The method of obtaining esters of 2,2-dimethyl 3-[(z)-1 - propenyl]cyclopropanecarbonyl acid and intermediate compounds

 

(57) Abstract:

The invention relates to a new process for the preparation of esters cyclopropanecarbonyl acid of the formula I

< / BR>
where R is the ester residue, split in neutral or acid medium and which WITH1-18the alkyl possibly substituted with halogen or benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of formula (a) -(g),

< / BR>
where R2Is h or methyl;

R3- aryl;

R4- CN, N.;

R5- fluorine, chlorine, bromine or hydrogen;

R6, R7, R8, R9is hydrogen or methyl;

S/1 symbolizes tetrahedrite.

The method consists in processing a complex ester of the formula II

< / BR>
about 2 equivalents of halogenation means followed by treatment received in the form of a mixture of isomers of compound III

< / BR>
the main tool in the presence of compounds R1OH in an environment appropriate co-solvent. The method is extremely selective, because it leads to the formation of compounds of formula 1 with the configuration ( Z ), that is, to the biologically active form of these compounds. 4 C. and 8 C.p. f-cyclopropane-carboxylic acid and intermediate compounds.

Thus, the object of the invention is a method of obtaining compounds of formula (I):

< / BR>
in which R is either cleaved ester residue or ester residue, known in the chemistry of pyrethrinoids, namely:

a) or benzyl radical, with the possibility of substitution on the level of aromatic peaks by one or more radicals selected from the group consisting of alkyl radicals comprising from 1 to 4 carbon atoms, alkylene radicals comprising from 2 to 6 carbon atoms, alkalinising radicals comprising from 2 to 6 carbon atoms, akadeemiline radicals comprising from 4 to 8 carbon atoms, methylenedioxyphenol radical and halogen atoms,

b) a group

< / BR>
in which replacement of R1represents a hydrogen atom or a methyl radical, and the replacement of R2is a monocyclic aryl or a group

C) a group

< / BR>
in which the substitute represents a hydrogen atom or a methyl radical, and R3is an organic aliphatic radical comprising from 2 to 6 carbon atoms and one or more unsaturated compounds with carbon-carbon,

g) a group

< / BR>
which predore, bromine or iodine, a radical is a methyl radical, a radical-CONH2, radical-CSNH2or the radical R5is a halogen atom or a methyl radical, and n represents the number 0, 1 or 2,

d) a group

< / BR>
which substitutes R6, R7, R8and R9are a hydrogen atom, a chlorine atom or a methyl radical and in which S/1 represents an aromatic cycle or a similar cycle dihydro, tetrahydro or hexahydro,

(e) or (succinimido or maleimido) metallinou group

W) or group

< / BR>
C) a group

< / BR>
in which R10represents a hydrogen atom or a CN radical, R12is a radical-CH2or an oxygen atom, R11is diazolidinyl or thiadiazolyl radical, a relationship which can be located in any of the vacant positions, and R12associated with R11carbon atom, concluded between the sulfur atom and nitrogen atom,

s) or group

< / BR>
in which R13represents a hydrogen atom or the radical-CN, or R14is triptorelin radical or alkyl, alkylene or alkynylaryl radical containing not more than 6 carbon atoms, a m represents the e,

l) or group

< / BR>
in which

R4defined as above, R15represents a fluorine atom, chlorine or bromine, a R16is a hydrogen atom, fluorine, chlorine or bromine,

m) or group

< / BR>
in which R4defined as above, and each of R17is an arbitrary alkyl group containing from 1 to 4 carbon atoms, CNS group containing from 1 to 4 carbon atoms, alkylthio group containing from 1 to 4 carbon atoms, alkylsulfonyl group containing from 1 to 4 carbon atoms, triptorelin, 3,4-methylene-dioxolo, chlorine, fluorine or bromine, p is a number equal to 0, 1, or 2, and a' is an oxygen atom or a sulfur atom,

n) or group

< / BR>
in which R18represents a fluorine atom or a methyl radical, a R'18is methyl, ethyl or propargyl radical,

o) or group

< / BR>
in which R21represents a hydrogen atom, the group-CF3or alkyl radical comprising from 1 to 3 carbon atoms, R20, R22, R23identical or different, represent a hydrogen atom, halogen atom, alkyl radical, vkljuchajuwih carbon atoms, zanily radical, radical-CF3, -CO2is an alkyl radical, containing up to 8 carbon atoms, the radical NO2, CNS radical, containing up to 8 carbon atoms, the radical

< / BR>
in which n is 0, 1 or 2 and the radicals R24, R25and K26are alkyl radicals comprising from 1 to 8 carbon atoms, and the radicals R22and R23may form a saturated or unsaturated carbon gomoll, containing up to 8 carbon atoms, a R19is:

or radical

< / BR>
in which R27and R28identical or different, represent a hydrogen atom, halogen atom, alkyl radical comprising from 1 to 8 carbon atoms, or aryl radical comprising up to 14 carbon atoms,

or radical

< / BR>
in which R'27, R'28and R28identical or different, represent one of the values specified above for R27and R28and the dotted lines represent possible second link,

or radical

< / BR>
in which R29can have the values specified above for R22and R23with the exception of halogen, cyano, NO2,

< / BR>
where n is 1 or 2 and

< / BR>
or radical

< / BR>
in kiuchumi from 1 to 18 carbon atoms, aryl radical comprising up to 14 carbon atoms, Aracely radical comprising up to 18 carbon atoms, the radical CF3, CO2is an alkyl radical, containing up to 8 carbon atoms, or CNS radical, containing up to 8 carbon atoms,

n) or group

< / BR>
in which X represents a sulfur atom or oxygen, Y represents a group >C= 0, >C= S or >CH2, R32represents a hydrogen atom, an alkyl radical, linear, branched or cyclic, saturated or unsaturated, containing up to 8 carbon atoms, with the possibility of substitution by one or more halogen atoms, or aryl radical comprising up to 14 carbon atoms, R33represents a hydrogen atom, an alkyl radical, linear, branched or cyclic, saturated or unsaturated, containing up to 8 carbon atoms, with the possibility of substitution by one or more halogen atoms, or R33represents an aryl radical comprising up to 14 carbon atoms, the radical-CF3, -NO2, a halogen atom, CNS radical, containing up to 8 carbon atoms, or-CO2is an alkyl radical, containing up to 8 carbon atoms, a is a hydrogen atom, alkyl radicule a hydrogen atom, alkyl radical comprising from 1 to 3 carbon atoms, the radical-CN, -CCH, or CF3, R36and R38the same or different, represents a hydrogen atom, an alkyl radical comprising from 1 to 3 carbon atoms, with the possibility of substitution by one or more halogen atoms, alkylene radical comprising from 2 to 4 carbon atoms or halogen atom, and R37represents a phenyl radical, with the possibility of substitution by one or more alkyl radicals comprising from 1 to 3 carbon atoms, or one or more halogen atoms, R' represents a hydrogen atom, an alkyl radical comprising from 1 to 18 carbon atoms, linear or branched, saturated or unsaturated, with the ability to replace one or more identical or different functional groups, or R' represents a cycloaliphatic radical comprising from 3 to 7 carbon atoms, with the ability to replace one or more identical or different functional groups, or R' is an aryl group containing from 6 to 14 carbon atoms, with the ability to replace one or more identical or different functional groups, or R if the different functional groups in the form of mixtures of isomers or isomer, split-level cyclopropanol cycle, with the peculiarity that the ester of the formula (II):

< / BR>
in which R is defined as above, is treated halogenation agent to obtain a compound of formula (III):

< / BR>
in which R is defined as above, a Hal represents a halogen atom, having the form of a mixture of isomers at the level of the carbon atom in position 1', which processed the primary tool in the presence of the compounds of formula R'-OH, in which R' is defined as above, to obtain the desired compounds of formula (I).

When R is a biodegradable ester residue, we can talk about any well-known specialists residue, in particular an alkyl radical comprising from 1 to 18 carbon atoms, such as methyl, ethyl, n-sawn, ISO-propyl, n-boutigny, isobutylene or, in the first place, tert-boutigny, or alkyl radical, as defined above, substituted by one or more halogen atoms, primarily chlorine or bromine, such as bromine or chloromethyl, mono-, di - or tri - bromacil or chloroethyl; it could also be about alkylsilanes radical in which the alkyl contains from 1 to 4 atoms of opertational-tert-butyl-millimeter; it could also be about an alkyl radical substituted by such groups as the O-alkyl, O-aryl or O-kalkilya, alkyl, comprising preferably from 1 to 4 carbon atoms, aryl containing 6 to 14 carbon atoms and represents, first and foremost, phenyl or colliny radical, and kalkilya representing, primarily, benzyl or finitely radical.

It should only be noted that the above ester residue should be split in a neutral or acidic environment.

When R is a benzyl radical substituted by one or more alkyl radicals, it is first and foremost about methyl, ethyl, sawn or isopropyl radicals.

When R is a benzyl radical substituted by one or more alkylene radicals, it is first and foremost about the vinyl, allyl, 2-methylallyl or isobutylene the radicals.

When R is a benzyl radical substituted by one or more etkilenecegini radicals, it is first and foremost about vinylacetylene, aliaksilla, 2-methylalumoxane or isobutylamine the radicals.

AMI it is first and foremost about butadienyl or pentadienyl radical.

When R is a benzyl radical substituted by one or more halogen atoms, it is first and foremost about the chlorine atom, bromine or fluorine.

When R2represents an aryl radical, it is first and foremost about a phenyl radical, and R in this case is, first and foremost, 5-benzyl-3-furylmethyl group.

R3can represent, in particular, the radical-CH2-CH=CH2, -CH2-CH= CH-CH3, -CH2-CH=CH-CH-CH2, -CH2-CH=CH-CH2-CH2-CCH.

In represents, in particular, an oxygen atom, and the corresponding group in this case is, first and foremost, a group such as 3-phenoxybenzyl, -cyano-3-phenoxybenzyl-ethinyl - 3-phenoxybenzyl, 1-(3-phenoxyphenyl)-ethyl or-thioamide-3-phenoxybenzene. In represents a group-CO-, and the corresponding group in this case is, first of all, 3 - benzoylmethylene group.

When R14represents an alkyl radical, it is first and foremost about such radicals as methyl, ethyl, through linear or razvitiia, we are talking about such radicals as vinyl, allyl, butonly, pettily or hexagonally.

When R14represents alkynylaryl radical, it is first and foremost about such radical, as etinilnoy, propargyl or routinely.

When R14represents an alkyl radical, we are talking about such radicals as methyl, ethyl, through linear or branched, or boutigny, linear or branched.

When R17is a CNS radical, we are talking about such a radical, as metaxylene, amoxilina, propoxyphenyl, linear or branched, or butoxyphenyl, linear or branched.

When R17represents alkilinity radical, we are talking about such a radical, as medicinally, aditionally, proportionally, linear or branched, or butylthioethyl, linear or branched.

When R17represents alkylsulfonyl radical, we are talking about radical corresponding to any of the above alkylthiols radicals.

When R21represents an alkyl radical, we are talking about such radicals as methyl, ethyl, Protasov R20, R22and R23or radicals contained in the definition of R19, R20, R22and R23represent a halogen atom, the question is, first of all, a fluorine atom, chlorine or bromine.

When one or more radicals R20, R22and R23or radicals contained in the definition of R19, R20, R22and R23represent an alkyl radical, it is, first of all, about such radicals as methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene or n-pentelenyi.

When one or more radicals R20, R22and R23or radicals contained in the definition of R19, R20, R22and R23represent an aryl radical, it is, first and foremost, the phenyl radical, with the possibility of substitution, in particular, alkyl or CNS radical comprising from 1 to 8 carbon atoms, or a radical as nitro, triptorelin, hydroxyl, halogen or amino.

When one or more radicals R20, R22and R23or radicals contained in the definition of R19, R20, R22and R23are Uralkaliy radical, re 22 and R23or radicals contained in the definition of R19, R20, R22and R23represent-CO2is an alkyl or CNS radical, under alkyl understand, first and foremost, methyl, ethyl, sawn or isopropyl radical, and under the CNS - metaxylene, amoxilina, propoxyphenyl or isopropoxyphenyl radical.

When R32or R33represents an alkyl radical, linear, branched or cyclic, saturated or unsaturated, talking, primarily, about the radical, such as methyl, ethyl, n-sawn, ISO-propyl, cyclopropyl, cyclopropylmethyl, boutigny, isobutylene, tert-boutigny, cyclobutyl, n-pentelenyi, cyclopentyl, n-sexily or tsiklogeksilnogo, or allyl, propargyl or bucinellina radical.

When these radicals substituted by one or more halogen atoms, under the halogen understand fluorine, chlorine, bromine or iodine.

When R32or R33represents an aryl radical, it is, first and foremost, on the phenyl radical.

When R33represents a halogen atom, the question is, first of all, a fluorine atom, chloro metaxylem, amoxilina, propoxyimino or isopropoxyphenol radical.

When R33represents-CO2is an alkyl radical, under alkyl understand, first of all, such a radical as methyl, ethyl, through linear or branched, or boutigny, linear or branched.

When R34represents an alkyl radical, it is, first of all, the methyl radical.

When R33represents an alkyl radical, it is, first of all, the methyl radical.

When R36and/or R38represents an alkyl radical, it is, first and foremost, a methyl or ethyl radical.

When the alkyl radical is substituted by one or more halogen atoms, under the halogen understand, first and foremost, fluorine, chlorine or bromine.

When R36and/or R38represents alkylene radical, it is, first of all, vinyl or allyl radical.

When R36and/or R38represents a halogen atom, the question is, first of all, a fluorine atom, chlorine or bromine.

When R37represents a phenyl radical, substituted alkyl radiosonde above for R36and R38.

When R' represents a linear or branched alkyl radical, under alkyl see, for example, such radicals as methyl, ethyl, through linear or branched, boutigny, linear or branched, sexily, linear or branched, decile, linear or branched, tetradecyl, linear or branched, octadecenyl, linear or branched.

When R' represents a linear or branched alkyl radical, under unsaturated alkyl see, for example, such radicals as attilly, properly, butonly, linear or branched, exenergy, linear or branched, dartilly, linear or branched, tetradecanol, linear or branched, octadecadienyl, linear or branched, or unsaturated aliphatic radicals containing two or more double bonds.

When R' represents an alkyl radical, substituted by one or more functional groups, under the functional group understand, first of all, a halogen atom, a group HE or SH group ORaor SRain which Rais an alkyl radical, Cai various, represent a hydrogen atom or alkyl radical comprising from 1 to 8 carbon atoms, the group CN, SO3H or PO4H2or group COalc1, SO2alc2, SO3alc3where alc1, alc2or alc3represent an alkyl radical comprising from 1 to 18 carbon atoms.

R' can also be an alkyl radical, a substituted aryl radical, for example benzyl or Penicillinum, which, in turn, can be substituted by one or more OH groups, Oalc or alc, comprising from 1 to 8 carbon atoms, by one or more groups of CF3, OCF3SCF3or group (G):

< / BR>
R' can also be an alkyl radical, substituted at two adjacent carbon atoms by a group (G1):

< / BR>
or substituted by group

When R' represents an alkyl radical, substituted by one or more functional groups, as the preferred values of R' can be called radicals:

-(CH2)n-CHal3in which n takes an integer value from 1 to 8, a Hal is a halogen atom, for example, the radical-CH2-CCl3, -CH2-CF3, -CH2-CH2-CCl3, the n1accepts a value from 0 to 8, for example, the radical-CH2-CHCl2, -CH2-CHF2or-CHF2,

-(CH2)n-CH2Hal, in which n and Hal are defined as above, for example, the radical-CH2-CH2CI or-CH2-CH2F,

-C(CHal3)3in which Hal is defined as above, for example, the radical-C(CF3)3or

< / BR>
< / BR>
< / BR>
< / BR>
or -(CH2)n- CN, in which n is defined as above,

< / BR>
in which Hal is defined as above, for example, the radical:

< / BR>
-(CH2)n-ORdin which n is defined as above, and Rdrepresents a hydrogen atom or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms, for example the radical-CH2-OCH3, -CH2-CH2-O-CH3, -CH2-CH2- O-CH2-CH3or-CH2-CH2-OH,

< / BR>
in which n and Rddefined as above, and the two radicals Rdcan be different, for example, radical

< / BR>
< / BR>
in which n is defined as above, for example, radical

< / BR>
< / BR>
in which n is defined as above, for example,

< / BR>
< / BR>
in which n is defined as above, for example, radical

< / BR>
is established, as above, for example, radical

< / BR>
When R' represents a cycloaliphatic radical comprising from 3 to 7 carbon atoms, we are talking about such a radical, as cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or cycloheptenyl, which can be linked to an oxygen atom with an alkyl radical comprising from 1 to 3 carbon atoms, in particular with a methyl radical.

When R' represents a cycloaliphatic radical comprising from 3 to 7 carbon atoms, substituted by one or more functional groups, under the functional group understand, first of all, a halogen atom, an alkyl radical comprising from 1 to 6 carbon atoms, CNS radical comprising from 1 to 6 carbon atoms, a group of NO2.

When R' is an aryl radical, with the possibility of substitution, it is, first and foremost, phenyl radical or phenyl radical, substituted by one or more groups HE Oalc or alc and alc represents an alkyl radical comprising from 1 to 8 carbon atoms, or a group of CF3, OCF3or SCF3or one or more halogen atoms.

When R' represents peredelnyj, shrilly, tofinally, oxazolidinyl or diazolidinyl, with the ability to replace one or more of the above groups.

The method which is the subject of the present invention, has an exceptional standard. It allows you to get as biodegradable esters, that is, the intermediate ester, which was transformed into biologically active esters by conventional methods interesterification or hydrolysis followed by esterification and biologically active esters.

In addition, this method is extremely selective, because it leads to the formation of compounds of formula (I) configuration (Z), that is, to the biologically active form of these compounds.

The object of the present invention is, in particular, the above-described method, wherein the halogenation agent is hareruya or bralirwa additive, and preference is given to the second Supplement.

Among halogenation means used in the present invention include bromine, used alone or polymer-based, chlorine, N-bromosuccinimide and N-chlorosuccinimide, N-bromoacetamide and N-chloro what ID phenyltrimethylammonium, perbromide 2-carboxyethyl-phenylphosphine, tribromide 2-hydropyridine, dibromide and dichloride of copper, 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, three - and pentabromide and chloride of phosphorus, a mixture of tertiary trimethylboron and trimethylchlorosilane-DMSO-amine, trichloride iron. Among them are, first of all, bromine, chlorine, N-bromosuccinimide and N-chlorosuccinimide and acetamide, perbromic and perchloric pyridinium, perbromic and perchloric hydrobromide and hydrochloride pyridinium.

The halogenation reaction is conducted in the environment of the solvent, which may be halogenated solvent, in particular methylene chloride, chloroform, carbon tetrachloride, dichloroethane or a mixture of these solvents, ether such as tetrahydrofuran, dimethoxyethane, methyl-tert-butylether or dioxane, an aromatic solvent such as benzene, toluene, xylene or the corresponding saturated solvent, in particular cyclohexane, alcohols, such as methanol or ethanol, ethyl acetate or dimethylformamide or dimethylsulfoxide.

Advantageously the maximum limit of the formation of mono - and trigalogenmetany derivatives near the target derivative (III), therefore, the object of the present invention is, in particular, the method, otlichayushiesya implementation of the invention used base material selected from the group consisting of hydride, alcoholate, amidino, alkali and alkaline earth carbonates, in particular sodium or potassium hydroxide, tertiary amines, in particular triethylamine, pyridine or dimethylaminopyridine.

The operation is performed in the environment of the solvent, which is either a compound of the formula R'-OH, or a mixture of this compound with an appropriate co-solvent. This co-solvent can be, in particular, halogen-containing solvent, an ether, an aromatic solvent or the corresponding saturated solvent of the numbers listed above, or dimethylformamide or dimethyl sulfoxide.

The operation is performed at a temperature suitable for the used solvent, and this temperature may be, depending on the case, from about -78oC to +40oC.

The object of the present invention, in particular, is the above method, wherein R is an ester residue, split in neutral or acidic medium selected from the group consisting of linear or branched alkyl radicals comprising from 1 to 18 carbon atoms, a linear or branched alkyl radicals comprising from 1 to 18 carbon atoms, Yes, substituted silyl group, and alkyl radicals comprising from 1 to 4 carbon atoms, substituted by such groups as the O-alkyl, O-aryl or O-kalkilya, alkyl comprising from 1 to 4 carbon atoms, and aryl containing 6 to 14 carbon atoms.

The object of the present invention, in particular, is the above method, wherein R is an ester residue, split in neutral or acidic medium selected from the group consisting of alkyl radicals comprising from 1 to 4 carbon atoms, alkyl radicals comprising from 1 to 4 carbon atoms, substituted by one or more chlorine atoms or bromine, alkyl radicals comprising from 1 to 4 carbon atoms, substituted alkylsilane group, and alkyl radicals comprising from 1 to 4 carbon atoms, substituted such groups, O-alkyl, O-aryl or O-kalkilya, as defined above.

The object of the present invention is, first, the above-described method, wherein R represents an alkyl radical comprising from 1 to 4 carbon atoms, primarily tert-boutigny, or a methyl or ethyl radical, substituted by one or several and chlorethylene radical.

The object of the present invention is also the above method, wherein R is an ester residue selected from the group consisting of:

benzyl radical, substituted by one or more halogen atoms,

radicals of the formula:

< / BR>
in which R1and R2defined as above,

radicals of the formula:

< / BR>
in which a and R3defined as above,

radicals of the formula:

< / BR>
in which R4, R5and n are defined as above,

radicals of the formula:

< / BR>
in which R6, R7, R8, R9and S/1 is defined as above,

radicals of the formula:

< / BR>
in which R13, R14and m are defined as above,

radicals of the formula:

< / BR>
in which R4, R15and R16defined as above,

radicals of the formula:

< / BR>
in which R18and R'18defined as above,

radicals of the formula:

< / BR>
in which R35, R36, R37and R38defined as above.

The object of the present invention is, first, the above-described method, wherein R pedago from 1 to 5 fluorine atoms,

radicals of the formula:

< / BR>
in which R3represents a radical-CH2-CH--CH2or-CH2=CCH,

radicals of the formula:

< / BR>
in which R4defined as above,

radicals of the formula:

< / BR>
radicals of the formula:

< / BR>
in which R14and m are defined as above,

radicals of the formula:

< / BR>
in which R4defined as above,

radicals of the formula:

< / BR>
in which R18and R'18defined as above,

radicals of the formula:

< / BR>
in which R36represents a hydrogen atom, a fluorine atom or chromium, R37is phenyl or 3-tortenelem radical, and R38is a hydrogen atom, fluorine atom or chlorine or a methyl radical.

The object of the present invention, in particular, is the above method, characterized in that at the initial stage of the connection of the formula R'-OH, in which R' represents a hydrogen atom, a linear, branched or cyclic alkyl radical comprising from 1 to 8 carbon atoms, and, in particular, ethyl radical, tert-botilony radical or cyclopropyl or cyclopropylmethyl radical, linear or razwell the ohms, and, in particular, by one or more fluorine atoms, the radical (CH2)m-O-(CH2)n-CH3in which m is an integer value from 1 to 8, and n is an integer value from O to 8, and, in particular, the radical-CH2-O-CH3.

The object of the present invention is, first of all, the above method, characterized in that at the initial stage of the connection of the formula (II) with the structure of (1R, CIS), in which R represents the residue (R, S) or (S) -cyano-phenoxybenzyl alcohol or the residue (R, S) or (S) -cyano 4-fluoro 3-phenoxybenzyl alcohol and a compound of the formula R'-OH, in which R' represents methyl, ethyl, tert-botilony or 1,1,1,3,3,3-geksaftorpropena radical.

Intermediate compounds of formula (III) are new compounds, so the subject of the present invention are the above compounds of formula (III) in the form of mixtures of isomers or individual isomers level cyclopropanol cycle.

A large part of the compounds of formula (I) are known and described in the patents or patent applications EEC N 38271, 41021, 48186, 110769, 114012, 215701, 357742, 300898, 176387, 261035, 381563 or in the French patent 2 612 184. We are talking about biologically active compounds, about the internal connections in the synthesis of active compounds.

Compounds of formula (I) in which R represents a methyl radical substituted by a bromine atom or chlorine, or ethyl radical, substituted by 1, 2 or 3 atoms of bromine or chlorine, are biodegradable esters, i.e. intermediate substance in the synthesis of biologically active esters. They to date have not been described and are also subject of the present invention.

Cleavage of esters of formula (I), which are intermediate compounds in the synthesis of biologically active esters can be made by conventional methods known to the specialists. Relevant examples are given in the patent EEC 48186, which was already discussed above, and, more generally, in the article of T. C. green, "Protective groups in organic synthesis".

The compounds of formula (II) used at the initial stage of the method which is the subject of the present invention can be obtained by one of the methods described below in the experimental part, that is, by esterification of the corresponding acid with a suitable alcohol. The compounds of formula (II), except those in which R represents a methyl, ethyl, 3-phenoxybenzyl or-cyano 3-phenoxybenzyl radical, I have ekasana acid in any of its configurations are well known and can be obtained using one of the methods well-known specialists. Acid (IR, CIS) described in the journal of Agr. Biol. Chem., vol. 29, No. 8, page 784 (1965); acid (IS, CIS) can be obtained according to the method described in U.S. patent 4 296 038; acid (IR, TRANS) can be obtained according to the method described in journal of the Synth. Comm. (1984) 14 p. 1239-46, and the acid IS, TRANS) - the same method, starting from (-) 3-Karen; acid (IR,S CIS) can be obtained using the methods described in the above journal Agr. Biol. Chem. or in U.S. patent 4 296 038, taking racemic 3-Karen, which can be obtained as described in the journal J. Org. Chem. (1987), volume 52, page 1493, or Tet. Letters (1984), pp. 5255; acid (IR,S, TRANS), and acid (IR,S CIS) can be obtained using the methods described in Japan Kokai J 81 079644.

The compounds of formula (II) in which R represents methyl, 3-phenoxybenzyl or-cyano 3-phenoxybenzyl radical, are described, for example, in the journal of the Synth. Comm. (1988) 18 p. 1139-49 and Tetrahedron (1986), 42 p. 5717-28.

The following examples illustrate the present invention, however, limiting it.

EXAMPLE 1 : (IR, CIS) 2,2-dimethyl 3-[(Z) 2-methoxycarbonyl) ethynyl] cyclopropane 1-methylcarbamoyl

STEP A : (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbamoyl3of methylene chloride, then cooled to +10oC and add 1.3 cm3bromine. Then shaken for 2 h at room temperature, and poured into a mixture of water and ice. Then extracted with methylene chloride, the organic phase is dried and evaporated to dryness. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain of 3.2 g of the desired product.

Chemical composition C10H14Br2ABOUT3= 342,04

% calculated: C 35,11; H 4,12; Br 46,72;

% obtained: C 35,0; H 4.2; Br 46,5.

IR spectrum (CHCl3)

Absorption:

C=O - 1736, 1719 cm-1< / BR>
COOCH3- 1438 cm-1< / BR>
Range Yarm: CDCl3; 250 MHz mn-1;

1,22(s), 1.27mm(s) of 1.34 (s): CH3paired.; 1,84(d) and to 1.98(m): H1and H3CIS; 3,63 (s) of 3.73 (s): CO2CH3; of 5.50 (d, J=11), 5,67 (d, J=11): Hal-CH-CH.

STEP B : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-methoxycarbonyl) ethynyl] cyclopropane 1-methylcarbazole

Inert gas is mixed 0.16 g of sodium methylate and 1.6 cm3of methanol. Then cooled to about 0oC and slowly add 0.5 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbamate dissolved in 2.5 cm3methane and reduced pressure at a temperature of about +30oC and add 10 cm3of methylene chloride. Then the solution is washed with water, dried and concentrated to dryness. So get 0,324 g crude product, which was subjected to chromatography on silica (eluant: cyclohexane - ethyl acetate (6:4), resulting in a gain 0,262 g of the target product.

The infrared spectrum; (CHCl3)

Absorption:

C=O - 1720 cm-1< / BR>
C=C - 1634 cm-1< / BR>
Compatible with Z isomer

Range Yarm: CDCl3; 250 MHz mn-1< / BR>
1,28 (s), 1,31 (s): CH3paired.; a 1.96 (d, J=3,5) at 3.25 (dd): H1/H3CIS; of 3.46 (s), and 3.72 (s): CH3a difficulty. ether in paragraph 3; 5,90 (dd), of 6.65 (dd): H in paragraph (1'- Isomer z

EXAMPLE 2 : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-tert-butoxycarbonyl) ethynyl] cyclopropane 1-methylcarbazole (Product a) and (1R, CIS) 2,2-dimethyl 3-[(Z) 2-carboxyethyl) cyclopropane 1-methylcarbazole (Product B)

Inert gas is mixed 12 cm3dimethoxyethane and 0,684 g of potassium tert-butylate. Then slowly add a solution 0,684 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbamate obtained in Stage a of Example 1, in 10 cm3dimethoxyethane and shaken for 40 min at a temperature of about -60oC. then add 3 cm3dimethoxy the Ute water and methylene chloride, defend, extracted the aqueous phase with methylene chloride, washed with water, the combined organic phases dried and concentrated to dryness at a temperature of about +30oC. Thus receive 0,219 g of the target product A.

Then acidifying the combined aqueous phase 2 N. hydrochloric acid and extracted with methylene chloride. After that, concentrate to dryness of the organic phase and get 0,211 g of product B, the corresponding crude (1R, CIS) 2,2-dimethyl 3-[(Z) 2-carboxyethyl) cyclopropane to methylcarbonate. Then the products a and B is subjected to chromatography on silica (eluant : methylene chloride - hexane (8 : 2), and then with cyclohexane - ethyl acetate (6 : 4).

The chemical composition of the product AND

IR spectrum (CHCl3)

Absorption

C=O - 1721 cm-1(Playground 1705 cm-1)

C=C - 1631 cm-1< / BR>
O-CH3- 1439 cm-1< / BR>
O-tBu - 1368 cm-1< / BR>
Range Yarm: CDCl3; 250 MHz mn-1;

1.27mm (s) and 1.31 (s): CH3paired.; 1,49: -CO2Bu; of 1.92 (d, J=8.5 a) and 3.26 (m): H1and H3CIS; 3,65: O-CH3; 5,80 (d, J=11,5): CH = CO; 6,51 (dd, J= 10,5-11,5): CH = CO. Delta z

The chemical composition of the product B

IR spectrum (CHCl3)

Absorption

OH KIS is3; 250 MHz mn-1;

1,28 (s) 1,32 (s): CH3paired.; 1,99 (d) and 3.21 (m): H1and H3CIS; 3,67 (s): CO2CH3; of 5.92 (d, J=11) and 6,77 (dd): CO-CH=CH-CH; 11,6 (m): 1H mobile.

EXAMPLE 3 : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaplar) propoxycarbonyl] ethynyl] cyclopropane 1-methylcarbamoyl

Inert gas is washed with cyclohexane 0,057 g of sodium hydride as a 50% suspension in oil, and then add 1 cm3dimethoxyethane. After that, in the thus obtained suspension is added 0.33 g hexafluoroisopropanol 1 cm3dimethoxyethane and shaken for 30 minutes the Solution is cooled to +5oC and slowly add a solution 0,173 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbazole 1 cm3dimethoxyethane. Then shaken for 1 h at a temperature of +3/+5oC, pour the reaction mixture into an aqueous solution of 1 N. hydrochloric acid, extracted with methylene chloride, the organic phase is dried and concentrated to dryness. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain of 0.16 g of the desired product.

Range Yarm: CDCl3); 250 MHz;

1,30 (s) of 1.34 (s): CH3paired.; 3,68 (s): CH
Inert gas is mixed 1.5 cm3dimethoxyethane, 0,056 g of potassium tert-butylate and 0.2 g hexafluoroisopropanol, and then added at a temperature of +5oC solution 0,170 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbazole 0.5 cm3dimethoxyethane. After that, the mixture was shaken for 18 h at room temperature, add 1 N. hydrochloric acid, extracted with methylene chloride, dried and concentrated to dryness. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain of 0.066 g of the desired product.

IR spectrum (CHCl3)

Absorption

>C=O - 1758, 1740 and 1718 cm-1< / BR>
C=C - 1624 cm-1< / BR>
EXAMPLE 5: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(1,1,1,3,3,3-hexaplar) propoxycarbonyl] ethynyl] cyclopropane 1-methylcarbamoyl

Operations are performed as described in Example 4, using instead of potassium tert-butylate or 0.027 g of sodium methylate. The result is the desired product, identical to the product obtained in Example 4.

EXAMPLE 6: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-carboxylate is Aliya, then add at a temperature of about +5oC solution 0,342 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-methylcarbazole 1.5 cm3tetrahydrofuran (THF). Then shaken for 1 h 30 min, allow the temperature to rise to 20oC and shaken for 4 hours and Then water is added, extracted with methylene chloride, the organic phase is dried and the solvent evaporated. The residue is subjected to chromatography on silica (eluant : methylene chloride - ethanol (97 : 3), resulting in a gain 0,046 g of the target product.

Range Yarm: CDCl3; 250 MHz

1,28 (s), 1,32 (s): CH3paired.; to 1.98 (d, J=8,5), 3,20 (m): H1/H3CIS; 3,67 (s): CH3a difficulty. ether; 5,91 (d, J=11,5), 6,77 (dd, J=11,5): H (C=C).

EXAMPLE 7: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate (S) -cyano 3-phenoxybenzyl

STEP A: (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate(S)- cyano 3-phenoxybenzyl

Inert gas mix of 1.75 g of 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate (S) - cyano-3-phenoxybenzyl and 17.5 cm3tetrahydrofuran (THF). Then at a temperature of 0/+5oC slowly add 3,29 g perbromide pyridinium hydrobromide and shaken in the course is iltram to dryness under reduced pressure at a temperature of +25oC. then the product was then purified by chromatography on silica (eluant : methylene chloride - hexane (7 : 3). The result is 0.8 g of the desired product.

Chemical composition C23H20NO4Br2= 535,2

% calculated: C of 51.6; H 3,8; Br 29,9; N 2,6;

% obtained: C 51,4; H 4,0; Br 29,4; N 2,5.

Range Yarm: CDCl3; 250 MHz mn-1;

The mixture of isomers at the level of bromine in p. 1'.

1,16 - 1,23 - 1,25 - 1,27: diMe paired.; 1,88 : H1; 2,07: H3cyclopropyl; 6,25 and 6.38: 4,06 (d) and 4,39 (d): -CH2Br-CO-; 5,20 (d) and are 5.36 (d): CHBr-CO; from 6.95 to 7.45: H aromatic.

Source ester was obtained as follows.

Inert gas is mixed with 15 cm3of methylene chloride, 2 g of 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylic acid, 2,59 g dicyclohexylcarbodiimide and 2.8 cm3pyridine, then added for 20 minutes at a temperature of +10oC the mixture is 2.74 g (S) -cyano 3-phenoxybenzyl alcohol, 20cm3of methylene chloride and 0.02 g of dimethylaminopyridine. Then shaken for 20 h at a temperature of +20oC, filter, concentrate the filtrate to dryness under reduced pressure at a temperature of +30oC. the Residue is subjected to chromatography on silica (eluent : cyclo-hexane-ethyl acetate (8 : 2), E.

Carbonyl - 1736 cm-1< / BR>
Phenoxy - 1588, 1498 cm-1< / BR>
The acid and OH - is Missing

Range Yarm: (CDCl3) 250 MHz

1,11 (s) 1,21 (s): diMe paired.; 1,63 (m): H1and H3CIS; 2,16 (s): CH3in p. carbonyl; 2,87 (m): CH3in p. carbonyl; 6,27 (s): H from 7.00 to 7.45 (9H): aromatic compounds.

Circular dichroism (dioxane)

Max. 225 nm = +1; 281 nm = +0,3; 288 nm = +0,3; 300 nm e = +0,07.

STEP B : (1R, CIS) 2,2-dimethyl 3-[(Z)2-methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate(S)- cyano 3-phenoxybenzyl

Inert gas is mixed 0,165 g of sodium methylate and 3 cm3methanol, and then added at a temperature of +5oC 0,770 g of the product obtained as described in Stage A, and 6 cm3of methanol. Then shaken for 1 h at a temperature of 0oC, and then within 2430 min at room temperature, and poured into 25 cm32 N. hydrochloric acid at a temperature of about +5oC. then extracted with methylene chloride, washed with water and dried. After evaporation of the solvent to obtain 0.6 g of crude product which is purified by chromatography on silica (eluant : methylene chloride - hexane (8 : 2) and then (7 : 3). The result 0,267 g of a mixture containing the target product.


STEP A: (1R, CIS ) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate(R,S)- cyano 3-phenoxybenzyl

Inert gas is mixed 0,380 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate (R, S) -cyano 3-phenoxybenzyl and 4 cm3carbon tetrachloride, and then at a temperature of about +15oC is added slowly 102 μl of bromine in 1 cm3carbon tetrachloride and shaken for 4 h Then concentrated to dryness at a temperature of about +30oC and get 0,530 g of the desired crude product used in the next step without additional processing. The product can be purified by chromatography on silica (eluant : methylene chloride - hexane (8:2).

Range Yarm: CDCl3250 MHz mn-1;

1,16-1,23-1,25-1,27: CH3paired. ; 1,88-2,07: H1and H3CIS; 4,06 (d) and 4,39 (d), 4,22: -CO-CH2Br; 5,20 (d) and are 5.36 (d): -CO-CH-Br; 6,25 and 6.38: CO2-CH-CN; from 6.95 to 7.45: aromatic compounds.

Source ester was obtained as follows.

Inert gas is mixed 0,344 g of 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylic acid, 3 cm3of methylene chloride, 0,48 cm3pyridine and 0,445 g dicyclohexylcarbodiimide, and then add a solution 0,471 g (R,S)- cyano 3-phenoxy what happens at room temperature for 18 h, filter and concentrate to dryness at a temperature of +30oC. the Residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (75 : 25), resulting in a gain 0,594 g of the target product.

Range Yarm: CDCl3; 250 MHz;

From 1.11 to 1.28: CH3paired.; 1.50 to 1.68: H cyclopropyl; 2,10 (s), 2,16 (s) (3H): -COCH3; 2,85 (m): =C-CH2-CH; 6,27 (s): -CO2-CH-; 7.03 is to 7.45: aromatic compounds.

IR spectrum (CHCl3)

Absorption

>C=0 - 1735, 1712 cm-1< / BR>
--O- - 1588, 1498 cm-1< / BR>
STEP B: (1R, CIS) 2,2-dimethyl-3-[(Z) 2 - methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate(R,S)- cyano 3-phenoxybenzyl

Operations are the same as in the above Step B of Example 7, using as starting product dipomacy the product obtained in the above Step A. After cleaning as described in the above Step B of Example 7, to obtain the target product.

EXAMPLE 9: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaplar) propoxycarbonyl] ethynyl] cyclopropane 1-carboxylate (R,S) -cyano 3 - phenoxybenzyl

Inert gas is washed with cyclohexane 0,030 g of sodium hydride as a 50% suspension in oil, and then add 1 cm3dimethoxyethane. POS dimethoxyethane and shaken for 30 min at a temperature of 0/+5oC. the Solution is cooled to -5oC and add a solution 0,163 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate(R,S)- cyano 3-phenoxybenzyl, obtained as described in Step a of Example 8, 1 cm3dimethoxyethane and shaken for 1 h 30 min Then poured into an aqueous solution of 1 N. hydrochloric acid, extracted with methylene chloride, the organic phase is dried and evaporated to dryness. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (8 : 2), resulting in a gain 0,056 g of the target product.

Range Yarm: CDCl3250 MHz

1,26 (s) of 1.30 (s), 1,35 (s), 1,36 (s): CH3paired.; 2,10 (d), 3,21 (m): H1/H3CIS; 5,8 (cept): H CO2-CH(F3)2; 6,02 (dm), between 6.08 (dm): H in p. 2'; 6,32 (s) 6,34 (s): H in Petrograd ; for 6.81 to 7.5 (m): H aromatic. and H p. 1'.

EXAMPLE 10: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate (R,S) -cyano 3-phenoxybenzyl

STEP A: (1R, CIS) 2,2-dimethyl 3-(1,3-dichloro 2-oxopropyl) cyclopropane 1-carboxylate(R,S)- cyano 3-phenoxybenzyl

Inert gas is mixed 0,300 g of (1R, CIS) 2,2-dimethyl 3-(oxopropyl) cyclopropane 1-carboxylate (R, S) -cyano 3-phenoxybenzyl obtained, as indicated in the Example is Uchenie 1 h and concentrated to dryness. So get 0,546 g of crude desired crude product used without further processing in the next step.

STEP B: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaplar) propoxycarbonyl) ethynyl] cyclopropane 1-carboxylate(R,S)- cyano 3-phenoxybenzyl

In an inert gas environment at a temperature of about -10oC mix 1 cm3toluene and 0.02 g of sodium hydride dissolved in 50% in oil, then slowly add 200 ál hexafluoroisopropanol and 1 cm3of toluene. The mixture is shaken at a temperature of -10oC for 35 min and add 0.1 g of the crude product obtained at Stage A, dissolved in 0.5 cm3of toluene. Then the temperature of the mixture is allowed to rise to room temperature and shaken for 2 hours the Solvent is evaporated and the residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (85 : 15), resulting in getting the desired product, identical to the product obtained in Example 9.

EXAMPLE 11: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaplar propoxy) carbonyl] ethynyl] cyclopropane 1-carboxylate tert-butyl

STEP A: (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate tert-butyl

Inert gas is mixed 0,113 g of (1R, Tissot at a temperature of +5oC 0.34 g of perbromide pyridinium hydrobromide. After the mixture is shaken at room temperature for 1 h, centrifuged and concentrated to dryness. The residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (7 : 3), resulting in a gain 0,165 g of the desired product.

Range Yarm: CDCl3; 250 MHz;

From 1.16 to 1.28 : CH3paired.; of 1.43 and 1.40: H tBu; from 1.7 to 1.9: H1and H3; 4,08 (d) 4,36 (d) and the 4.29: -CO-CH2-Br; 5,24 (d) and 5,50 (d): CO-CHBr-.

(1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate tert-butyl, can be obtained in the following way.

Inert gas is mixed 0.17 g of (1R, CIS) 2,2-dimethyl 3-(1-oxopropyl) cyclopropane 1-carboxylic acid and 1.7 cm3ethyl acetate, and then slowly add a solution of 0.36 g of tert-Butylochka N,N'-diisopropylcarbodiimide 1 cm3ethyl acetate. After 6 hours stirring at room temperature add 0.15 g of tert-Butylochka N,N'-diisopropylcarbodiimide and continue stirring for 16 hours Then centrifuged and the solvent is evaporated. The residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (7 : 3), resulting in a gain 0,153 g of the desired product is
Acid is Missing

Range Yarm: CDCl3; 250 MHz;

1,18 (s) and 1.20 (s): CH3paired.; 1,35 (m) 1,50 (d, J=8,5): H3and H11,45 (s): H tBu; 2,15 (s): H CH3in p. 3'; and 2.79 (dd) and 2.93 (dd): H CH2in p. 1'.

Tert-Butylochka N,N'-diisopropylcarbodiimide can be obtained in the following way.

Inert gas is mixed with 20 g of tert-butanol and 1.73 g of monochloride copper, and then at a temperature of +30oC/+35oC added 34 g of N,N'-diisopropylcarbodiimide and shaken, allowing the temperature to reach the level of the room. The mixture is then centrifuged, rinsed the filter simple isopropyl ether, the solvent evaporated and the residue is distilled at a pressure of 4-5 mm RT. Art. (t Kip. 47-48oC). The result 41,08 g of the desired product.

Range Yarm: CDCl3; 250 MHz;

1,05 (d) 1,09 (d): CH3; 3,14 (m), 3,68 (m): -CH<; 3,24 (d): NH; 1,47 (s): tBu.

IR spectrum (CHCl3)

Absorption

NH - 3436 cm-1< / BR>
C=N - 1656 cm-1< / BR>
STEP B: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate tert-butyl

Inert gas is mixed to 0.055 g of sodium hydride (50% suspension in oil) and 1 cm3toluene, after which the is of 30 minutes at a temperature of +10oC. Then add a solution 0,184 g of (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate tert-butyl 1.5 cm3toluene and shaken for 2 h at room temperature. After that, the mixture is poured into 2 N. hydrochloric acid at +10oC, extracted with ethyl acetate, the organic phase is washed with water, dried her and evaporated to dryness. The residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (95 : 5), resulting in a gain is 0.135 g of the target product (pl. t 95oC).

IR spectrum (CHCl3)

Absorption

C=O - 1742, 1710 cm-1< / BR>
C=C - 1622 cm-1< / BR>
Range Yarm: CDCl3; 250 MHz;

1,28 (s), 1,32 (s): CH3paired.; 1,45 (s): H tBu; 1,97 - 3,03 : H1/H3CIS; 5,81 (cept): H-CH(CF3)2; of 5.99 (dd, J=11): H in p. 2'; 7,00 (dd, J=11 and 10.5): H in paragraph (1', z isomer

EXAMPLE 12: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate 2,2,2-trichlorethyl

STEP A: (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate 2,2,2-trichlorethyl

Inert gas is mixed with 0.2 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate 2,2,2-trichloroethyl, 3 cm3metilinx the t at room temperature for 3 hours Then add a mixture of water and ice, defend and extracted with methylene chloride. The organic phase is dried and the solvent is evaporated. The residue is subjected to chromatography on silica (eluant : methylene chloride - cyclohexane (7 : 3), resulting in a gain of 0.23 g of the desired product.

Range Yarm: CDCl3; 250 MHz million-1;

1,22 (s), 1,31 (s) of 1.33 (s): CH3paired.; from 1,94 to 2.10 (m): H1and H3; 4,06 (d), 4,39 (d), 4,74 (d), to 4.87 (d), 4.26 deaths (s), 4,70 (s): 2 CH2-X; 5,24 (d) and 5.47 (d):

Source ester was obtained as follows.

Inert gas is mixed with 0.2 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylic acid, 4 cm3of methylene chloride, 280 μl of pyridine and 0,267 g dicyclohexylcarbodiimide. After 5 min add 135 μl of trichloroethanol and a few crystals of dimethylaminopyridine. The mixture is then shaken for 20 h at room temperature, centrifuged and evaporated to dryness. The residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (8 : 2), resulting in a gain 0,316 g of the desired product.

IR spectrum (CHCl3)

Absorption

Acid and HE is Missing

C=0 - 1732, 1719 cm-1< / BR>
The special is s):CH3-C=O; 2,89 (m): =C-CH2-C; 4,70 (s): -CO2-CH2-.

STEP B: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate 2,2,2-trichlorethyl

Inert gas is mixed 0.036 g of sodium hydride as a 50% suspension in oil and 1 cm3toluene, then added at a temperature of about +10oC the solution is 0.135 g hexafluoroisopropanol 0.5 cm3toluene and shaken for 30 min at the same temperature. Then add a solution 0,170 g of the product obtained at Stage A, 1 cm3toluene, shaken for 1 h, incubated at room temperature and again shaken for 1 h then at a temperature of +10oC add 0.1 N. hydrochloric acid to obtain a pH of 1 and shaken for 15 minutes and Then extracted with ethyl acetate, the organic phase is dried and concentrated to dryness. The residue is subjected to chromatography on silica (eluant : methylene chloride - cyclohexane (7 : 3), resulting in a gain of 0.1 g of the target product.

IR spectrum (CHCl3)

Absorption

C=0 - 1746 cm-1< / BR>
C=C - 1627 cm-1< / BR>
Range Yarm: CDCl3; 250 MHz million-1;

1,35(8): CH3paired. 2'; 6,93 (dd): H in p. 1'.

EXAMPLE 13: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate 2,2,2 - trichlorethyl

Inert gas mix 10 cm3methanol and 0,724 g of sodium methylate. Then at a temperature of 0/+5oC slowly add 4 g of the product obtained as described in Step a of Example 12, 30 cm3methanol and shaken for 16 hours at a temperature of about +5oC. Then poured into a mixture of water and ice with the addition of 15 cm32n. hydrochloric acid. Then shaken for 15 min and extracted with methylene chloride, the organic phase is washed with water, dried and cooked until dry. The residue is subjected to chromatography on silica (eluant : methylene chloride - cyclohexane (1 : 1), resulting in a gain 0,879 g of the target product.

Range Yarm: CDCl3; 250 MHz million-1;

1,33 (s): CH3paired. ; 2,10 (d): H1; 3,36 (m): H3; to 3.73 (s): CH3-O-; 4,73(A-B): -CO2= CH2-C; to 5.93(d, J=11,5): H in p. 2'; 6,59 (dd): H in p. 1'. The structure of the CIS, Delta z

EXAMPLE 14: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate 2-chloroethyl

STEP A: (1R, CIS) 2,2-dimethyl 3-(1,3-dibromo 2-oxopropyl) cycle cyclopropane 1-carboxylate 2-chloroethyl and 5 cm3chloroform, then slowly add 100 μl of bromine. Then shaken at room temperature for 2 h and add a mixture of water and ice, shaken for 15 min, defend and extracted with methylene chloride. After that, the organic phase is dried and the solvent is evaporated. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain 0,067 g of the desired product.

Range Yarm: CDCl3; 250 MHz million-1< / BR>
1,20 (s) of 1.26 (s), 1,29 (s) of 1.30 (s): CH3paired.; from 1,84 to 2.00 (m): H1and H3; to 3.64 (t), and 3.72 (t): -CH2Cl; 4,28 (t), and 4.40 (m): -CO2-CH2-; 4,07 (d), 4,20 up of 4.45 (m), 4,28 (m): C-CH2-X; 5,23 (d) and 5.47 (d): =C-CHX-.

Source ester was obtained as follows.

Inert gas is mixed 0,171 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylic acid and 0.7 cm31-bromo-2 chlorethane, and then at a temperature of 0/+5oC slowly added 145 μl of triethylamine and shaken at room temperature. After a few hours, add 20 μl of triethylamine and 0.2 cm3bremgarten. The mixture is shaken just for 20 h at room temperature, after which water is added, also the will eraut chromatography on silica (eluant : cyclohexane - ethyl acetate (75 : 25), resulting in a gain 0.172 g of the desired product.

Range Yarm: CDCl3; 250 MHz million-1;

1,16 (s), 1,23 (s): CH3paired.; and 1.63 (d, J=8,5), 1,48 (m): H1and H3CIS; 2,15 (s): -CH3-CO-; 2,88 (m): -CH2-CO-; 3,66 (t): CH2-Cl; 4,28 (m): -CO2-CH2-.

IR spectrum (CHCl3)

Absorption

C=O - 1720 cm-1< / BR>
Acid is Missing

STEP B: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate 2-chloroethyl

Inert gas is mixed 3 cm3toluene and 0.11 g of sodium hydride as a 50% suspension in oil, and then at a temperature of +5/+7oC slowly add a solution of 0.5 g of 1,1,1,3,3,3-hexafluoroisopropanol 1 cm3of toluene. Then at the same temperature shaken for 45 min and add slowly a solution of 0,341 g of the product obtained as described in Step A, 2 cm3toluene and shaken for 2 h at a temperature of +5/+7oC and for 1 h at room temperature. Then cooled to +10oC, add a little acetic acid, diluted by half, defend and extracted with ethyl acetate. The organic phase is dried and concentrated to dryness. The remainder of ucaut 0.11 g of the target product.

Range Yarm: CDCl3; 250 MHz million-1;

1,32(s) of 1.34(s): CH3paired. ; 2,10 (d), 3,15 (m): H1and H3CIS; 3,69 (t): -CH2-Cl; 4,33 (t): CO2-CH2-; of 5.81 (m): CO2-CH<; 6,01 (d, J=11): H in p. 2'; 6,95 (dd): H in p. 1'.

IR spectrum (CHCl3)

Absorption

C=O integrated. 1760, 1744 and 1726 cm-1< / BR>
C=C 1625 cm-1< / BR>
EXAMPLE 15: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane 1-carboxylate (S) -cyano 3-phenoxybenzyl

Operations are performed as described in Example 9, using at the initial stage of ester obtained in Stage a of Example 7. After treatment in the same conditions as described in Example 9, to obtain the target product.

EXAMPLE 16: (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaplar-propoxy) carbonyl] ethynyl] cyclopropane carboxylate 3,4,5,6-Tetra-hydroptilidae

STEP A : (1R, CIS) 2,2 - dimethyl 3-(1,3-dibromo 2-oxopropyl) cyclopropane 1-carboxylate 3,4,5,6 - tetrahydropyrimidine

Inert gas mixing 0.8 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate 3,4,5,6-tetrahydropyrimidine and 8 cm3of tetrahydrofuran, and then slowly add 1,72 g perbromide pyridinium in the form of the hydrobromide. After 6 hours is about concentrating the filtrate to dryness at a temperature of +25oC under reduced pressure. The residue is subjected to chromatography on silica (eluant : methylene chloride), resulting in getting 0.31 g of the desired product.

Range Yarm: CDCl3; 250 MHz million-1;

1,22 (s), 1,19 (s), 1,25 (s) of 1.30 (s): CH3paired.; 1,76 (d) and 1.34 (m): H1and H3; 1,78 (m): CH2in p. and of 2.38 (m) CH2in p. tetrahydropyrimido cycle; 4,07 (d) 4,36 (d) and 4,28 system (AB): -CO2-CH2Br; 5,22 (d) of 5.55 (d) and 5,57 system (AB): -CO2-CH2-; of 5.40 (d) and 5.42 (d): -COCHBr-.

Source ester was obtained as follows.

Inert gas is mixed 1 g of 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylic acid, 8 cm3of methylene chloride, 1,395 cm3pyridine and 1.29 g of dicyclohexylcarbodiimide, and then at a temperature of +5oC enter a solution of 1.1 g of 3,4,5,6-tetrahydrothiopyrano alcohol in 5 cm3of methylene chloride. Then add a few milligrams of dimethylaminopyridine and shaken for 18 h, allowing the temperature to rise. Then filter and concentrate the filtrate to dryness under reduced pressure at a temperature of +30oC. the Residue is subjected to chromatography on silica (eluant : cyclohexane - ethyl acetate (7 : 3), resulting in a floor(s): CH3paired.; 1,76 (d) and 1.34 (m): H1and H3; 1,78 (m) and of 2.38 (m): CH2in p. and CH2in p. tetrahydropyrimido cycle; 4,07 (d) 4,36 (d) and 4,28 system (AB): -COCH2Br; 5,22 (d) of 5.55 (d) and 5,57 system (AB): -CO2-CH2-; of 5.40 (d) and 5.42 (d): -COCHBr-.

STEP B : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[(1,1,1,3,3,3-hexaphosphate) carbonyl] ethynyl] cyclopropane carboxylate 3,4,5,6-tetrahydropyrimidine

Inert gas is mixed 1 cm3toluene and 20 mg of sodium hydride as a 50% suspension in oil. After that, the mixture is cooled to +5/+10oC and slowly add a solution of 67 mg hexafluoroisopropanol 0.5 cm3of toluene. Then shaken for 30 min at a temperature of 10oC and add a solution of 0.1 g of the product obtained at Stage A, 1 cm3of toluene. After that, the mixture shaken, allowing the temperature to rise. After 2 h, poured into a mixture of 2 N. hydrochloric acid and ice, shake for 5 min and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness at a temperature of +30oC under reduced pressure. The residue is subjected to chromatography on silica (eluant : methylene chloride), resulting in a gain of 0.04 g of the target product.

< 3 (CIS); 1,78 (m) and of 2.38 (m): CH2in p. and CH2in p. tetrahydropyrimido cycle; 5,52 system (AB): -CO2-CH2N; 6,01 (d, J=11,5): H p. 1'; 6,94 (dd, J=10.5 and 11,5): H in p. 2'; 5,80 (m): -CO2-CH-(CF3)2.

EXAMPLE 17 : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate of pentafluorobenzyl

STEP A : (1R, CIS) 2,2-dimethyl 3-(1,3 - dibromo 2-oxopropyl) cyclopropane 1-carboxylate of pentafluorobenzyl

Inert gas is mixed with 1.2 g of (1R, CIS) 2,2-dimethyl 3-(2-oxopropyl) cyclopropane 1-carboxylate of pentafluorobenzyl and 12 cm3tetrahydrofuran (THF). Then at a temperature of +5oC slowly add 2,45 g perbromide pyridinium hydrobromide and shaken for 7 h at a temperature of +5oC. the mixture is Then filtered and concentrated the filtrate to dryness under reduced pressure at a temperature of +25oC. the Residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain of 1.08 g of the desired product.

Range Yarm: CDCl3250 MHz million-1< / BR>
1,20 (s), 1,24 (s) of 1.26 (s) of 1.30 (s): CH3paired.; 1,73 (d) and 1.96 (m): H1and H3; 4,07 (d) 4,37 (d) and 4.26 (s): CO2-CH25,15 and 5,22: -COCH2Br-; 5,20 (d) and 5,41 (d): -COCHBr-.

Source ester receive trace 3-(2-oxopropyl) cyclopropane 1-carboxylic acid, 2 cm3of methylene chloride, 230 μl of pyridine and 0,213 g dicyclohexylcarbodiimide, then add a mixture comprising 0.2 g pentafluorobenzyl alcohol, 1 cm3of methylene chloride and a few milligrams of dimethylaminopyridine. Then the temperature is allowed to rise and shaken for 12 h then filtered, rinsing the filter with methylene chloride and concentrating the filtrate to dryness. The residue is purified by chromatography on silica (eluant : cyclohexane - ethyl acetate (80 : 20). The result is 0.25 g of the desired product.

Range Yarm: CDCl3; 250 MHz million-1< / BR>
1,16 (s) and 1.20 (s): CH3paired.; 1,48 (m) and 1,68 (d):H cyclopropyl (CIS); 2,14 (s): -CO-CH3; 2,88 (m): -COCH2-; 5,15 system (AB): -CO2CH2-.

STEP B : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate of pentafluorobenzyl

Inert gas mix of 0.022 g of sodium methylate and 0.3 cm3methanol, and then at a temperature of 0/+5oC is added slowly a solution of 0.1 g of the product obtained at Stage A, 1 cm3of methanol. Then shaken for 2 h and poured into a mixture of water, ice and 0.75 cm32 N. hydrochloric acid. After that, the mixture shaken for 15 min and extragere temperature +30oC under reduced pressure. The residue is subjected to chromatography on silica (eluant : methylene chloride - hexane (7 : 3), resulting in a gain 0,031 g of the target product.

Range Yarm: CDCl3; 250 MHz million-1< / BR>
1,28 (s) and 1.31 (s): CH3paired.; of 1.93 (d, J=8,5) and of 3.28 (m): H1and H3CIS; and 3.72 (s): -COOCH3; 5,18 (s): -CO2-CH2-; 5,91 (d, J=12): H p. 1; 6,60 (dd, J=12 and 10): H in p. 2'.

EXAMPLE 18 : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-[1,1,1,3,3,3-hexaplar) propoxycarbonyl) ethynyl] cyclopropane 1-carboxylate of pentafluorobenzyl

Inert gas mixing 0.03 g of sodium hydride as a 50% suspension in oil and 1 cm3of toluene. After that, when the temperature of +5/+10oC slowly add a solution 0,099 g hexafluoroisopropanol 1 cm3toluene, shaken for 30 minutes and add a solution of 0.15 g of the product obtained in Stage a of Example 17, 1 cm3of toluene. Then shaken for 2 h, allowing the temperature to rise, and then poured into a mixture of 2 N. hydrochloric acid and ice. Then extracted with ethyl acetate, the organic phase is washed with water, dried her and concentrated to dryness under reduced pressure. The residue is subjected to chromatography on silica, resulting in th is B>3
paired.; 2,03 (d, J=8.5 a) and 3.15 (m): H1and H3CIS; 5,20 system (AB): -CO2-CH2-; 5,80: -CO2-CH; 6,03 (d, J=11,5): H p. 1'; 6,03 (m): H in paragraph (2' Delta z

EXAMPLE 19 : (1R, CIS) 2,2-dimethyl 3-[(Z) 2-(methoxycarbonyl) ethynyl] cyclopropane 1-carboxylate tert-butyl

Inert gas is mixed with 0.02 g of sodium and 0.5 cm3toluene, and then at a temperature of about +5oC slowly add 0.2 cm3of methanol. The mixture is then shaken at room temperature for 30 min, then cooled to +5oC and add a solution 0,0768 of the product obtained at Stage a of Example II, 1 cm3of toluene. Then shaken for 3 h, allowing the temperature to rise, and then acidified with 2 N. hydrochloric acid to pH 3-4. After that add 5 cm3toluene, defend, washed the organic phase with water, dried and the solvent evaporated. The residue is subjected to chromatography on silica (eluant : cyclohexane - simple isopropyl ether (8 : 2), resulting in a gain of 0.03 g of the target product.

Range Yarm: CDCl3250 MHz million-1;

1.26(s), 1,29 (s): CH3paired.; of 1.80(d, J=8,5), 3,14 (dd): H1and H3CIS; 1.44MB(s): CO2tBu; 3,71 (s); CO2CH3; of 5.89(d, J=11,5), of 6.65 (dd, J=11.5 Fenil - cyclopropane-1-carboxylate 2-fluoro-6-cryptomelane.

Stage A: (1R, CIS) 2,2-dimethyl-3-(1,3-dibromo-oxopropyl) cyclopropane-1-carboxylate 2-formativeness.

Mix in the atmosphere of inert gas 1,185 g of (1R, CIS) 2, 2-dimethyl-3-(2-oxopropyl) cyclopropane-1-carboxylate 2 - fluoro-6-cryptomelane and 20 cm3tetrahydrofuran (THF). Add slowly at +5oC 2.5 g of perbromide, then for 3 h support under stirring at +5oC. Filter and concentrate the filtrate to dry under reduced pressure at 25oC. Chromatographic the residue on silica elwira with a mixture of cyclohexane - ethyl acetate (75-25), and obtain 1.1 g of the target product.

Range Yarm: (CDCl3250 MHz h/million) :

1.20 - 1.30: Me (spar); 1.78-2.00-: H1and H3; 4,08(d) and 4.38 (d): Bz-CH2-C; 5,20 - 5,65: the 5.25 to 5.35: 7,34 and 7,52: aromatic H.

The original ether was prepared as follows: mix in the atmosphere of inert gas at 0, +5oC 3.4 g of (1R, CIS) 2, 2-dimethyl-3- (2-oxopropyl) cyclopropane-1-carboxylic acid, 30 cm3of methylene chloride, 4.8 ml of pyridine and 4.5 g of dicyclohexylcarbodiimide, then add a mixture consisting of 4,07 g of 2-fluoro-6-triftormetilfosfinov alcohol, 20 cm3of methylene chloride and a few milligrams of dimethylaminopyridine. Increase the tempo of Trat. Purify the residue by chromatography on silica, elwira a mixture of methylene chloride-isopropyl ether (95-5), and get 4,39 g of the target product.

Range Yarm: (CDCl3250 MHz ppm) :

1.16 (s) and 1,19 (s) : Me (spar); 1.44MB (m): H3; 1,58 (d) H1; 2,15 (s): 2,78 - 3,02: 5,25 (s): O-CH2-; 7,33 and 7,51 : aromatic H

Stage b: (1R, CIS) 2,2-dimethyl-3-[(Z) 2-(methoxycarbonyl) ethinyl]-cyclopropane-1-carboxylate 2-fluoro-6-cryptomelane. Mix in the atmosphere of inert gas 0.083 g of sodium methylate and 1, 12 cm3methanol is then added slowly at 0, +5oC solution of 0,388: g of the product obtained at stage a, 3 cm3of methanol. Stirred for 15 min and extracted with methylene chloride. The organic phase is washed with water and dried and then concentrated until dry in 30oC under reduced pressure.

Chromatografic the residue on silica elwira with a mixture of cyclohexane-ethyl acetate (90-10), and get 9,182 g of the target product.

Range Yarm: (CDCl3; 250 MHz ppm)

1.26 and 1.31: Me (spar); 1,94 (d): H1; 3,26 (d,d: H3; 5,28 : 5,91 (d, d) and 6,46(d, d) 7, 36,7,44 and 7,56: aromatic H.

Example 21

(IR, CIS) 2.2-dimethyl-3-[(Z) 2-(methoxycarbonyl)ethynyl]cyclopropane-1-carboxylate alpha-lilat alpha-cyano-4-fluoro-3-phenoxybenzyl. Mix in the atmosphere of inert gas 0.17 g of (1R, CIS) 2,2-dimethyl-3-(2-oxopropyl) cyclopropane-1 - carboxylate alpha-cyano-4-fluoro-3-phenoxybenzyl and 2 cm3tetrahydrofuran (THF). Slowly add +5oC 0,38 g perbromide pyridinium, then incubated under stirring at +5oC for 7 h Filter and concentrate the filtrate to dryness under reduced pressure at 25oC. Chromatographic the residue on silica elwira with a mixture of cyclohexane-ethyl acetate (85-15), and obtain 0.07 g of the desired product (Mixture of 4 diastereoisomers).

Range Yarm: (CDCl3; 250 MHz ppm)

1.14 TO 1.48 : CH3(spar); 1,88: H1; 2.06 TO: H3; 6.18-6.54: 4.02-4.39: Br-CH2-C=O; 5,12-5,48: 7,00 - 7,40 : aromatic H.

The original ether was prepared as follows.

Mix in the atmosphere of inert gas at ABOUT +5oC 3.4 g of (1R, CIS) 2,2-dimethyl-3-(2-oxopropyl) cyclopropane-1-carboxylic acid, 30 cm3of methylene chloride, 4.8 ml of pyridine and 4.5 g of dicyclohexylcarbodiimide, then add a mixture of 4.15 g of alpha-cyano-4-fluoro-3-phenoxybenzyl alcohol, 20 cm3of methylene chloride and a few milligrams of dimethylaminopyridine, raise temperature and stirred for 12 hours Filtered, washed filter meticu methylene chloride-isopropyl ether (95-5), and gain of 2.45 g of the desired product (mixture of 2 diastereoisomers).

An NMR spectrum: (CDCl3; 250 MHz ppm):

isomer A:

1,19 and 1,24: Me (spar); 1,50 and 1.6 (d): H3and H12,08: 2,82: 6,22: 7.00 and 7,30: aromatic H.

the isomer IN:

of 1.09 and 1.20:Me (spar); 1,62 H1and H3; 2,15; 2,85; 6,21: 7,00-7,37: H aromatic.

Stage (1R, CIS) 2,2-dimethyl-3-[(Z) 2-(methoxycarbonyl) ethynyl]cyclopropane-1-carboxylate alpha-cyano-4-fluoro-3-phenoxybenzyl.

Work in conditions identical to the conditions described on the stage In the preceding example, but come from 0.07 g of the product obtained in stage A. Obtain the target product identified by NMR spectrum.

Example 22.

(1R, CIS) 2,2-dimethyl-3-[(Z) 2-(methoxycarbonyl)ethinyl]cyclopropane-1-carboxylate 5-benzyl-3-furylmethyl.

Stage A: (1R, CIS) 2,2-dimethyl-3- (1,3-dibromo-2-oxopropyl)cyclopropane-1-carboxylate 5-benzyl-3-furylmethyl.

Mix in the atmosphere of inert gas 0.34 g of (1R, CIS) 2,2 - dimethyl-3- (2-oxopropyl)cyclopropane-1-carboxylate 5-benzyl - 3-furylmethyl and 4 cm3tetrahydrofuran (THF). Add slowly at +5oC 0,716 g perbromide, then support under stirring at +5oC for 6 hours Filtered and karimnia, elwira with methylene chloride, and obtain 0.21 g of the target product.

An NMR spectrum: (CDCl3; 250 MHz ppm) :

1,14-1,26: CH3(spar) and 1.60-1,95: H1and H3; 3,02 and 3,93: CH2F; ANDROID 4.04-4.25 IN: 4,80-5,00; O-CH2-C; 5,20 6,10 - 7,40; H aromatic.

The original ether was prepared as follows.

Mix in the atmosphere of inert gas at ABOUT +5oC 1,02 g of (1R, CIS) 2,2-dimethyl-3-(2-oxopropyl)cyclopropane-1 - carboxylic acid, 10 cm3of methylene chloride, of 1.34 ml of pyridine and 1,334 g dicyclohexylcarbodiimide, then add a mixture consisting of 1,247 g 5 benzyl-3-furylmethanol, 8 cm3of methylene chloride and a few milligrams of dimethylaminopyridine. Increase temperature and stirred for 12 hours Filtered, washed the filter with methylene chloride and concentrating the filtrate to dryness. Purify the residue by chromatography on silica, elwira mixture of methylene chloride, and obtain 1.4 g of the target product.

An NMR spectrum: (CDCl3, 250 MHz ppm): 1,19 1,14 and: CH3(spar); 1,44: H3; 1,57: H1; 2,12 2,86: 3,94: CH2F.; A 4.86: O-CH2-; 6,03-7,34: N aromatic.

Stage; (1R, CIS) 2,2-dimethyl-3-[(Z) 2-(methoxycarbonyl) ethynyl]cyclopropane-1-carboxylate 5-bemail-3-furylmethyl. Work in terms identical to the terms of identifitsirovany using NMR-spectrum.

1. The method of obtaining esters of 2,2-dimethyl 3-[(Z)-1-propenyl]cyclopropanecarboxylic acid of the formula I

< / BR>
R represents an ester residue, split in neutral or acid medium and which is linear or branched alkyl radical comprising from 1 to 18 carbon atoms, possibly substituted by one or more halogen atoms, or a benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of the formula

< / BR>
where R2is hydrogen or methyl;

R3- aryl;

or a radical of the formula

< / BR>
where R4- CN; hydrogen;

or a radical of the formula

< / BR>
where R4as mentioned above;

R5is fluorine or chlorine, or bromine, or hydrogen;

or a radical of the formula

< / BR>
where R6, R7, R8, R9is hydrogen or methyl;

S/1 symbolizes tetrahedrite;

thus R1is a hydrogen or alkyl radical is a saturated linear or branched and has 1 to 18 carbon atoms, possibly substituted by one or more halogen atoms, in the form of mixtures of isomers or of the isomers separated on the level cyclopropanol the Stalinist KKE about two equivalents of halogenation means of obtaining the compounds of formula III

< / BR>
where R is defined above;

Hal is a halogen atom,

in the form of a mixture of isomers at position (1') of an atom of carbon, after which the compound obtained is subjected to processing the main tool in the presence of the compounds of formula R1OH, for which R1defined above, if necessary in an environment appropriate co-solvent.

2. The method according to p. 1, characterized in that as halogenation tools use glorious or promiseyou Supplement.

3. The method according to p. 2, wherein the halogenation agent is selected from the group consisting of bromine - or chlorine-containing compounds and which is N-bromosuccinimide, or N-chlorosuccinimide, or N-chloro - or N-bromoacetamide, or perbromide, or perchloride pyridinium, or perbromide or perchloride hydrobromide, or pyridinium hydrochloride.

4. The method according to PP.1 to 3, characterized in that as the asset is used as a compound selected from the group consisting of hydride or alcoholate, or amide or carbonate of alkali or alkaline earth metal or tertiary amine.

5. The method according to PP.1 to 4, characterized in that R is an ester residue, the split is about 18 carbon atoms and substituted by one or more chlorine atoms or bromine.

6. The method according to PP.1 to 5, characterized in that R represents an alkyl radical comprising from 1 to 4 carbon atoms and which is tert.-bootrom, or stands, or ethyl, substituted by one or more chlorine atoms or bromine, such as bromo - or chloromethyl, or mono-, or di-, or tribrom-or chloroethyl.

7. The method according to PP. 1 to 4, characterized in that R represents an ester residue selected from the group consisting of a benzyl radical, substituted by 1 to 5 fluorine atoms, or a radical of the formula

< / BR>
where R4and R5specified in paragraph 1,

or a radical of the formula

< / BR>
where R4specified in paragraph 1,

or a radical of the formula

< / BR>
where R2and R3specified in paragraph 1,

or a radical of the formula

< / BR>
where R6- R9specified in paragraph 1;

the symbol S/1 means tetrahedrite.

8. The method according to PP. 1 to 7, characterized in that the compounds of formula R1OH is used as a compound in which R1represents a linear or branched alkyl radical comprising from 1 to 8 carbon atoms, such as ethyl or tert.-botilony radical or a linear or branched alkyl radical comprising from 1 to 8 carbon atoms, substituted by one realy II structure (IR, CIS), in which R represents the residue (R, S) or (S)--cyanoprokaryota alcohol or the residue (R, S) or (S)--cyano-4-fluoro-3-phenoxybenzyl alcohol, and the compound of formula R1OH, where R1is methyl or ethyl, or 1,1,1,3,3,3-geksaftorpropena or tert.-botilony radical.

10. The compounds of formula I

< / BR>
where R is methyl substituted by chlorine or bromine, or ethyl, substituted by 1 or 2, or 3 atoms of chlorine or bromine,

R1is hydrogen, or alkyl radical, which is saturated linear or branched radical and containing from 1 to 18 carbon atoms, possibly substituted by one or more atoms of halogen,

as an intermediate connection.

11. The compounds of formula III

< / BR>
where R is an ester residue, cleaved in acidic or neutral medium and which is linear or branched alkyl radical comprising from 1 to 18 carbon atoms, possibly substituted by one or more halogen atoms, or a benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of the formula

< / BR>
< / BR>
< / BR>
in which R2- R9specified in simmetrichnogo carbon atoms, associated with cyclopropane ring,

as an intermediate connection.

12. The compounds of formula II

< / BR>
where R is the ester residue, split in neutral or acid medium and which is linear or branched radical comprising from 3 to 18 carbon atoms, or containing from 1 to 18 carbon atoms and substituted by one or more halogen atoms, or a radical of the formula

< / BR>
< / BR>
< / BR>
values of R2- R9specified above;

the symbol S/1 means tetrahedrite,

as intermediate compounds.

 

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The invention relates to the production of compounds which are useful as intermediates for obtaining spirotaenia derivatives of glutarimide, especially in connection with a registered brand name candoxatril and systematic name /S/-CIS-4-/1-[2-/5-intenrational/-3-/2-methoxyethoxy/propyl] -1 - cyclopentanecarboxylic/-1 cyclohexanecarbonyl acid

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