ml of 1 M solution in tetrahydrofuran/. The resulting orange solution was then treated with a solution of N-toluensulfonyl-3-phenyloxazolidine /obtained as described in Journal of Organic Chemistry, 1988, 53, 2087/ /1,16 g/ tetrahydrofuran /5 ml/. The mixture was left to stand for 66 hours, then was diluted with water and extracted with diethyl ether. The ether extract was dried /magnesium sulfate) and evaporated under reduced pressure, and the mixture was separated by chromatography on silica gel with elution with mixtures of ethyl acetate and hexane, giving a product which was obtained as a 2:1 mixture of unreacted 1-(3-trifluoromethyl)phenyl-2-piperidine, from which he could not be separated. This mixture was used directly in example 91.

1H NMR /CDCl3/: by the way 1,80-2,12 /3H, m/, 2,43 /1H, m,/, 3,60-3,71 /2H, m,/, 3,79 /1H, m,/, 4,25 /1H, m,/, 7,42-7,58 /4H, m/.

Preparative example 49

Getting dihydro-6-hydroxy-3-methyl-4-(3,5-bis(trifluoromethyl))phenyl-2H-1,3,4 - thiadiazin-5/6H/she

Stage 1

Getting dihydro-4-(3,5-bis(trifluoromethyl))phenyl-2H-1,3,4-thiadiazin-5/6H/she

Mix a solution of 3,5-bis/trifluoromethyl/hydrazine /1.22 g/ Tay acid /2 mg/. The mixture was mixed for 10 minutes, then added thioglycolate acid /0,46 g/, and the mixture was heated under conditions of reflux distilled, and the water gathered in the office of Dean-stark. After 3.5 hours, the mixture was cooled, it was diluted with ethyl acetate /30 ml/ were washed with water /30 ml, 2 M hydrochloric acid /30 ml, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a pale yellow solid. Rubbing with diethyl ether gave the target compound, the output 0,821,

1H NMR /CDCl3/: 3,65 /2H, S./, 4,57 /2H, S./, 6,99 /1H, s/, 7,05 /2H, S./, 7,39 /1H, s/.

Stage 2

Getting dihydro-3-methyl-4-(3,5-bis(trifluoromethyl))phenyl - 2H,1,3,4-thiadiazin-5-/6H/she

A solution of dihydro-4-(3,5-bis(trifluoromethyl))phenyl-2H-1,3,4-thiadiazin-5-/6H/she /received, as described above, stage 1/ /0,330 g/ tetrahydrofuran /2 ml was added dropwise to a stirred suspension of sodium hydride /24 mg/ tetrahydrofuran /3 ml/. After 15 minutes, the red solution was treated with methyliodide /0,142 g/, and the mixture is stirred for 2 hours. Added additional amount under the conditions /1.0 ml) and the mixture was mixed for another 30 minutes before it was diluted with diethyl ether /30 ml and were washed with water /30 ml/. The organic layer is pale-yellow solid, output 0,321,

1H NMR /CDCl3/: 3,29 /3H, s/, 3,59 /2H, S./, 4,50 /2H, broad/, 7,03 /2H, S./, 7,37 /1H, s/.

Stage 3

Getting dihydro-6-hydroxy-3-methyl-4-(3,5-bis(trifluoromethyl))phenyl-2H-1,3,4-thiadiazin-5-/6H/she

Stir dihydro-3-methyl-4-(3,5-bis(trifluoromethyl))phenyl - 2H, 1,3,4-thiadiazin-5-/6H/she /received, as described above, stage 2/ /0,321 g/ in dichloromethane /8 ml/ was cooled in an ice bath. After the solution was barotraumas stream of nitrogen, and was added sulfurylchloride /0,08 ml/. Once added, the solution stirred with cooling for 10 minutes, was left to warmed to room temperature and then stirred for a further 30 minutes while maintaining a current of nitrogen. The solution was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran /5 l/. This solution was treated with an aqueous solution of sodium bicarbonate /5 ml, and the mixture is stirred vigorously for 15 minutes, then was left to stand for 16 hours. The mixture was extracted with ethyl acetate /2 x 30 ml) and the combined extracts were dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave the pitch, which was pulverized with a mixture of ethyl acetate and hexane and filtered to remove solids. F. esami ethyl acetate and hexane, giving the target compound in the form of resin, the output 0,037 g

1H NMR /CDCl3/: 3,30 /3H, s/, 3,95 /1H, broad, S./, 4,39 /1H, broad D./, 4,78 /1H, D./, 5,55 /1H, s/, 7,02 /2H,/, of 7.36 /1H, s/.

Preparative example 50

Getting dihydro-4-hydroxy-2-(3-trifluoromethyl)phenyl-2H-1,2 - oxazin-3/4H/she

Stage 1

Obtaining N-(3-trifluoromethyl)phenyl-hydroxylamine

A solution of 3-nitro-, , -tittorture /4,95 g/ in ethanol /100 ml was mixed vigorously with an air stirrer and was treated sequentially with a solution of ammonium chloride /15,00 g/ in water /50 ml/, then powder zinc /12.00 g/. After 5 minutes, when ectothermy began to abate, and the mixture was filtered through Hyflo Super-a, it was diluted with water /100 ml and was extracted with ethyl acetate /3 x 100 ml. The combined extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a yellow oil. This oil was chromatographically on silica gel with elution with a mixture of dichloromethane/ethyl acetate /19:1/, giving the target compound, yield 3.75 g, so pl. 44 - 45oC.

Stage 2

The mixture dihydro-4-bromo-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/-she dihydro-4-chloro-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/she

A solution of N-(3-tratraditional /10 ml was added over 20 minutes to stir, chilled with ice to a solution of 2,4-dibromomalonamide /92% purity, obtained as described in Journal of Medical Chemistry, 1987, 30, 1995/ /of 5.81 g/ dry tetrahydrofuran /10 ml/. The mixture is stirred for 3 hours, filtered, and the filtrate was evaporated under reduced pressure. The residue was diluted with ethyl acetate, was washed with 2 M hydrochloric acid, water, aqueous sodium carbonate /three times and brine, dried /magnesium sulfate/ and evaporated under reduced pressure. The residue was chromatographically on silica gel with elution with a mixture of ethyl acetate and hexane /1:5/, giving a 1:1 mixture of the target compounds in the form of an orange oil, yield of 1.42 g

1H NMR /CDCl3/: 2,4 - 2,7 /1H, m,/, 2,8 - 3,0 /1H, 2 m/, 4,3 - 4,5 /2H, 2 m/, 4,8 - 4,9 /1H, 2 m/, 7,4 - 7,6 /2H, 2 m/.

Stage 3

Getting dihydro-4-iodine-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/she

A mixture of 1: 1 /dihydro-4-bromo-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/-she dihydro-4-chloro-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/she /received, as described above, stage 2/ /1.20 g/, sodium iodide /1,11 g/ and dry acetone /25 ml/ heated under conditions of reflux distilled for 2 hours, was left to cool, was diluted with water and extracted with ethyl acetate /thrice/. United organizatcionnii. It was shown that the balance is 93% dihydro-4-iodine-2-(3-trifluoromethyl)phenyl-2H-1,2 - oxazin-3/4H/she and 7% dihydro-4-chloro-2-(3-trifluoromethyl)phenyl-2H-1,2 - oxazin-/4/-she, the output of 1.50 g

1H NMR /CDCl3/: by the way 2,86 /1H, m/ 2,84 /1H, m,/, 4,33 /1H, m,/, 4,46 /1H, m,/, 4,88 /1H, T./, 7,40 - 7,55 /2H, m/, a 7.92 - 8.00 per 2H, D. and C./.

MS: m/e 371 /M+/

Stage 4

Getting dihydro-4-hydroxy-2-(3-trifluoromethyl)phenyl-2H-1,2 - oxazin-3/4H/she

A mixture of dihydro-4-iodine-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin - 3/4H/she (obtained as described above, in stage 3) /1.20 g/ and bis(triptoreline)odensala /1.68 g/ dry dichloromethane /25 ml and stirred for 24 hours. The mixture was then diluted with diethyl ether, was filtered aqueous sodium bisulfite, aqueous sodium bicarbonate and brine, dried /magnesium sulfate/ and evaporated under reduced pressure, giving triftoratsetata broadcast target compound. This substance was filtered through silica gel in a mixture of dichloromethane and methanol /49:1/, giving the alcohol, then chromatographically on silica gel with elution with a mixture of ethyl acetate/hexane /1: 3/, giving the target compound in the form of oil, which crystallized upon standing, the yield of 0.44 g, so pl. 45 - 46oC.

1H NMR /CDCl/

Preparative example 51

Getting 5-hydroxy-3-(3-N,N-dibenzyl)sulphonamido)phenyl-4 - thiazolidinone

Stage 1

Obtaining 3-(N,N-dibenzylamino)nitrobenzene

Dibenzylamine /10.9 ml/ was dissolved in dry dichloromethane /40 ml was mixed at 0oC. To this solution was added dropwise 3-nitrophenylacetylene /4,18 g/, and the stirring was continued at 0oC for 30 minutes. The cooling bath was then removed and the reaction mixture was left to run at room temperature for 2 hours. Then, water was added, and the product was extracted in dichloromethane /3 x/. The combined organic layers were washed with 2 M hydrochloric acid and brine, and then dried /magnesium sulfate/ .The solvent was removed under reduced pressure giving a residue /11,60 g/, which was chromatographically on silica gel using a mixture of ethyl acetate: hexane /1: 4 as eluent. The target connection /3.2 g/ had:

1H NMR /CDCl3/: 4,42 /4H, S./, 7,12 /4H, m/, 7,24 /6H, m/, 7,65 /1H, T./, 8,06 /1H, D./, scored 8.38 /1H, d/, /8,51 /1H, s/.

MS: m/e 382 /M+/

Stage 2

Getting 2-((N,N-dibenzyl)sulphonamido)aniline

3-(Dibenzylamino)nitrobenzene /received, as described above, n is th refrigerator for 1.5 hours. The reaction mixture was cooled to room temperature, and then filtered through celite. The filtrate was mixed with water and the product was extracted in dichloromethane /3 x/. The combined organic layers were dried /magnesium sulfate/ and mariveles under reduced pressure giving a residue /3,022 g/. The residue was chromatographically on silica gel using ethyl acetate and hexane /1:4 to 1:3/, giving the target compound /2,47 g/, which had:

1H NMR /CDCl3/: 3,90 /2H, broad, S./, 4,33 /4H, S./, 6,85 /1H, DD,./, 7,15 /5H, m/, 7,25 /8H, m/.

MC: 352 /M+/

Stage 3

Obtaining 3-(3-N,N-dibenzyl)sulphonamido)phenyl-4-thiazolidinone

3-/Dibenzoylmethanato/aniline /obtained as described above in stage 3/ /2,664 g/ turned into a target connection using a toluene /20 ml/, thioglycolic /0.63 ml/ and 37% aqueous formaldehyde /0,74 ml/ using a procedure similar to that described in preparative example 25, step 1. The solvent was removed under reduced pressure, giving a resin, which was taken in dichloromethane and was washed with 2 M hydrochloric acid, saturated sodium bicarbonate solution and water. The solvent was dried /magnesium sulfate/ and evaporated under reduced pressure, giving not quite white solid is 3/: 3,75 /2H, S./, 4,35 /4H, S./, 4,75 /2H,/, 7,09 /4H, m /, of 7.23 /6H, m/, 7,53 /1H, T./, 7,69 /1H, D./, 7,75 /1H, s/, 7,82 /1H, D./.

Stage 4

Getting 5-chloro-3-(3-N,N-dibenzyl)sulfonatophenyl)-4-thiazolidinone

3-(Dibenzylamino)phenyl-4-thiazolidinone /received, as described above, at stage 3/ /1.5 g/ turned into a target compound using a procedure similar to that described in preparative example 25, step 2, using dichloromethane /15 ml/ sulphonylchloride /0,29 ml/. The target compound was used immediately in stage 5.

Stage 5

Getting 5-hydroxy-3-/dibenzoylmethanato/phenyl-4-thiazolidinone.

5-Chloro-3-(3-N,N-dibenzyl)sulphonamido)phenyl)-4-thiazolidinone /received, as described above, in stage 4/ turned into a target compound using a procedure similar to that described in preparative example 25, step 3, using a mixture of tetrahydrofuran /10 ml and saturated sodium bicarbonate solution /10 ml/. The crude product /1,34 g/ purified on silica gel using a mixture of ethyl acetate : hexane /55:45/ as eluent, yielding the target compound in the form of brittle yellow foam /0,83 g/, which had:

1H NMR /CDCl3/: 3,83 /1H, broad, S./, 4,35 /4H, S./, 4,62 /1H, D./, 4,93 /1H, D./, 5,71 /1H, s/, 7,09 /4H, m/, of 7.23 /6H, m/, 7,54 /1H, ENT)phenyl-4-thiazolidinone

Stir a solution of 3-(3,4-dichloro)phenyl-5-hydroxy-4 - thiazolidinone /received, as described above in preparative example 1/ /1.50 g/ dichloromethane /40 ml/ was treated dropwise tert-utilitarianism /0.56 g/ triethylamine /0,58 g/. The solution was mixed for 6 hours and then left to stand for 18 hours. The solution was then washed with 2 M hydrochloric acid /30 ml, dried /magnesium sulfate and the solvent was removed under reduced pressure, giving a pale yellow solid. Recrystallization from a mixture of chloroform/hexane gave the target compound in the form of crystalline solid, yield 1.31 g, so pl. 133 - 134oC.

1H NMR /CDCl3/: 1,32 /9H, s/, 4,62 /1H, D./, 4,89 /1H, broad, S./, 4,98 /1H, D./, 6,18 /1H, s/, 7,33 - 7,50 /2H, m,/, 7,68 /1H, s/.

Example 2

Getting connection 5

5-ISO-propylgallate-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 5-hydroxy-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone (obtained as described above in preparative example 2) /3.00 g/ triethylamine /0.1 ml/ chloroform /40 ml/ was treated dropwise with a solution isopropylmalate /1,08 g/ chloroform /10 ml/. The mixture was mixed for 2 hours, then added an additional if the second pressure, giving a white solid. This substance was pulverized with hexane and precrystallization from a mixture of ethyl acetate/hexane, yielding the target compound as a white crystalline solid, yield 2,88 g, so pl. 167 - 168oC.

1H NMR /CDCl3/: 1,19 /6H, d/, 3,83 /1H, m,/, 4,69 /1H, D./, 4,78 /1H, broad D./, 5,07 /1H, D./, 6,21 /1H, s/, 7,51 - 7,62 /2H, m,/, 7,71 - 7,79 /2H, M./.

Example 3

Obtaining the compound (9)

5-methylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in example 2 but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2), methyl isocyanate and triethylamine were obtained target compound, so pl. 156oC.

Example 4

The connection 16

5-ethylcarboxylate-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 2 but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2 above) /1,00 g/, utilizationof /0.25 ml/ triethylamine /0.01 ml/ chloroform /5 ml/, was the target connection, so pl. 152 - 153oC.

1H NMR /CDCl3/
The connection 17

5-benzylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in example 2 but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described in example getting 2 above/ /0,90 g/, benzylisothiocyanate /0,46 g/ triethylamine /0.01 ml/ chloroform /3 ml/ get the target connection, so pl. 153 - 154oC.

1H NMR /CDCl3/: 4,39 /2,H D./, 4,68 /1H, D./, 5,07 /1H, DD/, 5,25 /1H, broad so /, 6,24 /1H, D./, of 7.23-7,38 /5H, m/, 7,50-7,60 /2H, m,/, 7,70-7,79 /2H, M./.

Example 6

The connection 20

5-phenylcarbamoyloxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 2 but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2 above) /0,80 g/, phenylisocyanate /0.33 ml/ triethylamine /0.01 ml/ chloroform /2 ml/ get the target connection, so pl. 192 - 194oC.

1H NMR /CDCl3/ d6-DMCO/: 4,71 /1H, DD,./, 5,12 /1H, DD,./, 6,29 /1H, DD. /, 7,02 /1H, m,/, 7,20-7,31 /2H, m,/, 7,40-7,65 /4H, m/, 7,72 /1H, m/, the 7.85 /1H, m, 9,01 /1H, broad, S./.

Example 7

The connection 26

5-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazole is in preparative example 2 above/ /0.84 g/ chloroform /5 ml/ was treated with triethylamine /0,01/, then tert-utilitarianism /0.32g/. The resulting solution was mixed for 2 hours, then evaporated under reduced pressure. The solid residue was precrystallization from hexane, giving the target compound as a white crystalline compound, the yield of 0.90 g, so pl. 98 - 99oC.

1H NMR /CDCl3/: 1,32 /9H, s/, 4,69 /1H, D./, 4,90 /1H, broad, S./, 5,04 /1H, D./, 6,21 /1H, s/, 7,52-to 7.59 /2H, m,/, 7,71-7,79 /2H, M./.

MS: m/e 361 /M+/

Example 8

The connection 30

5-ISO-propylgallate-3-(3,5-bis(trifluoromethyl))phenyl-4-thiazolidinone

Using a procedure similar to that described in example 2 but using 5-hydroxy-3-(3,5-bis(trifluoromethyl)) phenyl-4-thiazolidinone /obtained as described in preparative example 3 above/ /1,50/ ISO-propositionthe /0.39 g/, triethylamine /0.01 ml/ chloroform /5 ml/ and recrystallization of the crude product from a mixture of chloroform and hexane, was the target compound as a white solid, yield of 1.30 g, so pl. 141-142oC.

1H NMR /CDCl3/: 1,19 /6H, d/, 3,82 /1H, m,/, 4,72 /1H, D./, 4,76 /1H, broad D./, 5,13 /1H, D./, 6,20 /1H, s/, 7,78 /1H, s/, 8,04 /2H,/.

Example 9

The connection 33

5-ISO-propylgallate-3-(4-trifluoromethyl)phenyl-4-reformer)phenyl-4-thiazolidinone /received as described above in preparative example 4/ /0,185 g/ ISO-propositionthe /to 0.060 g/, triethylamine /0.01 ml/ chloroform /5 ml/ and recrystallization of the crude product from a mixture of chloroform and hexane were obtained target compound as a white solid, yield 0,180 g, so pl. 198oC.

1H NMR /CDCl3/: 1,19 /6H, d/, 3,81 /1H, m,/, 4,69 /1H, d/, 4,76 /1H, broad D./, 5,09 /1H, D./, 6,21 /1H, s/, 7,63-7,71 /4H, m/.

Example 10

The connection 35

5-tert-butylcarbamoyl-3-(3-chloro)phenyl-4-thiazolidinone

Stir a suspension of 3-(3-chloro)phenyl-5-hydroxy-4-thiazolidinone /obtained as described above in preparative example 5/ /16,60 g/ in dichloromethane /100 ml was treated with triethylamine /10 ml/ s followed by the addition of tert-utilizationof /8,5 ml/. The solution was mixed for 8 hours, then was left to stand for 18 hours. The solution was washed with 2 M hydrochloric acid /50 ml/, then brine, and then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave a solid residue, which was precrystallization of carbon tetrachloride, giving the target compound as a white solid, yield 21,20 g, so pl. 117 - 118oC.

1H NMR /CDCl3/ the connection 40

5-tert-butylcarbamoyl-3-(3,5-dichloro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3,5-dichloro)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 6) /14,30 g/, tert-utilizationof /7,0 ml/ triethylamine /7,6 ml and chloroform as solvent /100 ml and in the implementation of the recrystallization of crude product from carbon tetrachloride, was the target compound as a white solid, yield 17,00 g, so pl. 150 - 152oC.

1H NMR /CDCl3/: 1,32 /9H, s/, br4.61 /1H, D./, 4,88 /1H, broad, S./, 4,99 /1H, D./, 6,14 /1H, s/, 7,25 /1H, T./, 7,47 /2H, d/.

Example 12

The connection 44

3-(3-chloro-4-fluoro)phenyl-5-ISO-propylgallate-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3-chloro-4-fluoro)phenyl-5-hydroxy-4 - thiazolidinone (obtained as described in preparative example 7) /2.50 g/, isopropylmalate /0,86 g/, triethylamine /1.3 ml/ and dichloromethane /25 ml/ and recrystallization of the crude product from chloroform, was the target compound as a white solid, yield 3,20 g, so pl. 190 - 191oC.

1H NMR /CDCl3/: 1,18 /6H, d/, 3,83 /s connection 45

5-tert-butylcarbamoyl-3-(3-chloro-4-fluoro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3-chloro-4-fluoro)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 7) /2.50 g/, tertbutylbenzene /1,00 g/, triethylamine /1.3 ml/ and dichloromethane /25 ml/ and recrystallization of the crude product from a mixture of toluene/hexane, was the target compound as a white solid, yield 2,60 g, so pl. 130 - 133oC.

1H NMR /CDCl3/: 1,32 /9H, s/, br4.61 /1H, D./, 4,89 /1H, broad, S./, 4,95 /1H, d/, 6,18 /1H, s/, 7,21 /1H, m/, of 7.36 /1H, m,/, 7,60 /1H, m/.

Example 14

The connection 48

5-tert-butylcarbamoyl-3-(2-chloro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2-chloro)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 8 above) /2,74 g/, tert-utilizationof /1.20 g/, triethylamine /1.6 ml/ and dichloromethane /20 ml, was obtained target compound in the form of resin.

1H NMR /CDCl3/: 1,31 /9H, s/, 4,65 /1H, D./, 4,82 /1H, D./, 4,91 /1H, broad, S./, 6,21 /1H, s/, 7,33-7,42 /3H, m/, 7,51 /1H, m,/.

Example 15

The Connection 52

5-tert-butylcarbamoyl-3-(4-methoxy)of 5-hydroxy-3-(4-methoxy)phenyl-4-thiazolidinone (received as described in preparative example 9 above) /1,60 g/, tert-utilizationof /0,70 g/, triethylamine /0.94 ml and dichloromethane /25 ml/ and trituration of the crude product with diethyl ether was obtained target compound as a white solid, yield 1.90 g, so pl. 127 - 129oC.

1H NMR /CDCl3/: 1,32 /9H, s/, 3,80 /3H, s/, 4,62 /1H, D./, 4,89 /1H, broad, S./, 4,92 /1H, D./, 6,20 /1H, s/, 6,95 /2H, m,/, 7,33 /2H, M./.

Example 16

The connection 56

5-tert-butylcarbamoyl-3-(2,3-dichloro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2,3-dichloro)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 10 above) /0.50 g/, tert.-utilizationof /0,19 g/, triethylamine /0,26/ ml and dichloromethane /15 ml/ and trituration of the crude product with hexane was obtained target compound as a white solid, yield of 0.58 g, so pl. 145 - 147oC.

1H NMR /CDCl3/: 1,32 /9H, s/, 4,63 /1H, D./, 4,82 /1H, D./, 4,93 /1H, broad, S./, to 6.19 /1H, s/, 7,21 and 7.36 /2H, m,/, 7,53 /1H, m,/.

Example 17

The connection 59

5-ISO-propylgallate-3-(3,5-dichloro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3,5-dichloro)Hairdryer triethylamine was obtained target compound, so pl. 195 - 198oC.

Example 18

The connection 61

3-(2-chloro)phenyl-5-ISO-propylgallate-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2-chloro)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 8 above), isopropylmalate and triethylamine were obtained target compound.

1H NMR /CDCl3/: 1,19 /3H, d/ a, 1,20 /3H, D./, a 3.87 /1H, m,/, 4,58 /1H, D. /, a 4.83 /1H, broad/, 4,86 /1H, DD,./, 6,12 /1H, D./, 7,33-7,41 /3H, m/, 7,51 /1H, m,/.

Example 19

The connection 62

5-cyclohexylcarbamate-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained in preparative example 2 above) /0,53 g/, cyclohexylsulfamate /0.25 g/, triethylamine /0,28/ ml and dichloromethane /10 ml/ and recrystallization of the crude product from a mixture of ethyl acetate and hexane were obtained target compound as a white crystalline solid, yield 0.52 g, so pl. 183 - 185oC.

1H NMR /CDCl3/: 1,05-1,45 /5H, m/, 1,52-1,78 /3H, m/, 1,87-2,00 /2H, m,/, 3,50 /1H, m,/, 4,69 /1H, D./, 4,78 /1H, broad D./, 5,07 /1H, D./, to 6.19 /1H, s/, 7,49-to 7.61 /2H, m,/, 7,71-7,80 /2H, m)phenyl-4-thiazolidinone

Mix a solution of 1-methylcyclopropane-1-carboxylic acid /0,057 g/ and diphenylphosphinite /0,165 g/ toluene /15 ml/ was treated with triethylamine /0,079 ml/. The mixture was mixed for 1 hour, then was added 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2) /0,150 g/, and the mixture was heated under conditions of reflux distilled for 3 hours. The mixture was cooled, extracted with 2 M hydrochloric acid, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the resin. The crude product was separated by chromatography on silica gel with elution with mixtures of ethyl acetate and hexane. This product was dissolved in ethyl acetate, was washed with a saturated solution of sodium carbonate, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the pure target compound as a white solid, yield 0,016 g, so pl. 203 - 206oC.

1H NMR /CDCl3/: 0,60-0,67 /2H, m,/, 0,77-0,84 /2H, m,/, 1,38 /3H, s/, 4,70 /1H, D./, 5,07 /1H, D./, 5,25 /1H, broad, S./, 6,20 /1H, s/, 7,50-7,60 /2H, m,/, 7,69-7,80 /2H, M./.

Example 21

Getting connection 69

5 - (- dimethylbenzyl)carbamoylated-3-(3-trifluoromethyl)phenyl - 4-thiazolidinone

Using procedures similar to those described in the in preparative example 2) /0,53 g/, , -/ dimethylbenzylidene /0.26 g/, triethylamine /0,28/ ml and dichloromethane /10 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane followed by crystallization from a mixture of chloroform and hexane, was the target compound as a white solid crystalline substances, the yield of 0.42 g, so pl. 100 - 101oC.

1H NMR /CDCl3/: 1,69 /6H, s/, 4,68 /1H, D./, 5,02 /1H, D./, 5,30 /1H, broad, S. /, 6,18 /1H, s/, 7,18-7,42 /5H, m/, of 7.48-7,58 /2H, m/, to 7.61-7,78 /2H, M./.

Example 22

Getting connection 77

5-tert-butylcarbamoyl-3-(4-methyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(4-methyl)phenyl-4-thiazolidinone (obtained as described in preparative example 11) /2,00 g/, tert-utilizationof /0.95 g/, triethylamine /1.3 ml/ and dichloromethane /25 ml/, and recrystallization of the crude product from a mixture of chloroform and hexane were obtained target compound as a white crystalline solid, yield 1.90 g, so pl. 142 - 143oC.

1H NMR /CDCl3/: 1,31 /9H, s/, 2,38 /3H, s/, 4,63 /1H, D./, 4,89 /1H, broad, S. /, 4,94 /1H, D./, 6,20 /1H, s/, 7,18-7,26 /2H, m,/, 7,29-7,35 /2H, M./.

Example 23

The connection 84
oC.

1H NMR /CDCl3/: 1,31 /9H, s/, 4,62 /1H, D./, 4,88 /1H, broad, S./, 4,98 /1H, D./, to 6.19 /1H, s/, 7,35-7,49 /4H, m/.

Example 24

The connection 91

5-tert-butylcarbamoyl-3-(2,5-dichloro)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2,5-dichlorophenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 13 above) /0.36 g/, tert-utilizationof /0.14 g/, triethylamine /0,19/ ml and dichloromethane /15 ml/ s with a rubbing of the crude product with a mixture of diethyl ether and hexane were obtained target compound as white solid crystalline substances, the yield 0.25 g, so pl. 146-147oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 4,55 /1H, D./, 4,82 /1H, D./, 4,90 /1H, broad, S./, to 6.19 /1H, s/, 7,31-of 7.48 /3H, m/.

Example 25

Getting connection 890

4-tert-butylcarbamoyl the on /0.05 g, obtained as described in preparative example 14, and containing toluene-p-sulfonamide/, tert-utilizationof /0,042 g/ triethylamine /0,043 g/ dichloromethane /2 ml/ was left to stand over night at room temperature. Added additional quantity of isocyanate and triethylamine, and even after 4 hours the mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. Chromatography on silica gel using a mixture of hexane and ethyl acetate /3:1/ gave the product /0.02 g/ free from toluene-p-sulfonamida, but polluted N,N'-di-tert-butylacetyl.

1H NMR /CDCl3/: signals only target connection: 1,35 /9H, s/, 4,4 /1H, DD/, 4,85 /1H, DD/, 5,0 /1H, Shir, C./, 5,6 /1H, T./, 7,5 /2H, m,/, 8,0 /2H, M./.

MS: m/e 346 M+< / BR>
Example 26

The connection 100

5-tert-butylcarbamoyl-3-(2-fluoro-5-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2-fluoro-5-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone /obtained as described in preparative example 15 above/ /1,40 g/, tert-utilizationof /0.5 g/, triethylamine /0,70 the San was the target compound in the form of transparent glass, output 1,90,

1H NMR /CDCl3/: 1,32 /9H, s/, 4,60 /1H, D./, 4,91 /2H, D. + wide with./, to 6.19 /1H, s/, 7,34 /1H, m,/, 7,60 to 7.75 /2H, M./.

Example 27

Getting the connections 107 and 108

5-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone-S, S-dioxide and 5-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone-S-oxide.

Mix a solution of compound 26 /3,62 g/ in dichloromethane /70 ml/ processed portions solid 50 - 60% m-chlormadinone acid /3,10 g/ on for 1 hour. The resulting suspension was extracted with saturated aqueous sodium bicarbonate, and the organic layer was dried /magnesium sulfate/ and evaporated under reduced pressure, giving a white foam. Chromatography on silica gel with elution with mixtures of ethyl acetate and hexane gave the first connection 107, 5-tert-butylcarbamoyl-3-/3-trifluoromethyl/phenyl-4-thiazolidinone-S,S-dioxide, in the form of a white solid, yield 1.20 g, so pl. 181 - 184oC.

1H NMR /CDCl3/: 1,33 /9H. C./, 4,98 /1H, D./, 5,04 /1H, D./, 5,71 /1H, s /, 5,96 /1H, broad, S./, 7,55-7,66 /3H, m/, 7,75 /1H, m/, and then the connection 108, 5-tert-butylcarbamoyl-3-(3-trifluoromethyl)-phenyl-4-thiazolidinone-S-oxide, the yield 2.70 g, which was obtained in the form of a 3:1 mixture of diastereoisomers.

Example 28

The connection 112

5-tert-butylcarbamoyl-3-(3-chloro-4-methyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3-chloro-4-methyl)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 16 above) /2,44 g/ tert-utilizationof /1.0 g/, triethylamine /1,4/ ml and dichloromethane /25 ml/ and by using the recrystallization of crude product from a mixture of ethyl acetate and hexane were obtained target compound as a white solid, yield 2,80 g, so pl. 144 - 147oC.

1H NMR /CDCl3/: 1,32 /9H, s/, 4,62 /1H, D./, 4,90 /1H, broad, S./, 4,95 /1H, D./, to 6.19 /1H, s/, 7,22-7,30 /2H, m,/, 7,50 /1H, s/.

Example 29

The connection 119

5-(N-(1,1-dimethyl)propyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example 2) /0.56 g/ dichloromethane /10 ml/ was cooled in an ice bath and treated dropwise with tetrachloroplatinate /0,62 g/, and then pyridine /0.20 g/. The mixture peremeshivanie 65 hours. The solution was washed with 2 M hydrochloric acid /2 x 20 ml) and dried /magnesium sulfate/ and evaporated under reduced pressure, giving the resin. Chromatography on silica gel with elution with a mixture of ethyl acetate and hexane gave the crude product as a solid substance, which was pulverized twice with diethyl ether, giving the target compound as a white solid, yield of 0.14 g

1H NMR /CDCl3/: 0,89 /3H, T./, 1,28 /6H, s/, 1,67 /2H, m,/, 4,68 /1H, D. /, 4,82 /1H, broad, S./, 5,04 /1H, D./, to 6.19 /1H, s/, 7,49 - 7,58 /2H, m/, to 7.68-7,79 /2H, M./.

Example 30

The connection 122

5-(N,N-diethyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 29, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described in preparative example 2 above/ /0,30 g/, tetrachloroplatinate /0,31 g/, pyridine /0,13 ml/ diethylamine /0.10 g/ and chromatography of the crude product on silica gel /elution with a mixture of ethyl acetate and hexane/ get the target connection, the output of 0.10 g

1H NMR /CDCl3/ : 1,14 /6H, T./, 3,20-3,45 /4H, m/, 4,68 /1H, doctor/ 5,12 /1H, DD,./, 6,21 /1H, D./, 7,49-to 7.61 /2H, m/, to 7.68 - a 7.85 /2H, M./.

Example 33

Obtaining compounds 133 and 134

5-ISO-propellerblades-S-oxide

Using a procedure similar to that described in example 27, but using compound 5 instead of compound 26 was obtained compound 133 (5-ISO-propylgallate-3-(3-trifluoromethyl)phenyl-4-thiazolidinone-S,S-dioxide):

1H NMR /CDCl3/D6-DMCO/: 1.06 /6H, d/, 3.56 /1H, m,/, 5.29 /1H, D./, 5.43 /1H, D./, 6.36 /1H, s/, 7.30-8.10 /5H, m/

and the connection 134 (5-ISO-propylgallate-3-(3-trifluoromethyl)phenyl-4-thiazolidinone-S-oxide):

1H NMR /CDCl3/d6-DMCO/: 1,19 /6H, 2 days/, 3,76 /1H, m,/, 4,82 /1H, D. /, 5,27 /1H, D./, 6,51 /1H, s/, 7,53 - 7,69 /2H, m/, of 7.75-7,89 /2H, m,/, 7,95 /1H, m,/.

Example 34

Getting connection 138

5-tert-butylcarbamoyl-3-(3,5-bis(trifluoromethyl))phenyl-4-thiazolidinone

Using a procedure analogous to example 10, but using 5-hydroxy-3-(3,5-bis(trifluoromethyl))phenyl-4-thiazolidinone /received, as in preparative example 3 above/ /1.70 g/, tertbutylbenzene /0.51 g/, triethylamine /0.7 ml/ and dichloromethane /10 ml/ and recrystallization of the crude product from carbon tetrachloride was obtained target compound as a white solid, yield 1.90 g, so pl. 147 - 148oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,74 /1H, D./, 4,88 /1H, broad, S./, 5,11 /1H, D./, 6,20 /1H, s/, 7,78 /1H, s/, 8,05 /2H, S./.

Example 35

Polucheniya a solution of 5-hydroxy-3-(3,5-bis(trifluoromethyl))phenyl-4-thiazolidinone (received as in preparative example 3 above) /1.55 g/ triethylamine /0.68 oz/ in dichloromethane /10 ml/ processed by dimethylcarbamodithioato /0.50 g/. The mixture was mixed for 24 hours, then evaporated under reduced pressure. The residue was pulverized with a mixture of dichloromethane and hexane, the solid was filtered off. Evaporation of the filtrate under reduced pressure gave an oil, which was separated by chromatography on silica gel /elution with a mixture of chloroform and methanol/, gave the target compound in the form of resin, the yield of 0.41 g

1H NMR /CDCl3/ : 2,95 /6H, s/, 4,71 /1H, D./, 5,17 /1H, D./, to 6.19 /1H, s/, to 7.77 /1H, s/, 8,07 /2H, S./.

Example 36

Getting connection 159

5-(N,N-dimethyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2 above) /1,00 g/ pyridine /2 ml/ processed by dimethylcarbamodithioato /0,48 g/. After 20 minutes, water was added, and the mixture was extracted with diethyl ether. The ether layer was separated, washed with 2 M hydrochloric acid and brine, then dried /magnesium sulfate/. Evaporation of the solvent under reduced pressure gave the pitch, which OTDELENIE yellow solid. Rubbing with a mixture of diethyl ether and hexane gave the target compound as a pale yellow solid, yield of 0.60 g, so pl. 67-69oC.

1H NMR /CDCl3/: 2,94 /6H, s/, 4,68 /1H, D./, 5,10 /1H, DD,./, 6,21 /1H, D./, 7,50-7,60 /2H, m,/, 7,72-7,81 /2H, M./.

Example 37

The connection 166

5-ISO-propylgallate-3-phenyl-4-thiazolidinone

Stir a solution of 5-hydroxy-3-phenyl-4-thiazolidinone (obtained as in preparative example 17, above) /0.24 g/ triethylamine /0.01 ml/ chloroform /5 ml/ processed ISO-propositionem /0,116 g/. The mixture was mixed for 4 hours, then evaporated under reduced pressure. Recrystallization of the solid residue from a mixture of diethyl ether and hexane gave the target compound in the form of colorless needles, yield 0.14 g, so pl. 130-132oC.

1H NMR /CDCl3/: 1,18 /6H, d/, 3,82 /1H, m,/, 4,66 /1H, D./, 4,75 /1H, broad D./, 5,02 /1H, DD,./, to 6.22 /1H, D./, 7,29 /1H, m,/, 7,39-7,51 /4H, m /.

Example 38

Getting connection 171

5-(N-(1,1-dimethyl)-2-PROPYNYL)carbamoylated-3-(3-trifluoromethyl) phenyl-4-thiazolidinone

Mix a solution of phosgene in toluene /1,93 M, of 7.25 ml/ was cooled in an ice bath and slowly treated with solutions of 1-amino-1,1-dimethyl-2-propene /1,00 g/ in diety is hladini, then the organic layer was separated and passed through phase separating paper for drying. The infrared spectrum showed the presence of isocyanate in the solution /2200 cm-1/. To this solution was added 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as in preparative example 2 above) /0.10 g/ triethylamine /1.0 ml/, and the mixture was left to stand for 18 hours before it was evaporated to dryness under reduced pressure. The residue was pulverized with a mixture of ethyl acetate and hexane, and the solid substance was filtered off. The filtrate was evaporated under reduced pressure and the remaining mixture was separated by chromatography on silica gel /elution with a mixture of ethyl acetate/hexane/, giving the target compound as a white solid, yield 0.10 g, so pl. 97-99oC.

1H NMR /CDCl3/: 1,63 /6H, s/, 1,37 /1H, s/, 4,69 /1H, D./, of 5.05 /1H, D. /, a total of 5.21 /1H, broad, S./, 6,24 /1H, s/, 7,51-7,60 /2H, m,/, 7,70-7,78 /2H, M./.

Example 39

Getting connection 174

5-(N-1-cyano-1-methyl)ethyl)carbamoylated-3-(3-trifluoromethyl) phenyl-4-thiazolidinone

Using a procedure similar to that described in example 38, but using alpha aminoisobutyrate /1,00 g/ instead of 1-amino-1,1-dimethyl-2-propene, could target the soy /6H, C./, 4,71 /1H, D./, 5,09 /1H, D./, lower than the 5.37 /1H, broad, S./, 6,27 /1H, s/, 7,51-7,62 /2H, m/, to 7.68-7,79 /2H, M./.

MS: m/e 373 /M+/

Example 40

Getting connection 178

5-(N-(1-cyano)cyclopentyl)carbamoylated-3-(3-trifluoromethyl) phenyl-4-thiazolidinone

Using a procedure similar to that described in example 38, but using 1-amino-1-cyano-cyclopentane /1,00 g/ instead of 1-amino-1,1-dimethyl-2-propene, was the target compound, the yield of 0.18 g

1H NMR /CDCl3/: 1,75-1,92 /4H, m/, 2,02-2,18 /2H, m,/, 2,27-2,43 /2H, m,/, 4,69 /1H, D./, 5,09 /1H, m,/, 5,24 /1H, broad, S./, 6,26 /1H, s/, 7,52-to 7.61 /2H, m/, to 7.68-7,78 /2H, M./.

Example 41

Getting connection 197

3-(4-fluoro-3-trifluoromethyl)phenyl-5-ISO-propylgallate-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(4-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone /received, as in preparative example 18 above/ /2,00 g/ ISO-propositionthe /0.64 g/, triethylamine /1.0 ml/ and dichloromethane /25 ml/ and recrystallization of the crude product from a mixture of carbon tetrachloride and chloroform were obtained target compound in the form of colorless crystals, yield 2.15 g, so pl. 186-188oC.

1H NMR /CDCl3/: 1,19 /6H, d/, 3,82 /1H, m,/, br4.61 /1H, D./, 4,73 /1H, broad d is urbanology-3-(4-fluoro-3-trifluoromethyl)phenyl-4 - thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(4-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 18 above/ /2,00 g/, tertbutylbenzene /0.75 g/, triethylamine /1.0 ml/ and dichloromethane /25 ml/ and recrystallization of the crude product from a mixture of carbon tetrachloride and hexane were obtained target compound in the form of white crystals, yield 2.20 g, so pl. 116 - 118oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 4,65 /1H, D./, 4,88 /1H, broad, S./, 4,99 /1H, D./, 6,18 /1H, s/, 7,28 /1H, m,/, 7,65-7,76 /2H, M./.

Example 43

Getting connection 211

3-(3-pentafluoroethyl)phenyl-5-isopropylcarbamate-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3-pentafluoroethyl)phenyl-5-hydroxy-4-thiazolidinone /received, as in preparative example 19 above/ /0,42 g/ ISO-propositionthe /0.16 g/, triethylamine /0.1 ml/ and dichloromethane /10 ml/ and trituration of the crude product with diethyl ether was obtained target compound as white solid crystalline substances, yield 0.36 g, so pl. 171-173oC.

1H NMR /CDCl3/: 1,19 /6H, d/, 3,83 /1H, m, 4,70 /1H, D./, 4,74 /1H, broad D./, 5,07 /1H, D./, 6,20 /1H, s/, 7,55 /1H, m,/, 7,63-7,7 who alsultany)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(3-Pentafluoroethane)phenyl-5-hydroxy-4-thiazolidinone /obtained as described in preparative example 19/ /0,42 g/, tert-utilizationof /0.16 g/, triethylamine /0.1 ml/ and dichloromethane /10 ml/ and recrystallization of the crude product from a mixture of ethyl acetate and hexane were obtained target compound as a white crystalline solid, yield 0.34 g, so pl. 131 - 133oC.

1H NMR /CDCl3/: 1,31 /9H, c./, 4,69 /1H, d/, 4,86 /1H, broad, S./, 5,04 /1H, D./, 6,20 /1H, s/, 7,55 /1H, m/, of 7.64-7,72 /2H, m,/, 7,92 /1H. m/.

Example 45

Getting connection 220

3-(3-trifluoromethyl)phenyl-5-(N-(1,1-dimethyl)-2-butynyl) carbamoylated-4-thiazolidinone

Stir a suspension of 1-amino-1,1-dimethyl-2-butyn-hydrochloride /0.84 g/ in a solution of phosgene in toluene /12.5% wt./volume, 10 ml/ was treated with triethylamine /1,83 ml/, and the resulting mixture was heated under conditions of reflux distilled for 2 hours, then cooled. Was added a solution of 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2) /1,65 g/ toluene /54/ ml, and the mixture is stirred at room temperature for 3 days. The solution was extracted with water, then suspect diethyl ether and hexane, followed by crystallization from hexane gave the target compound as a white solid crystalline substances, the output of 0.07 g

1H NMR /CDCl3/: 1,58 /6H, c./, 1,80 /3H, s/, 4,69 /1H, D./, 5,06 /1H, D. /, 5,13 /1H, broad, S./, 6,23 /1H, s/, 7,50-7,60 /2H, m,/, 7,71-7,79 /2N, m/.

Example 46

Getting connection 221

5-tert-butylcarbamoyl-3-(2-fluoro-3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(2-fluoro-3-trifluoromethyl)phenyl-5-hydroxy-4-thiazolidinone (obtained as described in preparative example 20 above) /4,00 g/, tert-utilizationof /1,41 g/, triethylamine /1,43 g/ and dichloromethane /60 ml/ and trituration of the crude product with a mixture of diethyl ether and hexane were obtained target compound in the form of white crystals, yield 4,70 g, so pl. 136-137oC.

1H NMR /CDCl3/: 1,32 /9H, c./, 4,59 /1H, D./, 4,92 /2H, D. + wide with./, 6,18 /1H, s/, 7,33 /1H, m,/, 7,58-7,69 /2H, M./.

Example 47

Getting connection 227

5-tert-butylcarbamoyl-2-phenyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-2-phenyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example 21/ /36 ml/, tert-utilizationof /11 mg/ triethylamine /0.01 ml/ and dichloromethane /5 ml/ and purification of the crude produktlinie in the form of a mixture of diastereoisomers.

1H NMR /CDCl3/: the main diastereoisomer 1,33 /9H, s/, 4,95 /1H, broad, S./, 6,00 /1H, s/, of 6.49 /1H, s/, 7,22-7,35 /5H, m/, 7,35-7,50 /4H, m /; a secondary diastereoisomer 1,30 /9H, s/, 4,89 /1H, broad, S./, 6,27 /1H, s/, 6,38 /1H, s/, 7,22-7,35 /5H, m/, 7,35-7,50 /4H, m/.

Example 48

Getting connection 231

5-tert-butylcarbamoyl-3-(4-chloro-3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 3-(4-chloro-3-tripometer)phenyl-5-hydroxy-3-thiazolidinone (obtained as described in preparative example 22 above) /2,00 g/, tert-utilizationof /0,66 g/, triethylamine /0,93/ ml and dichloromethane /20 ml/ and recrystallization of the crude product from a mixture of ethyl acetate and hexane were obtained target compound in the form of white crystals, yield 1.90 g, so pl. 141-143oC.

1H NMR /CDCl3/: 1,31 /9H, s/, 4,65 /1H, D./, 4,89 /1H, broad, S./, 5,02 /1H, D./, to 6.19 /1H, s/, 7,56 /1H, D./, 7,69 /1H, DD,./, 7,84 /1H, D./.

Example 49

Getting connection 233

5-methyl-5-ISO-propylgallate-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-5-methyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example ewu chromatography on silica gel was obtained target compound as a white solid, yield 0.28 g, so pl. 77-83oC.

1H NMR /CDCl3/: 1,16 /6H, d/, 1,91 /3H, s/, 3,78 /1H, m,/, 4,58 /1H, D./, 4,72 /1H, broad D./, 5,07 /1H, D./, 7,49-7,58 /2H, m, 7.68 per-7,80 /2H, M./.

Example 50

Getting connection 241

5-tert-butylcarbamoyl-3-(2-methoxy)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(2-methoxy)phenyl-thiazolidinone /obtained as described above in preparative example 24/ /0,29 g/, tert-utilizationof /0,13 g/, triethylamine /0,18/ ml and dichloromethane /10 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane was obtained target compound in the form of a colourless resin, which contained ethyl acetate, the yield of 0.40 g

1H NMR /CDCl3/: 1,34 /9H, s/, 3,85 /3H, s/, 4,57 /1H, DD,./, 4,81 /1H, D. /, 4,92 /1H, broad, S./, 6,21 /1H, D./, 6,94-7,05 /2H, m,/, 7,26 /1H, m, 7,37 /1H, m,/.

Example 51

Getting connection 248 and 249

Diastereoisomer 5-((S)--methylbenzyl)carbamoylated-3-(3-trifluoromethyl)-phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described in preparative example 2, above/ /0,975 g/, /S/-alpha MSMEs of diastereoisomers. Fractional crystallization of the crude mixture of products from ethanol /x 2/ gave one diastereoisomer /Connection 248/ clean output 0,140 g, so pl. 178 - 179oC.

1H NMR /CDCl3/: 1,53 /3H, d/, 4,68 /1H, D./, 4,88 /1H, m/, of 5.05 /1H, D./, 5,19 /1H, broad D./, 6,25 /1H, s/, 7,21 - 7,40 /5H, m/, 7,51 - 7,60 /2H, m/, to 7.68 - 7,78 /2H, M./.

Recrystallization of the substances remaining in the uterine fluids, in the above-mentioned procedures crystallization from a mixture of ethyl acetate and hexane gave 1:1 mixture of diastereoisomers /Connection 248 and 249, release 0,150 g, so pl. 148 - 151oC.

1H NMR /CDCl3/ /Connection 249 only/ 1,55 /3H, d/, 4,68 /1H, D./, 4,88 /1H, m,/, 5,08 /1H, D./, 5,20 /1H, broad/, 6,18 /1H, s/, 7,21 - 7,40 /5H, m/, 7,51 - 7,60 /2H, m/, to 7.68 - 7,78 /2H, M./.

Example 52

Getting connection 255 and 256

Diastereoisomer 5-((R)-alpha-methylbenzyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in example 10, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example 2/ /2,00 g/, /R/-alpha methylbenzenesulfonate /1,10 ml/ triethylamine /0.10 ml/ and dichloromethane /25 ml, was obtained target compound in the form of a 3:2 mixture of diastereoisomers. Fractional Cree is g, so pl. 176 - 179oC.

1H NMR /CDCl3/: 1.52m /3H, d/, 4,68 /1H, D./, 4,88 /1H, m/, of 5.05 /1H, D./, 5,20 /1H, broad D./, 6,25 /1H, s/, 7,21 - 7,40 /5H, m/, 7,51 - 7,60 /2H, m/, to 7.68 - 7,78 /2H, M./.

Recrystallization of the material remaining in the uterine fluids from the above kristallizatsii from a mixture of ethyl acetate and hexane, gave a 1:1 mixture of diastereoisomers /connection 255 and 256, the output 0,163 g, so pl. 148 - 151oC.

1H NMR /CDCl3/: /the only connection 256/ 1,55 /3H, d/, 4,68 /1H, D./, 4,88 /1H, m,/, 5,07 /1H, D./, 5,18 /1H, broad/, 6,18 /1H, s/, 7,21 - 7,40 /5H, m/, 7,51 - 7,60 /2H, m/, to 7.68 - 7,78 /2H, M./.

Example 53

Getting connection 260

5-(3-morpholino)carbonyloxy-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone

Using a procedure similar to that described in example 35, but using 5-hydroxy-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example 2 above/ /0,100 g/, morpholinosydnonimine /0,057 g/, triethylamine /by 0.055 ml and dichloromethane /10 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate and hexane were obtained target compound, output, 0,092

1H NMR /CDCl3/: 3,45 - 3,56 /4H, m/, of 3.60 - 3.72 points /4H, m/, 4,69 /1H, D./, 5,09 /1H, D./, 6,22 /1H, s/, 7,50 - to 7.61 /2H, m,/, 7,70 - 7,81 /2H, M. /.

1H NMR /CDCl3/: 3,47 - 3,69 /4H, m/, 4,69 /1H, D./, 5,08 /1H, D./, 5,32 /1H, broad so/, 6,23 /1H, s/, 7,50 - 7,60 /2H, m,/, 7,69 - 7,80 /2H, M./.

Example 55

Getting connection 270

5-(4-(2,6-dichloropyridine)amino)carbonyloxy-3-(3-trifluoromethyl) phenyl-4-thiazolidinone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /obtained as described above in preparative example 2/ /0,100 g/, 4-(2,6-dichloro)pyridylacetate /0,072 g/, triethylamine /0,056 ml/ chloroform /10 ml/ as solvent and purification of the crude product through chromatography on silica gel with elution with mixtures of diethyl ether was obtained target compound, output 0,035 g

1H NMR /CDCl3/: 4,77 /1H, D./, 5,13 /1H, DD,./, 6,30 /1H, D./, 7,17 /1H, broad, S./, 7,33 /2H, S./, 7,56 - to 7.67 /2H, m,/, 7,72 - 7,80 /2H, M./.

Preliminan

Mix a solution of compound 171 /0,150 g/ ethyl acetate /10 ml/ processed poisoned by lead 5% palladium catalyst on a calcium carbonate /0.015 g/, and the mixture was gerasoulis within 4 hours.

Added additional amount of 0.015 g/ catalyst, and the mixture was then gerasoulis for an additional 5 hours. The mixture was filtered through celite, and the filtrate was evaporated under reduced pressure, giving the target compound in the form of resin, which crystallized upon standing, the output 0,090 g, so pl. 106 - 108oC.

1H NMR /CDCl3/: 1,42 /6H, s/, 4,69 /2H, D./, 4,92 - to 5.21 /4H, m/, 5,95 /1H, DD,./, 6,21 /1H, s/, 7,51 - 7,60 /2H, m,/, 7,69 - 7,80 /2H, M./.

MS: m/e 374 /M+/

Example 57

Getting connection 278

5-(N-(diphenylmethyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4 - thiazolidinone

Using a procedure similar to that described in example 38, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone /received, as in preparative example 2 above/ /0,109 g/, triethylamine /0,20 ml/ and isocyanate obtained on the spot from diphenylethylamine /1,00 g/, phosgene in toluene /1,93 M, 3,21 ml/, diethyl ether /5 ml and aqueous sodium hydroxide /to 0.480 g in 10 ml/ and purification of the crude product by chromatography on SIO substances, output 0,058 g, so pl. 170 - 172oC.

1H NMR /CDCl3/: 4,69 /1H, D./, 5,07 /1H, D./, 5,55 /1H, broad D./, 5,96 /1H, D./, 6,24 /1H, D./, 7,15 - 7,39 /10H, m/, 7,51 - to 7.59 /2H, m/, to 7.67 - to 7.77 /2H, M./.

Example 58

Getting connection 281

5-tert-butylcarbamoyl-3-(3-nitro)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-nitro)phenyl-4-thiazolidinone /obtained as described in preparative example 25, above/ /1,7088 g/ suspenderbelt in dry dichloromethane /30 ml and stirred at room temperature. Was added triethylamine /1 ml, and then, dropwise, tert-utilitzant /0,812 ml/. The suspension gradually passed into the solution, and stirring is continued for 4 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with 2 M hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer was dried /magnesium sulfate/ and evaporated under reduced pressure, giving a yellow solid /2,268 g/. This material was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /3:7 as eluent. The target compound was obtained as yellow solid, yield 2,176 g, so pl. 157 - 158oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,72 /2H, D./, 4,89 /1H, the program 282

5-tert-butylcarbamoyl-3-(3-cyano)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-cyano)phenyl-4-thiazolidinone /obtained as described in preparative example 26, above/ /1,62 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /15 ml/ triethylamine /1,02 ml/ and tert-utilizationof /0,84 ml/. The crude product was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /3:7 as eluent. The target compound was obtained in the form of solids, yield 2.20 g, so pl. 149 - 151oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,68 /1H, D./, 4,89 /1H, broad, S./, 5,06 /1H, D./, 6,20 /1H, s/, 7,58 /2H, m,/, 7,80 /1H, m,/, 7,88 /1H, s/.

Example 60

Getting connection 285

5-tert-butylcarbamoyl-3-(3-fluoro)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-fluoro)phenyl-4-thiazolidinone /obtained as described in preparative example 27 above/ /0,42 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /4 ml/ triethylamine /0,274 ml/ and tert-utilizationof /0,225 ml/. The crude product was purified using chromatography on silica gel using ethyl acetate and hexane /1:4 as eluent. Relevar /CDCl3/: 1,33 /9H, s/, 4,66 /1H, D./, 4,87 /1H, broad, S./, 5,02 /1H, DD,./, 6,20 /1H, broad, S./, 6,99 /1H, dt./, 7,22 - 7,45 /3H, m/.

Example 61

The connection 301

5-tert-butylcarbamoyl-3-(3-(1,1,2,2-tetrafluoroethoxy)) phenyl-4-thiazolidinone

5-Hydroxy-3-(3-(1,1,2,2-tetrafluoroethoxy))phenyl-4-thiazolidinone /obtained as described in preparative example 28, above,/ /1,9 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /20 ml/ triethylamine /0,85 ml/ and tert-utilizationof /0,70/ ml. The crude product was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /1:4 as eluent. The target connection /2,063 g/ was obtained as a white solid, which was further purified through recrystallization from a mixture of ethyl acetate and hexane, yielding white crystals, yield 1,338 g, so pl. 74 - 75oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 4,68 /1H, D./, a 4.86 /1H, broad, S./, 5,03 /1H, D./, of 5.92 /1H, TT/, 6,21 /1H, s/, 7,15 /1H, m,/, 7,46 /3H, m/.

Example 62

Getting connection 307

5-tert-butylcarbamoyl-3-(3-amino)phenyl-4-thiazolidinone

5-Tert-Butylcarbamoyl-3-(3-nitro)phenyl-4-thiazolidinone /obtained as described in example 58, above/ nergeco in an atmosphere of hydrogen overnight, and the catalyst was then removed by filtration through celite. After removal of the solvent under reduced pressure the residue was re-dissolved in ethyl acetate /25 ml and was injected fresh 5% palladium on coal /0.25 g/. The hydrogenation was continued for 72 hours, and the catalyst was again removed by filtration through celite. The solvent was removed under reduced pressure, giving solid /1,166 g/. This substance was precrystallization from a mixture of ethyl acetate and hexane, yielding the target compound in the form of solids, the output 0,488 g, so pl. 134 - 136oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 3,80 /2H, broad, S./, 4,63 /1H, D./, 4,85 - 5,0 /2H, m,/, 6,20 /1H, s/, 6,60 /1H, DD,./, 6,75 /1H, DD,./, 6,9 /1H, T./, 7,18 /1H, T./.

Example 63

Getting connection 316

5-tert-butylcarbamoyl-3-(3-methyl)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-methyl)phenyl-4-thiazolidinone /obtained as described in preparative example 29 above/ /0,300 g/ dissolved in dry dichloromethane /5 ml and stirred at room temperature under nitrogen atmosphere. Was added triethylamine /0,220 ml/, and then, dropwise, tert-utilitzant /0,180 ml/. The mixture is stirred at room temperature for about 72 hours and then was diluted with dichloromethane. This is the solution. The organic layer was dried /sodium sulfate/ and evaporated under reduced pressure giving the crude product /0,401 g/. This substance was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /3:7 as eluent, giving a white semi-solid substance /0,357 g/, which was precrystallization from a mixture of ethyl acetate and hexane. Was the target compound as a white solid, yield 0,300 g, so pl. 141 - 142oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 2,38 /3H, s/, 4,66 /1H, D./, 4,89 /1H, broad, S. /, equal to 4.97 /1H, D./, 6,21 /1H, s/, 7,11 /1H, D./, 7,20 was 7.36 /3H, m/.

Example 64

Getting connection 318

5-tert-butylcarbamoyl-3-(3-N, N-(biomethanation)amino) phenyl-4-thiazolidinone

5-tert-butylcarbamoyl-3-(3-amino)phenyl-4-thiazolidinone /obtained as described above in example 62/ /0,3447 g/ dissolved in dichloromethane /5 ml and stirred at room temperature under nitrogen atmosphere. Was added triethylamine /0,194 ml/ and methanesulfonanilide /0,095/ ml, and the reaction mixture stirred at room temperature for 72 hours. Added additional portion of triethylamine /0,194 ml/ methanesulfonanilide /0,095 ml/, and, after 1 hour, the reaction mixture was diluted with dichloromethane and about the content of inorganic fillers layer was dried /sodium sulfate/ and evaporated, giving a yellow solid /0,464 g/. This substance was chromatographically on silica gel using a mixture of ethyl acetate-hexane /2: 3 as eluent, yielding the target compound, the output 0,236 g, which had:

1H NMR /CDCl3/: 1,33 /9H, c./, 3,44 /6H, c./, 4,72 /1H, D./, a 4.86 /1H, broad, S. /, 5,06 /1H, D./, 6,22 /1H, s/, 7,28 /1H, m,/, 7,53 /2H, m/, to 7.77 /1H, s/.

MS: m/e 465 /M+/

Example 65

Getting connection 321

5-tert-butylcarbamoyl-3-(3-methoxy)phenyl-4-thiazolidinone

5-hydroxy-3-(3-methoxy)phenyl-4-thiazolidinone /obtained as described in preparative example 30/ /0,350 g/ turned into a target compound using a procedure analogous to the procedure described in example 58 using dichloromethane /5 ml/ triethylamine /0,26/ ml and tert-utilizationof /of € 0.195 ml/. The crude product /0.45 g/ was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /3:7/, giving the foam /0,389 g/, which in turn was purified on silica gel using methanol-dichloromethane /0,5:99,5/. The target compound was obtained as a hygroscopic white solid, yield 0,227,

1H NMR /CDCl3/: 1,33 /9H, s/, 3,82 /3H, s/, 4,67 /1H, D./, 4,85 - 4,95 /1H, broad, S. /, 4,99 /1H, D./, 6,21 /1H, s/, 6,84 /1H, DD/, 7,00 /1H, DD,./, 7,12 /1H is boloxi-3-(3-methoxycarbonyl)phenyl-4 - thiazolidinone

5-Hydroxy-3-(3-methoxycarbonyl)phenyl-4-thiazolidinone (obtained as described in preparative example 31 above) /2,258 g/ turned into a target compound using procedures similar to those described in example 58 using dichloromethane /35 ml/ triethylamine /1,37 ml/ and tert-utilizationof /1,12 ml/. The crude product was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /1:3/. The target compound was obtained as a white solid, yield 2,881 g, so pl. 123 - 125oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 3,93 /3H, s/, 4,70 /1H, D./, 4,90 /1H, broad, S./, 5,07 /1H, d/, 6,22 /1H,, 7,52 /1H, T./, 7,83 /1H, DD,./, 7,97 /1H, DD/, 8,0 /1H, m,/.

Example 67

Getting connection 328

5-tert-butylcarbamoyl-3-(3-bromo)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-bromo)phenyl-4-thiazolidinone (obtained as described in preparative example 32) /0,964 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /10 ml/ triethylamine /of 0.48 ml/ and tert-utilizationof /0,39 ml/. The crude product was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /2:4 as eluent, giving a solid residue /1.07 g/. This substance is in Evoe compound as a white powdery solid, the output of 0.83 g, so pl. 153 - 155oC.

1H NMR /CDCl3/: 1,33 /9H, s/, with 4.64 /1H, D./, 4,85 /1H, broad, S./, 5,00 /1H, D./, to 6.19 /1H, s/, 7,30 /1H, T./, 7,45 /2H, m,/, 7,69 /1H, T./.

Example 68

Getting connection 331

5-tert-butylcarbamoyl-3-(3-iodine)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-iodine)phenyl-4-thiazolidinone (obtained as described in preparative example 33) /1.68 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /15 ml/ triethylamine /0,73/ ml and tert-utilizationof /a 0.59 ml/. The crude product was purified using chromatography on silica gel using a mixture of ethyl acetate: hexane /1:4/, giving the target compound in the form of solids, yield 1.2 g, so pl. 161 - 162,5oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,62 /1H, D./, 4,85 /1H, broad, S./, 4,98 /1H, D./, to 6.19 /1H, s/, 7,16 /1H, DD,./, 7,49 /1H, DD,./, 7,63 /1H, D./, 7,84 /1H, m,/.

Example 69

The connection 336

5-tert-butylcarbamoyl-3-(3-phenoxy)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-phenoxy)phenyl-4-thiazolidinone /obtained as described above in preparative example 34/ /0,255 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /likehere using a mixture of ethyl acetate/hexane /1:4 as eluent, giving a sticky orange solid. This substance was precrystallization from a mixture of ethyl acetate-hexane, giving the target compound as a white solid, yield of € 0.195 g, so pl. 131 - 132oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,63 /1H, D./, 4,80 - 4,95 /1H, broad, S./, 4,98 /1H, D./, 6,20 /1H, s/, 6,92 /1H, DD,./, 7,00-7,42 /8H, m/.

Example 70

Getting connection 337

5-tert-butylcarbamoyl-3-phenyl-4-thiazolidinone

5-hydroxy-3-phenyl-4-thiazolidinone (obtained as described in preparative example 17) /0,095 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /2 ml/ triethylamine /0,068 ml/ and tert-utilizationof /0,056 ml/. The crude product was purified using chromatography on silica gel using a mixture of ethyl acetate: hexane /1:4 as eluent. The target compound was further purified through recrystallization from a mixture of ethyl acetate and hexane /2 x/ /0,065 g/, so pl. 146 - 148oC /but yet polluted 9% di-tert-butylacetyl/.

1H NMR /CDCl3/: by the way 1,33 /9H, s/, 4,67 /1H, D./, 4,88 /1H, broad, S./, 5,01 /1H, D./, 6,22 /1H, s/, 7,28 /1H, m,/, 7,45 /4H, m/.

MS: m/e 294 /M+/

Example 71

Getting connection 339
oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 2,08 /3H, s/, 4,62 /1H, D./, 4,78 /1H, broad, S./, equal to 4.97 /1H, D./, of 5.05 /1H, broad, S./, 6,22 /1H, s/, 7,11 /1H, m,/, 7,30 /2H, m,/, 7,75 /1H, broad, S./, 7,98 /1H, broad, S./.

Example 72

Getting connection 340

5-tert-butylcarbamoyl-3-(3-methanesulfonyl)phenyl-4-thiazolidinone

5-hydroxy-3-(3-methanesulfonyl)-4-thiazolidinone (polu, similar to that described in example 58, using dichloromethane /17 ml/ triethylamine /0,38 ml/ and tert-utilizationof /0,31 ml/. The crude product /0,917 g/ purified on silica gel using a mixture of ethyl acetate: hexane /1:1/ as eluent. The target compound was obtained as a white solid, yield 0,845 g, and had:

1H NMR /CDCl3/: / 1,33 /9H, s/, is 3.08 /3H, s/, 4,72 /1H, D./, 4,87 /1H, broad, S./, 5,09 /1H, D./, 6,21 /1H, s/, 7,66 /1H, T./, 7,88 /2H, m,/, 8,04 /1H, m,/.

MS: m/e 372 /M+/

Example 73

Getting connection 341

5-tert-butylcarbamoyl-3-(3,4,5-trichloro)phenyl-4-thiazolidinone

5-Hydroxy-3-(3,4,5-trichloro)phenyl-4-thiazolidinone (obtained as described in preparative example 36) /1.2 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /20 ml/ triethylamine /0.6 ml/ and tert-utilizationof /of 0.48 ml/. The crude product /1,57 g/ was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /15:85 to 20:80/ as eluent, giving an orange solid /1.35 g/. This substance is, in turn, was further purified through recrystallization from a mixture of ethyl acetate-hexane, giving the target compound as a pale pink with./, 4,99 /1H, D./, 6,16 /1H, s/, of 7.64 /2H, S./.

Example 74

The connection 342

5-tert-butylcarbamoyl-3-(3-methylthio)phenyl-4-thiazolidinone

5-Hydroxy-3-(3-methylthio)phenyl-4-thiazolidinone (obtained as described in preparative example 37) /0,578 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /20 ml/ triethylamine /0,37 ml/ and tert-utilizationof /0,30 ml/. The crude product /0,765 g/ chromatographically on silica gel using a mixture of ethyl acetate: hexane /1:3 as eluent, but the substance still contained some impurities, and the sample was re-chromatographically using a mixture of ethyl acetate and hexane /18:88/. This procedure gave a yellow-white solid /0,42 g/, which was precrystallization from a mixture of ethyl acetate and hexane. The target compound was obtained as white needles, yield 0.32 g, so pl. 144,2-146,2oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 2,50 /3H, s/, 4,65 /1H, D./, 4,88 /1H, broad, S./, 5,00 /1H, D./, 6,21 /1H, s/, 7,15 - 7,42 /4H, m/.

Example 75

Getting connection 344

5-tert-butylcarbamoyl-3-(3-triptoreline)phenyl-4-thiazolidinone

5-hydroxy-3-(3-triptoreline)phenyl-4-thiazolidinone (is Edery, similar to that described in example 58, using dichloromethane /70 ml/ triethylamine /1,48 ml/ and tert-utilizationof /1,21 ml/. The crude product /3,483 g/ purified on silica gel using mixtures of ethyl acetate and hexane /20:80/ as eluent. The obtained pale yellow solid was further purified through recrystallization from a mixture of ethyl acetate and hexane, yielding the target compound as a white solid, yield 2,62 g, so pl. 103 - 105oC.

1H NMR /CDCl3/: 1,33 /9H, s/, 4,68 /1H, D./, 4,87 /1H, broad, S./, 5,03 /1H, D./, 6,21 /1H, s/, 7,15 /1H, m,/, 7,47 /3H, m/.

Example 76

Getting connection 346

5-tert-butylcarbamoyl-3-(3-methoxy-5-trifluoromethyl)phenyl-4 - thiazolidinone

5-Hydroxy-3-(3-methoxy-5-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 39 above) /2,49 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /25 ml/ triethylamine /1.25 ml/ and tert-utilizationof /1,02 ml/. The crude product /3,521 g/ was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /1:4 to 3:7 as eluent, giving a white solid /3.0 g/. This substance is, in turn,solid substances, output 2,673 g, so pl. 111 - 112oC.

1H NMR /CDCl3/: 1,33 /9H, s/, a 3.87 /3H, s/, 4,69 /1H, D./, 4,89 /1H, broad, S. /, 5,04 /1H, D./, 6,21 /1H, s/, 7,05 /1H, s/, 7,29 /1H, s/, 7,38 /1H, s/.

Example 77

Getting connection 348

5-tert-butylcarbamoyl-3-(3-nitro-5-trifluoromethyl)phenyl-4 - thiazolidinone

5-Hydroxy-3-(3-nitro-5-trifluoromethyl)phenyl-4-thiazolidinone /received, as in preparative example 40 above/ /1,11 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /30 ml/ triethylamine /of 0.53 ml/ and tert-utilizationof /of 0.43 ml/. The crude product /1,43 g/ was purified using chromatography on silica gel using ethyl acetate-hexane /1:3 as eluent, giving a yellow-orange solid /1,17 g/. This substance is, in turn, was further purified through recrystallization from a mixture of ethyl acetate and hexane, yielding the target compound as a pale yellow solid, yield 0,437,

1H NMR /CDCl3/: 1,33 /9H, s/, 4,76 /1H, D./, 4,87 /1H, broad, S./, 5,16 /1H, D./, 6,20 /1H, s/, 8,31 /1H, s/, scored 8.38 /1H, s/, 8,61 /1H, m,/.

MS: m/e 408 /M++H/

Example 78

Getting connection 350

5-tert-butyl-3-(3-trifloromethyl)phenyl-4-thiazolidinone
<0,46 g/ turned into a target compound using the procedures similar to that described in example 58, using dichloromethane /10 ml/ triethylamine /of 0.21 ml/ and tert-utilizationof /0,17 ml/. The crude product /0.65 g/ was purified using chromatography on silica gel using mixtures of ethyl acetate and hexane /35:65/ as eluent. The target compound was obtained as a white solid, yield of 0.47 g

1H NMR /CDCl3/: 1,33 /9H, s/, 4,73 /1H, D./, 4,88 /1H, broad, S./, 5,12 /1H, D./, 6,21 /1H, s/, 7,76 /1H, T./, 7,94 /1H, D./, 8,12 /1H, s/, 8,18 /1H, D./.

MC: 427 /M++H/

Example 79

Obtaining compounds 359 and 360

(+)-5-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone and

(-)-5-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Racemic compound 26 (obtained as described in example 7) were divided into covalently linked D-phenylglycinol Pirkle column, with elution by the mixture hexane/tetrahydrofuran/acetonitrile /90:10:0,26/. The size of the column was 25 ml /length/ x 0,8 cm /diameter/, and the connection was separated in amounts of about 0.4 - 0.5 mg per cycle /only 75 cycles/. In this method, compound 359, /+/-5-tert-butylcarbamoyl-3-/3-trifluoromethyl/phenyl-4-thiazolidinone, was obtained as a white solid, yield of 14.0 mg, ()2D9= +1182D0= -71o/s = 0.12 g /100 ml; toluene/.

Example 80

Getting connection 361

3-tert-butylcarbamoyl-3-(3-trifluoromethyl)phenyl-2-pyrrolidinone

Stir a solution of 3-hydroxy-1-(3-trifluoromethyl)phenyl-2 - pyrrolidinone /obtained as described in preparative example 42 above/ /0,220 g/ dichloromethane /2 ml/ processed tert-utilitarianism /0,063 g/, then triethylamine /0,084 ml/. The solution was mixed for 24 hours, then evaporated under reduced pressure. Purification of the residue by chromatography on silica gel with elution with mixtures of ethyl acetate and hexane, gave the target compound in the form of a transparent resin, exit to 0.060 g

1H NMR /CDCl3/: 1,35 /9H, s/, 2,13 /1H, m,/, 2,73 /1H, m,/, 3,80 - 3,89 /2H, m,/, 4,94 /1H, broad, S./, 5,38 /1H, T./, 7,38 - 7,53 /2H, m,/, 7,89 - 7,95 /2H, M./.

Example 81

Getting connection 369

3-out-propylgallate-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone

Using a procedure similar to that described in example 80, using 3-hydroxy-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone (obtained as in preparative example 42 above) /of 0.085 g/ ISO-propositionthe /0,030 g/, triethylamine /0.01 ml/ and dichloromethane /1 localos target compound as white solid crystalline substances, output 0,095 g, so pl. 114 - 117oC.

1H NMR /CDCl3/: 1,19 /3H, d/ a, 1,20 /3H, d/ a, 2,18 /1H, m,/, 2,78 /1H, m/, of 3.77 - 3,93 /3H, m/, 4,79 /1H, broad D./, 5,41 /1H, T./, 7,40 - 7,58 /2H, m,/, 7,88 - of 7.96 /2H, M./.

Example 82

Getting connection 383

1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-ISO-propylgallate-2 - pyrrolidinone

Mix a solution of 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-hydroxy-2-pyrrolidinone (obtained as described above in preparative example 43) /0,500 g/ chloroform /5 ml/ was treated with triethylamine /0.25 ml/, and then ISO-propositionem /0,150 g/. The clear solution stirred at room temperature for 24 hours, and then was rapidly cooled with water and pagkilala 2 M hydrochloric acid. The organic phase was separated, washed with 2 M hydrochloric acid, dried /magnesium sulfate/ and evaporated under reduced pressure, giving a white solid. This substance was precrystallization from a mixture of chloroform and hexane, giving the target compound in the form of colorless needles, yield 0,507 g, so pl. 133 - 136oC.

1H NMR /CDCl3/: 1,18 /6H, d/, and 2.26 /1H, m,/, 2,79 /1H, m,/, 3,68 /1H, m,/, 3,75 - 3,92 /2H, m,/, 4,81 /1H, broad D./, the 5.45 /1H, dt./, 7,39 /1H, D./, to 7.59 /1H, s/.

Example 83

Getting connection 390

1-(2-chloro-6-FPO is Noah in example 82, but using 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-hydroxy-2 - pyrrolidinone (obtained as described in preparative example 43) /0,500 g/, tert-utilizationof /0,174 g/, triethylamine /0.25 ml/ chloroform /5 ml/ and recrystallization of the crude product from a mixture of chloroform and hexane were obtained target compound in the form of colorless crystals, yield 0,355 g, so pl. 134 - 137oC.

1H NMR /CDCl3/: 1,31 /9H, s/, 2,28 /1H, m,/, 2,79 /1H, m,/, 3,59 - 3,82 /2H, m,/, 4,92 /1H, broad, S./, 5,40 /1H, m,/, 7,39 /1H, D./, 7,58 /1H, s/.

Example 84

Getting connection 404

3-(N, N-dimethylamino)carbamoylated-1-(3-trifluoromethyl)phenyl-2 - pyrrolidinone

Stir a solution of 3-hydroxy-1-(3-trifluoromethyl)phenyl-2 - pyrrolidinone (obtained as described in preparative example 42) /0,175 g/ pyridine /1 ml/ processed by dimethylcarbamodithioato /0,084 g/. The mixture is stirred at room temperature for 24 hours, then was added 2 M hydrochloric acid. The emulsion was extracted with chloroform, and the extract was washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the resin. Purification via chromatography on silica gel, with elution with mixtures of chloroform and methanol gave the target is - ,92 /2H, m,/, 5,43 /1H, t/, 7,39 - 7,53 /2H, m,/, 7,88 - 7,98 /2H, m/.

Example 85

Getting connection 409

1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3-(N, N-dimethylamino) carbamoylated-2-pyrrolidinone

Mix a solution of 1-(2-chloro-6-fluoro-4-trifluoromethyl)phenyl-3 - hydroxy-2-pyrrolidinone (obtained as in preparative example 43 above), /0.400 g/ pyridine /2 ml/ was treated with sodium hydride /0,071 g of a 50% emulsion in oil/ and then dimethylcarbamodithioato /strength of 0.159 g/. The mixture is stirred at room temperature for 5 hours, then was added 2 M hydrochloric acid. The emulsion was extracted diethyl ether /x 2/, and the combined extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the resin. Purification via chromatography on silica gel with elution with mixtures of chloroform and methanol gave the target compound as a white solid, yield 0.104 g g, so pl. 121 - 122oC.

1H NMR /CDCl3/: 2,30 /1H, m,/, 2,75 /1H, m,/, 2,93 /3H, m/, 2,95 /3H, m/, to 3.58 - 3,85 /2H, m,/, 5,44 /1H, m,/, 7,38 /1H, D./, 7,58 /1H, s/.

Example 86

Getting connection 421

1-(3-trifluoromethyl)phenyl-3-(N-(1,1-dimethyl)-2-butynyl) carbamoylated-2-pyrrolidinone

Stir a solution of 3-hydroxy-g/ toluene /2 ml was treated with a solution of phosgene in toluene /0,65 ml of 12.5% weight/volume of solution, and the resulting suspension stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was treated with triethylamine /0.06 ml/, and then 1-amino-1,1-dimethyl-2-butyn-hydrochloride /0,41 g/. This mixture was mixed for 24 hours, then was added 2 M hydrochloric acid, and the organic phase was separated. The aqueous layer was further extracted with diethyl ether, and the combined organic phases were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the resin. Purification via chromatography on silica gel with elution with mixtures of ethyl acetate and hexane, and then with mixtures of chloroform and methanol, yielding the target compound, the yield of 0.004,

1H NMR /CDCl3/: 1,62 /6H, s/, 1,79 /3H, s/, 2,15 /1H, m,/, 3,76 /1H, m,/, 3,80 - 3,91 /2H, m,/, 5,19 /1H, broad, S./, 5,39 /1H, T./, 7,38 - 7,54 /2H, m/, the 7.85 - 7.95 is /2H, M./.

Example 87

Getting connection 448

Dihydro-2-tert-butylcarbamoyl-4-(3-trifluoromethyl)phenyl-4H - 1,4-oxazin-3/2H/he

Mix a solution of dihydro-2-hydroxy-4-(3-trifluoromethyl) phenyl-4H-1,4-oxazin-3/2H/she /received, as in preparative example 44 above/ /0,140 g/ dichloromethane /2 ml/ processed tert-utilitarianism /0,054 g/, and for. recristallization from a mixture of ethyl acetate and hexane gave the target compound as a white solid, yield 0,091 g, so pl. 160 - 162oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 3,59 /1H, m,/, 3,98 - 4,18 /2H, m,/, 4,35 /1H, m,/, 4,87 /1H, broad, S./, 6,18 /1H, s/, 7,52 - 7,60 /3H, m/, 7,65 /1H, m,/.

MS: m/e 360 /M+/

Example 88

Getting connection 508

Dihydro-2-tert-butylcarbamoyl-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/he

Dihydro-2-hydroxy-4-(3-trifluoromethyl)phenyl-4H-1,4-thiazin-3/2H/he

Dihydro-2-hydroxy-4-(3-tripometer)phenyl-4H-1,4-thiazin-3/2H/he /obtained as described above in preparative example 45/ /0,66 g/ turned into a target compound using procedures similar to those described in example 58, using dichloromethane /10 ml/ triethylamine /0.33 ml/ and tert-utilizationof /a 0.27 ml/. The crude product /0,877 g/ precrystallization from a mixture of ethyl acetate and hexane, yielding the target compound as white needles, yield 0,562 g, so pl. 113 - 114oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 3,11 /2H, m,/, 4,03 /1H, m,/, 4,27 /1H, m/, a 4.83 /1H, broad, S./, 6,23 /1H, s/, of 5.53 /4H, m/.

Example 89

Getting connection 561

3-tert-butylcarbamoyl-1-(3-trifluoromethyl)phenyl-2 - imidazolidinone

Stir a solution of 3-hydroxy-loretana /5 ml/ was treated with triethylamine /0,03 ml/, and then tert-utilitarianism /0,020 g/. The solution was mixed for 30 minutes and then were washed with 2 M hydrochloric acid, dried /magnesium sulfate/ and evaporated under reduced pressure, giving the target connection, exit to 0.060 g

1H NMR /CDCl3/: 1,37 /9H, s/, 3,78 - 3,85 /2H, m/, a 3.87 - 3,94 /2H, m,/, 5,10 /wide with./, 7,38 /1H, D./, 7,49 /1H, T./, 7,79 /1H, s/, 7,84 /1H, D./.

Example 90

The connection is 667

Tetrahydro-3-tert-butylcarbamoyl-1-(3-trifluoromethyl)phenyl - 2/1H/-pyrimidinone

Using a procedure similar to that described in example 89, but using tetrahydro-3-hydroxy-1-(3-trifluoromethyl)phenyl-2/1H/- pyrimidinone /obtained as described above in preparative example 47/ /0.075 g/, tert-utilizationof /0,029 g/, triethylamine /0,039/ ml and dichloromethane /54 ml/ and purification of the crude product through chromatography on silica gel with elution with mixtures of ethyl acetate and hexane were obtained target compound, the output 0,053 g, so pl. 156 - 158oC.

1H NMR /CDCl3/: 1,34 /9H, s/, 2,25 - 2,36 /2H, m,/, 3,72 - a 3.87 /4H, m/, 4,95 /1H, broad, S./, 7,38 - 7,56 /4H, m/.

Example 91

The connection is 700

3-tert-butylcarbamoyl-1-(3-trifluoromethyl)phenyl-2-piperidino

Stir a solution of 3-hydroxy-1-(3-cryptomaterial)phenyl-2 - piperidine and 1-(3-trifluoromethyl)phenyl-2-piperidino/ dichloromethane /10 ml/ processed tert-utilitarianism /0,094 g/ triethylamine /0,13 ml/. The solution was heated under reflux for 4 hours, and then cooled and left to stand for 16 hours. The solution was then evaporated under reduced pressure, and the residue was purified using chromatography on silica gel, with elution with mixtures of ethyl acetate and hexane, yielding the target compound in the form of a transparent resin, the output 0,124,

1H NMR /CDCl3/: 1,32 /9H, s/ a, 1,98 - 2,14 /3H, m/, 2,33 /1H, m,/, 3,65 /1H, m,/, 3,75 /1H, m,/, 4,85 /1H, broad, S./, from 5.29 /1H, m,/, 7,45 - 7,55 /4H, m/.

Example 92

Getting connection 796

Dihydro-6-tert-butylcarbamoyl-3-methyl-4-(3,5-bis (trifluoromethyl))phenyl-2H-1,3,4-thiadiazin-5/6H/he

Mix a solution of dihydro-6-hydroxy-3-methyl-4-(3,5-bis (trifluoromethyl))phenyl-2H-1,3,4-thiadiazin-5/6H//is it /is obtained as described above in preparative example 49 /0,037 g/ dichloromethane /1 ml/ was treated sequentially with triethylamine /of 0.013 ml/ and tert-utilitarianism /to 0.011 ml/. The solution was left to stand for 18 hours before he was evaporated under reduced pressure and dissolved in ethyl acetate /5 ml/. The solution was filtered 2M hydrochloric acid /2 x 10 ml, saturated solution of sodium bicarbonate /2 x 10 ml) and dried /magnesium sulfate/ and evaporated under reduced pressure, giving the target of the/, br4.61 /1H, D./, 4,82 /1H, D./, 6,18 /1H, s/, 7,03 /1H, broad, S./, 7,37 - 7,41 /2H, S./, of 7.48 - 7,51 /1H, s/.

MS: m/e/ 469 /M+/

Example 93

Getting connection 813

Dihydro-4-tert-butylcarbamoyl-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/he

Mix a solution of dihydro-4-hydroxy-2-(3-trifluoromethyl)phenyl-2H-1,2-oxazin-3/4H/is it /is obtained as described above in preparative example 50/ /0.26 g/ dichloromethane /5 ml/ processed sequentially dichlormethane solution of tert-utilizationof /0,099 g in 1 ml)/ triethylamine /0,101 g in 1 ml/. Throughout the night was a partial response. The mixture was left for 5 days, was carried out adding similar amounts of tert-utilizationof and triethylamine with daily intervals. The mixture was then evaporated under reduced pressure, diluted with water and ethyl acetate and was extracted several times with ethyl acetate. The combined extracts were washed with saline, dried /magnesium sulfate/ and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and N,N'-di-tert-butylation was precipitated with hexane and filtered. The filtrate was evaporated under reduced pressure, and the deposition procedure was repeated two more times, and then, finally, Kagel when elution with a mixture of ethyl acetate and hexane /1:4/, giving the target compound in the form of resin, which crystallized upon standing, the output 0,147 g, so pl. 83 - 84oC.

1H NMR /CDCl3/: 1,38 /9H, s/, 2,16 /1H, m,/, 4,28 /1H, m,/, 4,46 /1H, m,/, 5,00 /1H, s/, 5,68 /1H, DD,./, 7,46 /2H, D.+so/, 7,98 /C. + D./.

MS: m/e 360 /M+/

Example 94

The connection 353

5-tert-butylcarbamoyl-3-(3-1-ethoxyphenyl)phenyl-4-thiazolidinone

5-tert-Butylcarbamoyl-3-(3-iodine)phenyl-4-thiazolidinone /obtained as described in example 68/ /0,19 g/ dissolved in dry dimethylformamide /10 ml and stirred at room temperature under nitrogen atmosphere. To this solution was added alpha-ethoxyphenyl-tri-n-butylstannane /0,163 g/, and then bis/ triphenylphosphine/palladium/2/chloride /0.125 g/. The reaction mixture was heated in an oil tub /bath temperature 130oC/ within 4 hours. The heating bath was then removed and the reaction mixture was left to stand at room temperature over night. The mixture was then poured into 1 M aqueous solution of potassium fluoride /50 ml and was diluted in diethyl ether /30 ml/. The mixture is stirred at room temperature for 2 hours, and the precipitated solids were removed by filtration through celite. The organic layer was separated, and the aqueous phase extrag the om magnesium/ and evaporated under reduced pressure, giving the crude product /0.28 g/. This substance was chromatographically on silica gel /precautions: the product is quite unstable to undergo prolonged exposure of silica gel with a mixture of ethyl acetate/hexane /1:4 to 3:7 as eluent, yielding the target compound /0,042 g/, which had:

1H NMR /CDCl3/: 1,33 /9H, s/, 1,41 /3H, T./, 3,92 /2H, square/, 4,24 /1H, doctor/. 4,67 /2H, m,/, 4,90 /1H, broad, S./, 5,01 /1H, D./, 6,22 /1H, s /, 7,40 /2H, m,/, 7,56 /1H, m,/, 7,69 /1H, m,/.

Example 95

Getting connection 156

5-tert-Butylcarbamoyl-3-(3-acetyl)phenyl-4-thiazolidinone

5-tert-Butylcarbamoyl-3-(3-1-ethoxyphenyl))phenyl-4-thiazolidinone (obtained as described in example 94 above) /0.40 g/ dissolved in acetone /2 ml was mixed at room temperature. Was added 2 M hydrochloric acid /0.1 ml) and the mixture was mixed for 30 minutes. The solvent was removed under reduced pressure and the residue was distributed between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was extracted with additional portions of ethyl acetate /x 2/. United an ethyl acetate layers were washed with water, dried /magnesium sulfate/ and evaporated under reduced pressure giving a residue /0,039 g/. Given the enta, giving the target connection /0,020 g/, which had:

1H NMR /CDCl3/: 1,33 /9H, s/, 2,62 /3H, s/, 4,72 /1H, D./, 4,90 /1H, broad, S. /, 5,07 /1H, D./, 6,22 /1H, s/, 7,54 /1H, T./, 7,80 /1H, D./, 7,87 /1H, D./, 8,03 /1H, C./. MS: m/e 336 /M+/

Example 96

The connection 354

5-(N-1-substituted)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidone

Using a procedure similar to that described in example 10, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidone /received, as in preparative example 2, above/ /0,100 g/, 1-adamantylidene /0,067 g/, triethylamine /0,053 ml/ chloroform /10 ml/ and purification of the crude product through chromatography on silica gel with elution with a mixture of ethyl acetate/hexane was the target connection, the output 0,121 g/.

1H NMR /CDCl3/: 1,68 /6H, broad/, 1,94 /6H, broad/ 2,05 /3H, broad/, 4,71 /1H, D./, 4,78 /1H, broad, S./, 5,06 /1H, DD,./, to 6.19 /1H, D./, 7,55-to 7.61 /2H, m,/, 7,71-7,79 /2H, M./.

MS: m/e 440 /M+/

Example 97

Getting connection 319

5-(N-1-ethinyl)cyclohexyl)carbamoylated-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure similar to that described in example 38, but using phosgene in toluene /1,93 M, with 0.93 ml, 1-ethynylcyclohexanol /0,200 g/, diethyl ether /2 ml, of sodium hydroxide /0,14 the tive example 2/ /0.156 g/ triethylamine /0,278 ml/ and purification of the crude product through chromatography on silica gel was obtained target compound, output 0,181,

1H NMR /CDCl3/: 1,51-1,79 /7H, m/, 2,03-2,17 /2H, m,/, 2,42 /1H, s/, 4,69 /1H, d/, 5,04 /1H, broad, S./, 5,07 /1H, DD,./, 6,23 /1H, D./, 7,52-7,60 /2H, m,/, 7,70-7,80 /2H, M./.

MS: m/e 412 /M+/

Example 98

Getting connection 355

5-tert-Butylcarbamoyl-3-(3-(N, N-dibenzyl)sulphonamido)phenyl - 4-thiazolidinone

5-Hydroxy-3-(3-N,N-dibenzyl)sulphonamido)phenyl-4-thiazolidinone /obtained as described above in preparative example 51 /0,823 g/ turned into a target compound using procedures similar to those described in example 58 using dichloromethane /25 ml/ triethylamine /0,265 ml/ and tert-utilizationof /to 0.127 ml/. The crude product /0.95 g/ was purified using chromatography on silica gel using a mixture of ethyl acetate-hexane /3:7 as eluent. The target connection /0,745 g/ was obtained as a brittle white foam which had:

1H NMR /CDCl3/: 1,34 /9H, s/, 4,36 /4H, S./, 4,59 /1H, D./, 4,89 /12H, broad, S./, equal to 4.97 /1H, D./, 6,21 /1H, s,/, 7,09 /4H, m/, 7,22 /6H, m /, 7,55 /1H, T./, 7,72 /1H, D./, 7,81 /2H, M./.

Example 99

Getting connection 356

5-tert-butylcarbamoyl-3-(3-hydroxyamino-5-trifluoromethyl)phenyl - 4-thiazolidinone

5-tert-Butylcarbamoyl-3-(3-nitro-5-trifluoromethyl)phenyl - 4-thiazolidinone (obtained as described in example si stirred in hydrogen atmosphere for 5 hours /long processing in these conditions gives Amin, see example 100/. The catalyst was removed by filtration through celite, and the filter cake was well washed with ethyl acetate. The solvent was removed under reduced pressure, giving the target compound by essentially quantitative yield. A small number of samples /to 0.108 g/ selection and chromatographically on silica gel using mixtures of ethyl acetate and hexane /45:55/ as eluent. Could white solid which had:

1H NMR /CDCl3/: 1,33 /9H, s/, 4,68 /1H, D./, 4,88 /1H, broad, S./, 5,03 /1H, D./, 5,32 /1H, broad, S./, 6,20 /1H, s/, of 6.96 /1H, broad, S./, 7,14 /1H, s/, 7,22 /1H, s/, 7,42 /1H, s/.

FAB MS: 393 /MH+/

Example 100

Getting connection 357

5-tert-Butylcarbamoyl-3-(3-amino-3-trifluoromethyl)-4-thiazolidinone

5-tert-Butylcarbamoyl-3-(3-hydroxylamino-5-triptoreline)-4-thiazolidinone /obtained as in example 99/ /0,68 g/ dissolved in ethyl acetate /20 ml) was added 10% palladium on charcoal /0.4 g/. The reaction mixture is stirred in hydrogen atmosphere for 22 hours. NMR was found that there is source material, and the process was repeated after removal of the catalyst through celite, and the introduction of a fresh portion/ within 72 hours. The reaction was again incomplete, and p is hinnon pressure, giving the foam /0,579 g/, which contained approximately 10% of the unchanged starting material together with several other impurities. The target connection approximately 80% purity were:

1H NMR /CDCl3/: along with other 1,33 /9H, s/, 4,00 /2H, broad, S./, with 4.64 /1H, D. /, 4,91 /1H, broad, S./, 4,99 /1H, D./, 6,20 /1H, s/, 6,79 /1H, s/, of 6.96 /1H, s/, 7,12 /1H, s/.

Example 101

Getting connection 306

5-Cyclohexyloxycarbonyloxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Stir a solution of 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2) /0.50 g/ dichloromethane /15 ml/ was treated dropwise cyclohexylstyrene /of 0.28 ml/ triethylamine /of 0.28 ml/. The solution was mixed for 24 hours, after which was added additional cyclohexylstyrene /of 0.28 ml/ triethylamine /of 0.28 ml/. After 72 hours the solvent was removed under reduced pressure and the remaining mixture was separated by chromatography on silica gel /elution with a mixture of ethyl acetate and hexane/ followed by recrystallization from a mixture of ether and hexane, giving the target compound in the form of a very pale pink crystalline solid substance, yield 0.14 g, so pl. 132-132,5oC.

Example 102

Getting connection 358

5-isopropylidenedioxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone

Using a procedure analogous to the procedure described in example 101, but using 5-hydroxy-3-(3-trifluoromethyl)phenyl-4-thiazolidinone (obtained as described in preparative example 2), isopropylethylene and triethylamine were obtained target compound, so pl. 138-139oC.

1H NMR showed a 5:1 ratio conformational isomers.

1H NMR /CDCl3/: /the main conformer/ 1,27 /6H, d/, 4,36 /1H, m,/, 4,71 /1H, D./, 4,98 /1H, D./, 6,38 /1H, broad/, 6,70 /1H, D./, 7,52-7,62 /2H, m,/, 7,74-7,82 /2H, m,/; /minor conformer/ 1,21 /6H, DD,./, 4,07 /1H, m,/, 4,71 /1H, D./, of 5.05 /1H, D./, 6,64 /1H, broad/, 6,76 /1H, D./, 7,52-7,62 /2H, m,/, 7,74-7,82 /2H, M./.

Biological data

Herbicide activity of the compounds was tested as follows.

Each chemical compound was converted into finished preparative form in one of two ways. Chemical substance or dissolved in according to the CSO substances so the total volume was 5 cm3. Then the mixture with a solvent comprising of 78.2 g/l tween-20 and 21.8 g/l, span 80, brought to 1 l using methylcyclohexanone series, were added to the solution. Alternatively, the chemical was dissolved in water to the desired concentration and added 0.1% tween. Tween-20 is a trademark of the surface-active agent comprising a condensate of 20 molar quantities of ethylene oxide with serbiancafe.com. Span 80 is a trademark of the surface-active agent, including sorbitan-monolaurate. If a chemical compound is not dissolved, the volume was brought to 5 cm3water was added to the glass beads, and the mixture was then shaken for dissolution or suspension of the chemical agent, after which the beads were removed. In all cases, the mixture was then diluted to the desired volume of spray. When independent spraying, for post-harvest trials were required volumes 25 and 30 cm3; if the spraying was carried out jointly, required 45 cm3. Water emulsion for spraying contained 4% of the initial mixture of solvent and surfactants and test chemical compounds in the appropriate concentration.

Composition of spray, paspaley, equivalent to 1000 liters per hectare. Damage to plants was assessed after 13 days after spraying by comparison with untreated plants, on a scale from 0 to 9, where 0 corresponds to 0% damage, 1 means damage 1-5%, 2 - 6-15%, 3 - 16-25% damage 4 - 26-35%, 5 - damage or damage on 36-59%, 6 - 60-69%, 7 - 70-79%, 8 - at 80-89%, and 9 means 90-100% damage.

In the test carried out to determine predsjedava herbicide activity, seed cultures were inoculated to a depth of 2 cm, and weed seeds at a depth of 1 cm below the compost, and sprinkled compositions at the rate of 1000 liters per hectare. 20 days after spraying, the seedlings in the treated plastic trays were compared with neaprekinami the seedlings in the control trays, the damage or injury was assessed on the same scale from 0 to 9.

The results of the tests are given below in Table XVI.

The chemical formula (used in the description)

1. Substituted heterocyclic compounds of the formula I

< / BR>
in which E represents oxygen or sulfur;

And is CR3or N, where R3represents hydrogen or lower alkyl;

D completes a 5 - or 6-membered non-aromatic heterocyclic ring, which optionally contains esino C1-C10-alkyl or phenyl;

R1and R2are each independently hydrogen, C1-C10-alkyl, C2-C10-alkenylphenol, C2-C10-alkylamino, cyclopropylamino, cyclopropylmethyl, tsiklogeksilnogo, adamantly, phenyl or pyridyloxy group, each of which may be substituted with halogen, cyano or phenyl; or R1and R2together with the nitrogen atom to which they are attached, form morpholino ring;

Z represents halogen, cyano, NHOH, SF5acylamino, COOR7, NR13R14, dibenzylideneacetone, or Z represents C1-C10-alkyl, C2-C10alkenyl, C1-C10-alkoxy, phenoxy, C1-C10-alkylthio, C1-C10-alkylsulfonyl or CO(C1-C10)alkyl, each of which may be substituted with halogen or C1-C6-alkoxy;

R7represents C1-C10alkyl;

R13and R14each independently represents hydrogen or SO2(C1-C10)alkyl;

provided that when there are two Vice-Z, they may be the same or different;

m represents 0 or an integer of 1 or 2.

2. Connection on p. 1, represents the formula I in p. 1;

W, X and Y are independently selected from CR4R5, NR6, 0, and S(O)pwhere p is 0, 1 or 2;

R4, R5and R6selected independently from hydrogen, C1-C10-alkyl and phenyl;

n represents 0 or 1, provided that not more than two of A, W, X and Y include heteroatoms in the ring, and when more than one of W, X and Y represents NR6, R6may be the same or different.

3. Connection on p. 2, in which the ring system

< / BR>
selected from any of the ring systems (a) - (o)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which R3matter specified in paragraph 1;

R4, R5and R6independently selected from hydrogen, C1-C10-alkyl and phenyl;

R4and R5may be the same or different;

R4', R4", R5'and R5"have the meanings given respectively for R4and R5.

4. Connection on p. 3, in which the ring system

< / BR>
is thiazolidin sub-formula (a) or pyrrolidin sub-formula (b), where R3, R4, R4', R5and R5'have the meanings given in paragraph 3.

5. The compound according to any one of paragraphs.1 to 4, in which Z is CF1-C4)-alkyl, SO2(C1-C4)-alkyl, OCF2, CHF2, CF2CF3,

m represents 1 or 2.

6. The compound according to any one of p. 1 - 5, in which R1is isopropyl, sec-butyl, tert-butyl or 3 - to 6-membered cycloalkyl ring.

7. The compound according to any one of p. 1 -6, where R2represents hydrogen or C1-C4-alkyl.

8. The compound according to any one of paragraphs.3 to 7, in which R4, R4', R4", R5, R5'and R5"independently represent hydrogen or C1-C4-alkyl.

9. The compound according to any one of paragraphs. 3 to 8, in which R6represents C1-C4-alkyl.

10. The compound according to any one of paragraphs.1 to 9, in which R3represents hydrogen.

11. Connection on p. 1, where D completes thiazolidinone ring of sub-formula (a)

< / BR>
E is oxygen;

R3represents hydrogen;

R1, R2and m have the meanings given in paragraph 1,

R4and R5have the meanings given in paragraph 3, provided that when there are two Vice-Z they can be the same or different.

12. Derivatives of 3-phenyl-5-oxothiazolidine-4-it formula III

< / BR>
in SUB>1-C10-alkyl, C1-C10-alkoxy, C1-C10-alkylthio or C1-C10-alkylsulfonyl, each of which may be substituted with halogen;

R7represents C1-C10-alkyl;

R4and R5each independently represents hydrogen or phenyl;

m represents 0, 1 or 2;

provided that when there are two Vice-Z, they may be the same or different.

13. Method of producing compounds of the formula I, characterized in p. 1, characterized in that the compound of formula III

< / BR>
in which Z, m, a and D have the meanings defined in relation to formula I,

subjected to reaction with the compound of the formula IV

< / BR>
in which R1and R2have the meanings given for formula I in p. 1;

R19- the group to delete.

14. Method of producing compounds of the formula I, characterized in p. 1, characterized in that the compound of formula III

< / BR>
in which Z, m, a and D have the meanings defined in relation to formula I,

subjected to reaction with the compound of the formula V

< / BR>
in which R1has the values defined for formula (I) in paragraph 1.

15. The method of controlling undesirable plants, which includes PR is este active agent is used as a compound of the formula I, in herbicide effective amount.

 

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,

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