Derivatives of heterobinuclear

 

(57) Abstract:

Usage: in agriculture as pesticides, especially against arthropod pests. The inventive product-geteroseksualen f-ly I with certain values radicals. Connection structure of f-crystals of I are given in the text description. 5 table.

The present invention relates to new chemical compounds having pesticidal activity. Disclosed are methods for their preparation and compositions containing them and their use in pest control. More specifically, the invention relates to the class of heterobinuclear.

The use of certain 2,6,7-dioxabicyclo [2.2.2] -octanol disclosed in applications for Europatent N 152229 /1/, N 211598 /2/, N 216625 /3/ and N 216624 /4/. Now discovered that derivatives of these compounds show significant pesticide activity.

In European patent application 152229 and in article I. Agric. Food. Chem. 33, 1085, 976-980 along with other disclosed compounds of the formula (O):

< / BR>
where the substituents in positions 1 and 4 are defined as organic substituents having pesticidal activity. Examples of when the substituent in position 1 is optionally substituted by phenyl,3-7cycloalkyl,5-6 cycloalkyl and phenyl. Those compounds that do not contain cycloalkyl group or optionally substituted phenyl group in position 1, as reported, was relatively inactive.

In European patent applications 211598, 216624 and 216625 along with other disclosed compounds of the formula:

< / BR>
where Y and Y1is oxygen or S/O/mwhere m is 0,1 or 2, Z is CH2CH2CH2O or CH2S, the substituent in position 1 is optionally substituted by phenyl, cycloalkyl or cycloalkenyl; the substituent in position 3 is hydrogen, halogen, optionally substituted alkyl, alkenyl, quinil or nitrile; the substituent in position 4 is optionally substituted hydrocarbon group.

Thus, the present invention provides a compound of the formula

< / BR>
where Y and Y1O or S

Z CH2O or CH2S,

R1a hydrogen atom, R2hydrogen atom, a C1-C3alkyl unsubstituted or substituted by halo or cyano,

AH contains from 4 to 20 carbon atoms,

where X is a hydrogen atom,

And straight or branched C2-C12-alkyl, unsubstituted or substituted C1-C6- quinil,what Rupay or1-C6-alkyloxyaryl,2-C6alkenyl, nesamani or substituted by a halogen atom2-C12alkenyl, unsubstituted or substituted by a hydroxy-group, C1-C6-alkoxygroup or Si(CH3)3group, a C1-C6-alkyloxyaryl, N-(C1-C6quinil)carbarnoyl or N-(C11-C2- quinil)acetaminophe,

R C1-C6-alkyl unsubstituted or substituted

C2-C6-alkoxygroup,

WITH2-C6alkenyl,

WITH3-C6-cycloalkyl nesamani or substituted by a halogen atom.

When determining Z first mentioned atom attached to position 4 of the system bicyclic ring.

When R stands for alkyl, alkenyl or quinil, cycloalkyl or cycloalkenyl group, it preferably contains up to 6 carbon atoms. Conveniently, when R is substituted, that was before 7 Deputy when the Deputy is fluorine, 3 Deputy, when substituents are chlorine or bromine, or 1 Deputy, when it is other than halo.

Suitable, if R denotes an aliphatic or alicyclic group containing from 2 to 8 carbon atoms, or phenyl, each of them optional is use. Most suitable when R represents propyl, butyl, pentyl, C2-C5alkenyl or quinil, cyclopropylmethyl, C3-C7-cycloalkyl or phenyl, each of which is optionally substituted with fluorescent, chloro or bromo, for example, n-propyl, n-butyl, and-butyl, sec-butyl, t-butyl, prop-2-enyl, 2-methylprop-2-enyl, but-3 - enyl, phenyl, cyclopentyl or cyclohexyl. Preferably, when R represents n-propyl, n-butyl, and-butyl, t-butyl or phenyl.

Suitable, if R1denotes hydrogen, halo, cyano, methyl or ethyl, each of which is optionally substituted by cyano, methoxy, methylthio, chloro, bromo or fluorescent. The most suitable, if R1denotes hydrogen, methyl, cyano, trifluoromethyl or ethyl. Preferably, when R1denotes hydrogen, methyl, cyano or trifluoromethyl.

Suitable, if R2denotes hydrogen, cyano, methyl or trifluoromethyl. The most suitable, if R2denotes hydrogen or methyl. Preferably, if R2denotes hydrogen. Preferably, when Z represents CH2S or CH2O.

Suitable, if Y and Y1both selected from oxygen or sulfur.

Suitable, if a represents C2-C8-nah hydrocarbonous GRU who represents C5-C8-nah hydrocarbonous group which optionally contains one heteroatom and ends in the fragment - C C adjacent to X. Preferably, refers to a group -(CH2)4C C-group group-CH = CH(CH2)2C C -, a group of CH2O(CH2)2C C -, a group -(CH2)3CH(CH3)C C -, a group -(CH2)2CH(CH3)CH2C C -, a group-CH2CH(CH3)(CH2)2-C C -, a group -(CH2)2CH = CHC C - or a group -(CH2)3C C -, and X is C1-C4-alkyl, optionally substituted hydroxy, C1-C4-alkoxy or C1-C4-acyloxy or 1-3 galeatomy. In the second preferred embodiment, And represents-CH2CH2-, -CH= CH - or - C C - group and X denotes a group

< / BR>
Suitable when R8, R9and R10each selected from chloro, bromo, methoxy or methyl, optionally substituted by methoxy or fluorescent.

The compounds of formula (I) can exist in multiple isomeric forms. The present invention offers the individual isomers of the compounds of formula (I) and their mixtures. The present invention also encompasses the compounds of formula (I) containing radioactive isotopes, in particular those in which a respectful group of compounds of the present invention are the compounds of formula (IA)

< / BR>
where Rarepresents C2-C10-alkyl, alkenyl or quinil, each optionally substituted or methylamide, cyano, halo, C3-C4- cycloalkyl, optionally substituted by halo, C1-C4-alkoxy, optionally substituted by halo, or a group S(O)mR3defined above, or Rarepresents C3-C10-cycloalkyl, C4-C10- cycloalkenyl or phenyl, each optionally substituted C1-C4- alkoxy, C1-C3-alkyl, optionally substituted up to C-x galeatomy, C2-C4-quinil, halo, cyano or a group S(O)mR3defined above;

R1aand R2amay be the same or different and each denotes hydrogen, halo, or aliphatic group containing up to 3 carbon atoms, optionally substituted by halo, cyano, C1-C4-alkoxy or a group S(O)m'R4defined above; allylcarbamate containing up to 6 carbon atoms, or quinil, substituted three-TO1-C4-alkylsilanes, or R1adenotes COO-C1-C4- alkyl, cyano, gandemer, or R1aand Raand the carbon atoms to which they are attached, form a5-C7-carbocyclic Col
R15represents a simple bond or a group R15'where R15'refers to a group or optionally substituted by 1-5 methyl groups or galeatomy, where W represents oxygen, a group S(O)pwhere p is 0, 1 or 2, or (CH2)rwhere r is 1, 2 or 3, and a fragment of (C C)tXaattached to the position a or b ring, or R15'denotes an aliphatic chain containing from 1 to 8 carbon atoms, where one or two heteroatoms may be placed, and the chain, or R15'optionally substituted by 1-4 substituents, which may be the same or different and are independently from each other are selected from hydroxy, oxo, halo, C1-C4-alkyl or C1-C4-alkoxy, each of which is optionally substituted up to 3 galeatomy,1-C4-acyloxy, epoxy,1-C4-alkylidene group1-C66-carbalkoxy, cyano, a group S(O)p'R4awhere p' is 0, 1 or 2 and R4astands WITH1-C4-alkyl, Xaselected from hydrogen, halo, C1-C10-hydrocarbide, optionally substituted hydroxy, C11-C4-alkoxy or C1-C4-alloctype or 1-3 galeatomy, or Xaoboznachilsya or different and each denotes hydrocarbonous group, containing from 6 to carbon atoms, optionally substituted by 1-3 halo, cyano, alkoxy, alkylthio, acyloxy or carbalkoxy containing 6 carbon atoms, or Xadenotes a group R16CCA, where R16stands WITH1-C4-alkyl;

g denotes 0 or 1, and t represents 1 or 2, provided that the sum of g and t is not greater than 2;

Y and Y1the same or different and each selected from oxygen and S(O)n'where n' is 0, 1 or 2; Z represents CH2O or CH2S(O)n, where n is 0, 1 or 2, except that Xacannot be hydrogen when g is 0, t is 1 and R15indicates a simple relationship.

Suitable heteroatoms to be placed in alkylenes chain include oxygen, nitrogen and sulfur, and sulfur optionally oxidized as sulfoxide or sulfon. The atoms of oxygen and nitrogen can adjoin to each other, and in this case they can form the oxime.

Suitable and preferred values for the groups Ra, R1a, R2a2, Y, Z, and Y1defined above for the groups R, R1, R2, Y, Z, and Y1respectively. Suitable, if R15represents a simple bond, 1,4-cyclohexyloxy group or an aliphatic chain, as defined above, which is a hadenotes hydrogen, C1-C3-alkoxymethyl or group SiR17R18R19where R17R18and R19the same or different and each represents C1-C4-alkyl. Preferably, if n is equal to 0.

One preferred group of compounds of formula (I) of the present invention are the compounds of formula (IB):

< / BR>
where Ra, R1a, R2aXaY, Y1, Z and t have the above meanings and R15arepresents a simple bond or a group R15'defined above.

Suitable, if R15adenotes a 1,4-cyclohexyl, t is 1 and Xadenotes hydrogen or C1-C4-alkyl, optionally substituted hydroxy, C1-C4-alkoxy or C1-C4-alloctype, or 1-3 galeatomy, or R15arepresents a simple bond, t is 1 and Xastands WITH1-C44-alkyl, optionally substituted hydroxy, C1-C4-alkoxy or C1-C44-alloctype or 1-3 galeatomy. Xapreferably refers to the tertiary group. Preferably, if R15adenotes cyclohexyl and Xadenotes hydrogen, or R15arepresents a simple bond and Xaobuchaet the compounds of formula (IC):

< / BR>
where Rbstands WITH2-C10-nah hydrocarbonous group, optionally substituted by cyano, halo, C1-C4-alkoxy or a group S(O)mbR3bwhere R3bstands WITH1-C4-alkyl and mbis 0, 1 or 2, or Rbdenotes phenyl, optionally substituted C1-C4-alkoxy, C1-C3-alkyl, C2-C4-quinil, halo, C1-C4-haloalkyl, cyano or a group S(O)mbR3bdefined above;

R1band R2bmay be the same or different and each denotes hydrogen, halo, or C1-C3-aliphatic group, optionally substituted by halo, cyano, C1-C5-carbalkoxy or1-C4-alkoxy; a group S(O)m'R4where m' is 0, 1 or 2 and R4stands WITH1-C4-alkyl, C2-C3-quinil, cyano, gandemer or1-C5-carbalkoxy, or R1band Rband the carbon atoms to which they are attached, form a C5-C7-carbocyclic ring, optionally substituted by halo, C1-C3the alkyl or alkoxy or C2-C3-alkenyl;

R8, R9have the above meanings and R20-C6-aliphatic chain, which may contain one or two heteroatoms and/or double bond, but not a triple bond, is introduced into the circuit, and which may be substituted by 1-4 substituents, same or different, each independently selected from hydroxy, oxo, halo, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-acyloxy, epoxy,1-C4-alkylidene group, C1-C6- carbalkoxy, C1-C4-haloalkyl or cyano;

D represents a simple bond or a group CH2O, CH2S(O)nwhere n is 0, 1 or 2, or D denotes a 1,2-cyclopropylamino group;

Y and Y1and Z have the above meanings, with the proviso that B cannot be a simple bond or a methylene group, when D represents a simple bond.

Suitable when Rbdenotes propyl, butyl, pentyl, C2-C5alkenyl or quinil, C5-C7-cycloalkyl or phenyl, each of which is optionally substituted with fluorescent, chloro or bromo. The most suitable, if Rbdenotes n-propyl, n-butyl, and-butyl, sec-butyl, t-butyl, phenyl, cyclopentyl or cyclohexyl, and preferably, if Rbdenotes n-propyl, n-butyl, and-butyl or t-butyl.

< is cyano, methoxy, methylthio, chloro, bromo or fluorescent. The most suitable, if R1bdenotes hydrogen, methyl, cyano, trifluoromethyl or ethyl. Preferably, if R1bdenotes hydrogen, methyl, cyano or trifluoromethyl.

Suitable heteroatoms for inclusion in b are oxygen, nitrogen and sulfur, and sulfur optionally oxidized as sulfoxide or sulfon.

Suitable, if R8, R20and R9each chosen from chlorine, bromine, methoxy or methyl, optionally substituted by methoxy or fluorescent.

Suitable, if a denotes the group (CH2)2or-CH=CH-.

Suitable, if D denotes a simple link.

Suitable and preferred values for the groups R2b, Z, Y and Y' are defined above for groups of R2, Z, Y and Y' respectively.

Preferred compounds of the present invention include:

1-(Gex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]octane

1-(Penta-4-inyl)-4-propyl-3-trifluoromethyl-2,6,7-dioxabicyclo[ 2.2.2]octane

1-(Gex-5-inyl)-4-propyl-3-trifluoromethyl-2,6,7-dioxabicyclo[2.2.2]octane

1-(Penta-4-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]-octane 3-carbonitril

1-(Gex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]Octan-3 - carbonitril

4-(W2] octane

4-t-Butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2.2.2]octane

4-t-Butyl-1-(6-trimethylsilyloxy-5-inyl)-2,6,7-dioxabicyclo[2.2.2] octane

1-(4-Ethynylcyclohexanol)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane

4-t-Butyl-1-(4-ethynylcyclohexanol)-2,6,7-dioxabicyclo[2.2.2] octane (CIS - and TRANS-isomers)

4-t-Butyl-1-(3,3-dimethylbutan-1-inyl)-2,6,7-dioxabicyclo[2.2.2] octane

1-(3,3-Dimethylbutan-1-inyl)-4-propyl-2,6,7-dioxabicyclo [2.2.2] Octan-C-carbonitril

4-t-Butyl-1-(Gex-5-inyl)-2,6,7-dioxa-7-diabetico[2.2.2] octane

1-(Gex-5-inyl)-4-propyl-2-oxa-6,7-diabetico[2.2.2]octane

1-(Gex-5-inyl)-4-propyl-2,6,7-trimebutina[2.2.2]octane

4-t-Butyl-1-[2-(prop-2-initio)ethyl]-2,6,7-dioxabicyclo [2.2.2]octane

4-Propyl-1-[2-(prop-2-initio)ethyl]-2,6,7-dioxabicyclo [2.2.2]octane

4-t-Butyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-dioxabicyclo[2.2.2]octane

4-Propyl-1-[2-(prop-2-ynyloxy)ethyl] -2,6,7-dioxabicyclo [2.2.2] -Octan-C-carbonitril

1-(but-3-Unlocker)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane

4-t-Butyl-1-(but-3-Unlocker)-2,6,7-dioxabicyclo[2.2.2] octane

1-(but-3-Unlocker)-4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

4-t-Butyl-1-(hept-6-inyl)-2,6,7-dioxabicyclo[2.2.2]octane

1-(Hept-6-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]Oct the,6,7-dioxabicyclo[2.2.2] Octan-3-chronical

1-(Gex-5-inyl)-4-(prop-2-enyl)-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

1-(Gex-5-inyl)-4-(prop-2-enyl)-2,6,7-dioxabicyclo[2.2.2] Octan-3-carbonitril

1-(but-3-Unlocker)-4-(prop-2-enyl)-2,6,7-dioxabicyclo[ 2.2.2]Octan-3-carbonitril

4-(but-3-enyl)-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

4-t-Butyl-1-(4-metrex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] octane

1-[2-(but-3-enyloxy)-ethyl]-4-propyl-2,6,7-dioxabicyclo [2.2.2]octane

1-[1-(but-3-ynyloxy)ethyl]-4-propyl-2,6,7-dioxabicyclo [2.2.2]octane

1-(but-3-initimate)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane

4-t-Butyl-1-(but-3-initimate)-2,6,7-dioxabicyclo[2.2.2] octane

4-Butyl-1-(Gex-5-inyl)-2-oxa-6,7-diabetico[2.2.2]octane

4-t-Butyl-1-(Gex-5-inyl)-2-oxa-6,7-diabetico[2.2.2]octane

4-t-Butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] Octan-3 - carbonitril

1-(Gex-5-inyl)-4-isobutyl-2,6,7-dioxabicyclo[2.2.2]Octan-3 - carbonitril

4-Ethoxymethyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

1-(1-Metrex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane

4-t-Butyl-1-(1-metrex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] octane

1-(1-Metrex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

Methyl 7-(4-propyl-2,6,7-trioxa the butyl-2-oxa-6,7-diabetico[2.2.2] octane

1-(Gex-5-inyl)-3-methyl-4-propyl-2-oxa-6,7-diabetico [2.2.2]-octane

1-(3-Metrex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

1-(2-Metrex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

1-(3,3-Dimethylbutan-1-inyl)-4-isobutyl-2,6,7-dioxabicyclo [2.2.2] -Octan-C-carbonitril

1-(but-3-Unlocker)-4-propyl-2,6,7-trimebutina[2.2.2] octane

1-(TRANS-4(e)-ethynylcyclohexanol)-4-propyl-2,6,7-dioxabicyclo[2.2.2]OK - tan-3-carbonitril

4-Propyl-1-[(E)(Z)-6-(trimethylsilyl)Gex-3-EN-5-inyl] -2,6,7 - dioxabicyclo[2.2.2]Octan-3-carbonitril

1-[(E)(Z)-Gex-3-EN-5-inyl] -4-propyl-2,6,7-dioxabicyclo [2.2.2] Octan-C-carbonitril (E:2 1:2)

1-[(E)(Z)-7-Meloxicam-3-EN-5-inyl] -4-propyl-2.6.7-dioxabicyclo[ 2.2.2]Octan-3-carbonitrile (E: Z 1:2)

1-[(E)(Z)-7-Hydroxymet-3-EN-5-inyl] -4-propyl-2,6,7-dioxabicyclo[ 2.2.2]Octan-3-carbonitril

4-t-Butyl-1-[(E)-Gex-1-EN-5-inyl] -2,6,7-dioxabicyclo [2.2.2]-octane-3-carbonitrile

4-Propyl-2,6,7-dioxabicyclo[2.2.2]octane-1-carboxaldehyde the oxime

0-(2-inyl)ether

1-(Gex-5-inyl)-4-isobutyl-2,6,7-trimebutina[2.2.2]octane

1-(Gex-5-inyl)-4-phenyl-3-oxa-6,7-diabetico[2.2.2] octane 4-Propyl-1-(4-metrex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] Octan-3-carbonitril

4-Ethyl-1-(Gex-5-inyl)-2,6,7-threat is Teal-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

4-Isobutyl-1-(3-metrex-5-inyl)-2,6,7-dioxabicyclo [2.2.2] Octan-3-carbonitril

1-[(S)-3-Metrex-5-inyl] -4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-3-carbonitril

1-(2-Metrex-5-inyl)-4-prop-2-enyl)-2,6,7-dioxabicyclo[2.2.2]octane-- 3-carbonitril

4-t-Butyl-1-(3,3-dimethylbutyl)-2,6,7-dioxabicyclo[2.2.2] octane

1-(3,3-Dimethylbutyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] Octan-C-carbonitril

1-[(E)-3,3-Dimethylbutan-1-enyl]-4-propyl-2,6,7-dioxabicyclo[2.2.2]Octan - 3-carbonitril

1-(t-Butylthioethyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]Octan-carbonitril

1-[(Z)-1-fluorescent-3,3-dimethylbutan-1-enyl] -4-propyl-2,6,7-dioxabicyclo[ 2.2.2]Octan-C-carbonitril

1-(Hept-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2]octane

The term "gidrolabilna" group refers to alkyl, Alchemilla (including cyclic alkyl and alkenyl, as well as alkyl and alkenyl, substituted cyclic alkyl and alkenyl), Alchemilla, aryl and kalkilya group. "Hydrocarbonate" implies hydrocarbonous group as defined above, when attached to the oxygen.

The term "aliphatic group" means an alkyl, Alchemilla or Alchemilla group.

The term "halo" refers to the fluorescent, chloro, bromo im in this area to obtain similar compounds, for example:

(1) when Y and Y1denote hydrogen and Z represents CH2O:

a) the cyclization of the compounds of formula (II):

< / BR>
where R, R1, R2And X have the above meanings, in the presence of an acid catalyst. Efrat boron TRIFLUORIDE is particularly preferred acid catalyst for the cyclization, which is usually carried out in an inert solvent, such as galijasevic hydrocarbon, typically dichloromethane, at ambient temperature or below, such, for example, from -100 to 50oAnd, usually from -70 to -25oC.

The compounds of formula (II) can be obtained by the interaction of the compounds of the formula (III) and (IV):

< / BR>
< / BR>
where R, R1, R2And X have the abovementioned meanings and L represents tsepliaeva group, such as halo or hydroxy. This reaction is conveniently carried out in the conditions, well known to the person skilled in the art, for example, when L represents halo, in an inert solvent in the presence of a base at non-extremal temperatures, and when L represents hydroxy, in an inert solvent in the presence of a condensing agent in the non-extremal temperature. When L represents halo, golozhabernyi WhiteLine base; when L denotes hydroxy, dimethylformamide is suitable solvent, dicyclohexylcarbodiimide is the preferred condensing agent; and the reaction is conveniently carried out at a temperature of from -50 to 100oC, preferably from 0 to 25oC.

The compounds of formula III can be obtained, as described in simultaneously considering applications for Europatent N 211598 and 216624. The compounds of formula IV can be obtained by methods well known to the person skilled in the art, the synthesis XA-CO2H (HA 4-ethynylcyclohexanol) described in Appendix 1.

b) when a contains terminal fragment C C:

1) interaction connection HC C - X with a compound of formula (V):

< / BR>
where R, R1and R2have the above values, AC C forms a group and L1means tsepliaeva group. Suitable otsepleniya groups include halides such as bromine. The reaction can conveniently be in a strong base, such as utility, lithium amide or sodium amide, at ambient temperature or below, such, for example, from -70 to 30oC, in an inert solvent, typically tetrahydrofuran or diethyl ether. Liquid ammonia is a suitable solvent, when sootvetstvujushij compounds of the formula (VI):

< / BR>
The compounds of formula (VI) can be obtained and cyklinowanie in similar conditions used to obtain and cyclization of compounds of formula (II),

IIwhen a contains a terminal fragment of C C and X denotes hydrogen, the interaction of a strong base with a compound of formula (VII):

< / BR>
where R, R1, R2AND1Y, Y1and Z have the above meanings, and Q represents a group capable of being converted into tinylove group, e.g. the group CH=C(Gal)2, (Gal)CH=CH2or

where Gal represents chloro or bromo, lk represents C1-C4- alkyl.

The reaction can conveniently be by methods well known to the person skilled in the art, for example, where 9 denotes the group-CH=((Gal)2at a temperature of about or below room temperature, for example, from -70 to 25oC, in an inert solvent, as a rule, ether such as tetrahydrofuran.

Utility is a strong base for use in this reaction. The educt of the formula (VII) can be obtained by reaction of compounds of formula (VIII)

with the compound of the formula (lkO)3S-A1HE=S(Gal)2or by cyclization of compounds similar to the compound of formula (VI), where LIt link - CH = CH - C C - X interaction of the corresponding compounds of formula (IX):

< / BR>
with HC C - X, where R, R1, R2X and Gal have the above values and A3- CH = CH - C C - X denotes groupco AH, defined above. This reaction is carried out in the presence of a suitable palladium catalyst, a well-known specialist in this area for this type of reaction, for example bystroprotochnogo dvuhgolosnogo palladium, and catalytic amounts of copper halide such as copper iodide. The reaction is usually carried out in the presence of a basic solvent, such as diethylamine or triethylamine, at non-extremal temperatures, for example from -50 to 100oSince, as a rule, at a temperature of 25oWhen Gal represents iodine or bromine.

(C) when a contains group-NH-, the interaction of the compounds of formula (X):

< / BR>
connection NH2CH2AND3-X, where R, R1, R2X have the above meanings, lk refers to a group WITH1-C4-alkyl and A2CONHCH2A3X denotes a group A-X, defined above. This reaction is carried out in an inert solvent, suitable, alkanol, such as methanol, non-extremal temperatures, for example from 0 to 100oWith, the compounds of formula (X) can be obtained by well known methods, for example, as described for similar compounds in applications for Europatent N 152229 and N 211598.

(d) when a contains a group-COO-, the interaction of the compounds of formula (XI):

< / BR>
or its alkali metal salt, with a compound X AND3CH2Gal, where R, R1, R2and X have the above meanings, Gal represents halogen, for example bromine or chlorine, and A2CO2CH2A3X denotes a group A-X, defined above. This reaction is carried out in an inert solvent, suitable polar aprotic solvent such as dimethylformamide, at non-extremal temperatures, for example from 0 to 180oWith conveniently from 0 to 30oC.

(e) when a contains a group-CH=NO-, the interaction of the compounds of formula (XII):

< / BR>
with the compound of the formula XC CCH2- Gal, where R, R1, R2X and Gal have the above values. This reaction is carried out in an inert solvent, suitable, alkali metal alkoxide, such as sodium methylate, when non-extremal temperatures, for example from 20 to 30oC. the compounds of formula (XII) can be obtained by methods well known to the person skilled in the art, for example as shown in Annex 4.

(f) when a contains group-the 1
1, R2and X have the above meanings and A2CH2OCOA3-X represents the OH group as defined above. This reaction occurs in an inert solvent, usually Alojamientos hydrocarbon, such as dichloromethane, at non-extremal temperatures, for example from 0 to 100oC, conveniently from 20 to 30oC. the Reaction is preferably carried out in the presence of binders, such as carbodiimide, such as dicyclohexylcarbodiimide, and in the presence of a catalyst such as 4-dimethylaminopyridine. The compounds of formula (XIII) can be obtained by methods well known to the person skilled in the art, for example as described for similar compounds in applications for Europatent N 152229 and 211598.

(II) when n' is 0, Y10 or S, Y is 0 or S, Z is CH2or CH2O, the interaction of the compounds of formula (XIV) with the compound of the formula (AlkO)3CAX

< / BR>
where R, R1, R2AND, X, Y, Y11 and Z have the above meanings and lk refers to a group WITH1-C4-alkyl. Condensation occurs in the presence of an acid catalyst, for example a mineral acid such as concentrated hydrochloric acid or Ateret boron TRIFLUORIDE and/or p-toluensulfonate. P>oC. the compounds of formula (XIV) can be obtained as described in the application for Europatent N 216624, or as described in Appendix 2. The compounds of formula (XIV), where Y=Y1=S, Z=CH2S and R1=R2=H, can be also obtained by the method described by G. R. Franzen and G. Binsch I. Amer. Chem. Soc. 1973, 95, page 175, and D. I. Martin, and C. R. Shea, J. Org. hem. 1968, 33, page 1275. Compounds of the formula (AlkO)3CAX can be obtained by basic methods of synthesis of orthoepical described by S. M. McElvain and R. E. Stam, J. Amer. Chem. Soc. 1955, 77, pp. 4571.

(III) when Z is CH2S or CH2O, and Y and Y1denote sulfur, the interaction of the compounds of formula (XV):

< / BR>
connection L2AX, where R, R1, R2And X have the above values, Z1denotes CH2S or CH2O and L2means tsepliaeva group, such as halo. The reaction is suitable to implement in the presence of a strong base, such as utility, in an inert solvent, such as simple air, and convenient tetrahydrofuran, at a non-extremal temperatures, for example from -70 to 30oC. the Compound of formula (XV) can be obtained by the reaction of the analogous compounds of formula (XIV) with HC(OAlk)3under the conditions described for the reaction of (II) above.

(IV) when Y represents 0 and Y1R11, R2And X have the above meanings. The reaction is carried out in acidic conditions, it is convenient to the silica gel, followed by addition of diluted hydrochloric acid under non-extremal temperatures, for example from 0 to 100oWith, conveniently room temperature, i.e. from 20 to 30oC. the compounds of formula (XVI) can be obtained, as shown in Annex 3 to this application.

(V) by the mutual transformation of compounds of formula (I), for example

(a) when it is necessary to obtain the compound of formula (I), where a contains terminal fragment of C C and X is other than hydrogen, by reacting the corresponding compounds where X is hydrogen, with a compound X11 Gal, where Gal represents halogen and X1means is other than hydrogen. This reaction is particularly suitable for the production of those compounds in which X represents C1-C4is an alkyl group or a group R21where R21stands WITH1-C6-alkoxygroup; or X represents a substituted silyl or tin. The reaction is usually carried out in the presence of a strong base, such as alkylate, conveniently utility, in an inert solvent, such as a simple ether, for example tetrahydrofuran, there is unsubstituted alkynylaryl bicycloalkyl, can be obtained as described above.

(b) when it is necessary to obtain the compound of formula (I), where a represents a saturated or contains a double bond, the recovery of the corresponding compounds containing double or triple bond respectively. This reaction is conveniently performed by hydrogenation in the presence of a catalyst such as palladium charcoal, or when a triple bond is restored and you want to stop immediately restore form a double bond, and not continue to the fully saturated compound, in the presence of such a catalyst poison, such as barium sulphate. The reaction can conveniently be in a suitable solvent for hydrogenation experiments such as methanol or ethyl acetate. The reaction is usually carried out at non-extremal temperatures, for example from 5 to 50oWith, normally at a temperature of 25oC.

(C) when a contains a terminal fragment of C C and X denotes hydrogen, disilylgermane the compounds of formula (XVII)

< / BR>
where R, R1, R2, R17, R18, R19Y, Y1, Z and A1have the above values. This reaction can be performed are well known in the field methods, neprimemlemo temperature, for example, from 0 to 70oC, conveniently at a temperature of 25oC.

New chemical intermediate compounds also form an important aspect of the present invention. Preferred intermediate compounds include intermediate compounds of formula (II), (V), (VII), (XIV) and (XV).

The compounds of formula (I) can be used to control pests such as arthropods, such as insects and acaricide pests and parasitic worms, i.e. nematodes. Thus, the present invention provides a method of combating arthropods and/or helminths (parasitic worms), which comprises applying to claystone and/or worms, or their environment arthropode-effective amount of compounds of formula (I). The present invention also provides a method of combating and/or destruction of infections arthropod and/or helminth animals (including humans), and/or plants (including trees), and/or stored products which comprises applying to the animal or hearth effective amount of the compounds of formula (I). The present invention also provides compounds of formula (I) for use in human and veterinary medicine, in the management of public staudingeri formula (I) are of particular value in the protection field, forage, perennial (on plantations), greenhouse, garden, and vineyard crops, ornamental plants, as well as plantacii and forest trees, for example cereals (such as corn, wheat, rice, sorghum), cotton, tobacco, vegetables and salads (such as beans, cabbage, lettuce, onions, tomatoes and peppers), field crops (such as potatoes, sugar beet, peanut, soybean, turnip), sugar cane, forage crops (such as corn, sorghum, alfalfa), plantacii (such as tea, coffee, cocoa, banana, oil palm, coconut, rubber, spices), horticultural and forestry (such as stone and one-seeded fruit, citrus, avocado, mango, olives and nuts), vineyard, ornamental plants, flowers and shrubs under glass and in gardens and parks, trees (both deciduous and evergreen) forests, plantations and nurseries.

They are also valuable in the protection of timber (at the root, harvested, processed or building) from attack by sawflies (e.g., Urocerus) or beetles (for example, scolytids, platypodids, liquidow, bostrichids, cerambicidos, anobiids).

The compounds of formula (I) also finds application in the protection of stored products such as grain, FEMA. Also protect the stored animal products, such as skin, hair, wool and feathers in natural or processed form (e.g., in the form of a carpet or textiles) from attack by moths and beetles, but also protects the meat and fish from attacking beetles, mites and flies.

Compounds of General formula I are particularly valuable in combating arthropods or helminths, which are detrimental or act as vectors of diseases to humans and domestic animals, such as those mentioned above, and especially when dealing with ticks, lice, fleas, small two-winged insects and biting and nuisance flies. The compounds of formula (I) can be used for such purposes by application of the compounds by themselves or in diluted form in a known manner as an impregnating composition of the sprayed material, fog, lacquer, foam, dust, powder, aqueous suspension, paste, gel, cream, shampoo, grease, combustible solids, evaporating sod, fuel tangle, seed, feed additives, wettable powder, granules, sprays, emulsifiable concentrate, oil suspensions, packing pressure, impregnating products, or other standard formulations, Harosheth immersed in an impregnating the Gang, contain preservative leaching. The sprayed material may be applied manually or using a spray channel or arch. The treated animals, soil, plants or the surface can be filled with spray material by placing small or super small doses. Aqueous suspensions may be made in the same way as the sprayed material or impregnating compositions. Dusty can be spread by spreader powder of the drug or, in the case of treatment of animals, to be entered in perforated bags, attached to trees or poles. Pastes, shampoos and grease can be applied manually or spread on the surface of inert material, such, about which RUB against animals and transfer the material to their skin. Pour compositions dispersed in the form of a unit of liquid a small amount on the back of the animal so that all the liquid or the greater part remains on animals.

The compounds of formula (I) can be obtained either in the form of compositions, ready to use on animals, plants or surface, or in the form of compositions, requiring dilution before use, however, both types of composition containing the compound of formula (I) in the mixture in one or more carriers or R is the Union of the formula (I) may be present at a concentration of from 0.025 to 99% in mass to volume depending on whether the further dilution of the composition or not.

Dusty, powders and granules and other solid compositions contain a compound of the formula (I) in the mixture with the powdered solid inert carrier, for example, suitable clay, kaolin, bentonite, attapulgite, adsorbing carbon black, talc, mica, chalk, gypsum, tricalcium phosphate, poroshkovaya tube, magnesium silicate, vegetable carriers, starch and diatomea earth. Such solid compositions are generally produced by impregnating the solid diluents solutions of the compounds of formula (I) in volatile solvents, evaporation of the solvents and, if necessary, grinding the products so as to obtain powders and, if desirable, granulation, compaction or kapsulirovaniem products.

Sprayed materials the compounds of formula (I) may contain a solution in an organic solvent (for example, from among the following) or emulsion in water (macotela flushing or irrigation flushing), obtained in the field of emulsifiable concentrate (otherwise known as miscible with water, oil), which can also be used for dipping. The concentrate preferably contains a mixture of the active component with dobavlyalost within wide limits, however, preferably, from About 90% in the ratio of the mass to the volume of the composition, and can be selected from kerosene, ketones, alcohols, xylene, aromatic naphtha and other solvents known in the technology of formulation. The concentration of emulsifiers may vary within wide limits, but preferably in the range from 5 to 25% weight to volume, and emulsifiers, as a rule, represent nonionic surfactants, including complex polyoxyalkylene ethers of ALKYLPHENOLS and polyoxyethylene derived anhydrides of exit, as well as anionic surfactants, including nutriceuticals, ether sulfates of fatty alcohols, sodium and calcium salts alkylarylsulfonates and alkylsulfonates. Cationic emulsifiers include chloride benzalkonium and Quaternary ammonium ethosulfate.

Amphoteric emulsifiers include karboksimetilirovaniya oleic imitation and alkyldiphenylamine.

Evaporative derenyi usually contain a mixture of cotton and cellulose, compressed into a tile with dimensions of approximately 35 x 22 x 3 mm, treated with 0.3 ml of the concentrate containing the active ingredient in organicsolvents heat source, such as electrically operated heater turf.

Flammable solids typically contain wood powder and binder are mixed with the active component and molded in figure (usually spiral strip. Can also be added to the dye and fungicide.

Wettable powders contain inert solid carrier, one or more surfactants and, optionally, stabilizers and/or antioxidants.

Emulsifiable concentrates contain emulsifiers and often organic solvent, such as kerosene, ketones, alcohols, xylene, aromatic naphtha and other solvents known in the literature.

Wettable powders and emulsifiable concentrates usually contain from 5 to 95% by weight of the active component and diluted, for example, water before using.

Varnishes contain a solution of the active ingredient in an organic solvent together with a resin and, optionally, a plasticizer.

Mekatelyu washing can be obtained not only from emulsifiable concentrates, but also from wettable powders, impregnation based soap and water suspensions containing a compound of the formula (I) in a mixture with dispersing agent which may contain a suspension in water together with suspenders, stabilizing or other agents. Suspensions or solutions can be applied reg se or in diluted form.

Grease (or ointment) can be obtained from vegetable oils, synthetic esters of fatty acids or wool fat together with an inert base, such as syskoplan - cue paraffin. The compound of formula (I) preferably is applied through the mixture in solution or suspension. Lubrication can also be made of emulsifiable concentrates by dilution based ointments.

Toothpastes and shampoos are also semi-solid preparations, in which the compound of formula (I) may be present in the form of a homogeneous dispersion in a suitable base, such as low-melting or liquid paraffin, or low-fat based glycerin, gum Arabic or suitable soap. As lubricants, shampoos and toothpastes usually applied without dilution, they must contain the appropriate percentage of the compounds of formula (I), is required for processing.

Aerosol sprays can be obtained in the form of a solution of the active ingredient in spray aerosol substance and the co-solvent, such as golozhabernyi alkanes and solvents, upominuemie above, sootvetstviii or mlekopitayushchie the owner can be protected from infection acaricide ectoparasite using carry suitable molded, figure plastics, impregnated with a compound of formula (I). Such products include soaked buckles, labels, patches, decals & stripes, usually attached to appropriate parts of the body. Suitable, if the plastic is polyvinyl chloride (PVC).

The concentration of the compounds of formula (I) for application to the animal, the inner or the outer zone will vary in accordance with the selected connection, the interval between treatments, the nature of the composition and contamination, however, is usually from 0.001 to 20.0% in the ratio of mass to volume, preferably from 0.01 to 10% of the compound must be present in the applied composition. The amount of compound applied to an animal will vary in accordance with the method of application, the size of the animal, the concentration of the compound in the applied composition, the factor by which the composition is diluted, and the nature of the composition, but generally will be in the range from 0.0001 to 0.5% by weight, with the exception of undiluted formulations, such as pour the compositions, which are typically applied at a concentration in the range from 0.1 to 20.0%, preferably from 0.1 to 10% of the Number of connections, damage to stored products typically ranges from 0.1 to 20 ppm. Rasilainen formula (I) per cubic meter of treated space.

The compounds of formula (I) are also used in the protection and processing of plant species, thus causing an effective insecticidal, acaricidal or nematocide the number of the active component. The ava will vary in accordance with the selected connection, nature, composition, method of making, plant species, plant density and infection, as well as other factors, however, generally, a suitable dose use for crops ranges from 0.001 to 3 kg/ha, preferably from 0.01 to 1 kg/ha Typical compositions for agricultural use contain from 0.0001 to 50% of compounds of formula (I), conveniently from 0.1 to 15% by weight of compounds of formula (I).

Dusty, greases, pastes and aerosols are usually applied randomly, as described above, and can be used in concentrations of from 0.001 to 20% in weight to the amount of the compounds of formula (I) in the applied composition.

The compounds of formula (I), are detected as being active against normal flies bedroom (us mestica). In addition, certain compounds of formula (I) are active against other arthropod pests, including Myzus persical, tetlarychus urticae, Plutella. xylostella, Culex spp. Tribolium Gas-baneum, Sitophilus granarius, Periplaneta amiercona and BIatela germanica.

th environment, where they are pests, such as agriculture, livestock farm, in the management of public health and in domestic situations.

Insect pests include members of groups of Coleoptera (e.g., nobium, Ceutorhynchus, Phynchophorus, Cosmopolites, Lissorhoptrus, Meligethes, Hypothenenms, Hylesinus, Acalymma, Lema, Phylliodes, Leptinotarsa, Genocephalum, Agriotes, Demlolepida Heteronychus, Phaedon, Tribolium, Sitophilus, Diabrotica, Anthono - nlus hw Antherenus spp.), Lepidoptela ( for example, Ephestia, Mamestla, Eajias, Pectinolhora, Ostridia, Trl.choplusia, Pieris, Laphygma, Agrotis, Amathes, Wiseana, Tripolysa, Diatreae, Sporga - nothis, Cydia, Alchils, Plutella, Chile, Heliothis, Spodoptela shares Tineolaspp.), Rptela ( mn@Kej) Musca, Aedes, Anopheles Culex, Glossina, SinluU-um, Stomoxys, Haenrtobia, Tabanus, Hydro-IAEA, Lucilia, Cheysoma, Callitroga, Dennatobia, Gasterophilus, Hypc'derma Hylemyla, Atherigona, Chlorols, Phytonyza, Celatitis, Liriomyza and Melophagus spp. ). Phthilaptela ( Malophaga, e.g., Damalina spp. Anoplula spp. hanokWej) Linognathus And Haematopi-nus spp. ) Henliptela ( e.g., Aphis, Bemisia, Phorodon, Aeneomalia, Empoasca, Padd-nsiella, Pyrilla, Acnidiella, Coccus, Pseudococus, Helopeltis, lydus on, Dysdercus, Oxycarenus, Nezala, Aleurodes, Tria - toma, Psylla, Mysus, Megoula, Phulloxera, Adelyes. Nilolb.rvata, Nephlotetix or Cinlex spp. ) Orthoptela ( e.g., Locusta, GlyUus, Schistocerca or Achet spp. ), Dictyoptela ( e.g., Blatella, Periplaneta or Blatta spp. ), Hymenoptela (for example, Athalia, Celhus, Atta, Solenopeis, Mononloriumspp. ), Isoptela (e.g., Odontotermes Reticulitemles spp. ) Siljmnaptera (for example, Ctenocephalidesmak Pulex spp. ), Thysanum (for example Lepisnb. ), Dennaptela (for example, Forficula ), Pscoptela (for example, Perilbocus Thysanoptela ( ThrilB baci) Carecidaaniesy and cause itching insects, such as Acarus, Tetla nychus, Psoroptes, Notoednes, Sarcoptes, Psolergates, Chori - optes, Eutrombicula, Denlodex, Panonychus, Blyobia, Eriophyes, Blanilus, Polyphagotarsonenlus, Scutigerella and Oniscus spp.

Nematodes that infect plants and trees of importance to agriculture, forestry, horticulture either directly or by spreading bacterial, viral, microplastics or fungal diseases of plants, include the root nematodes, such as Meloidogyne (e.g., M. incognita ), cyst nematodes, such as Globodela (for example, S. rostochiensis Heterodela (e.g., N. avenae ), Radopholus (for example, r. similis ), damaged nematodes, such as Platylenchus (for example, R. Pmtensis ), Belonolaimus (for example, Century eyacilis ), Tylenchulus (for example, So semipenetlans ), Rotylenchulus (for example, R. reniformis/, Rotylenchus (for example, R. robustus/, Helicotyl - enchus (for example, H. multicinctus ), Hemicycliophola (for example, H. gracilis ), Criconemoides (for example, C. similis ), Tlichodorus (for example, So prinlitivus ), Xiphinema. (for example, X. diversicaudatum /, Longidorus (for example, L. elongati ), Hoplolaimus (for example, H. corowtus ), Aphelenchoides spp. (for example, A. besseyi ), a stem and Lyovochkin nematodes, such as ditylenchus (for example, D. dipsaci).

Compounds of the present invention can be combined with one or more other pesticide-active components (e.g., pyrethroids, carbamates and organic is like. In addition, it was found that the activity of the compounds of the present invention can be improved by the addition of a synergist or potentiator, for example, one class oxidase-inhibitors, synergists, such as piperonylbutoxide or propyl 2-propylpentanoic, a second connection of the invention or the pesticide connection PYRETHROID. When in the claims is present oxidizability the synergist, the ratio of synergist to the compound of formula (I) is from 25:1 to 1:25, for example, about 10:1.

Stabilizers to prevent any chemical degradation, which can happen with the compounds of the present invention include, for example, antioxidase (such as Tocopherols, butylhydroxyanisole and equivalent) and sinks ( such as epichlorohydrin) and organic or inorganic bases, such as trialkylamine, such as triethylamine, which can act as a stabilizer of the base and as the absorber.

Without limiting the scope of the invention below examples illustrate preferred embodiments of the invention.

Example 1. 1-(Penta-4-inyl-)-4-propyl-2,6,7-dioxabicyclo [2.2.2] octane.

(1) To thoroughly incorporated into the 112 g) and formaldehyde solution (1.4 l of a 40% aqueous solution). The reaction temperature is supported below the 40oFrom and after the introduction of the mixture intensively shaken for approximately 45 minutes. Then the reaction mixture was kept at a temperature of 60oC for 5 hours. The reaction mixture is filtered through diatomaceous earth, and then the filtrate is evaporated in vacuum. The remainder of the clear hot solution of methanol (2 l) followed by filtration through diatomaceous earth. The filtrate is evaporated in vacuum. Get viscous, oily product, which is purified by the following method.

The solution containing the crude product and acetic acid ( 200 ml) was stirred at room temperature. Acetic anhydride (1.2 l) was added to this mixture for 4 hours. The reaction temperature is brought to 65,198>C. Stirring of the mixture continued for 12 hours. After this reaction mixture is added within 3 hours to cold water (3 l), mixing thoroughly. The resulting aqueous mixture is extracted with simple diethyl ether. The ether extracts are washed with aqueous sodium bicarbonate solution and then brine. The extract is dried over anhydrous magnesium sulfate and evaporated in vacuum.

After distillation get 2-hydroxymethyl-2-n-propylparaben-1,3-diltiazem (the specified triacetate (238 g) in methanol (2.5 l) was added sodium (0.5 g). The mixture is heated under reflux, carefully stirring for 72 hours. Then the reaction mixture is evaporated in vacuum.

Get 2-hydroxymethyl-2-n-propylparaben-1,3-diol (87 g) as colorless crystals (so pl. 93oC).

(II). A mixture consisting of 2-hydroxymethyl-2-n-propylparaben-1,3-diol ( 24.6 g), diethylmalonate (20,1 ml), potassium hydroxide (0.3 g) and dry ethanol was heated to mild reflux ( oil bath at a temperature of 110-120o(C) in a stream of nitrogen for 30 minutes. After this spin-off, the ethanol is removed by distillation at atmospheric pressure (oil bath with a temperature of 130-140oTemperatures helmet boiling cube 76oC). The pressure is reduced to 20 mm Hg and the temperature of the oil bath was adjusted to 230oC. After distillation C-oximeter-C-n-propylparaben in the form of a colourless liquid (16.7 g) (the temperature of the head part 120-126oC). (see application for Europatent N 216624).

(III). The solution containing 5-chloro-1-Pentin (20 g, produced by Aldrich Chemical Company) and potassium cyanide (19 g) in 20% aqueous ethanol (120 ml) is heated under reflux for 20 hours. Then add water (600 ml) and the resulting mixture extracted with diethyl ether. The combined ether extracts Plaut in a vacuum.

After distillation 5-cyan-1-Pentin (9,9 g) as a colourless oil (so Kip. 67-68oC, 15 mm Od).

(IV). A mixture of 5-cyano-1-pentyne (9,9 g) and 10% aqueous solution of potassium hydroxide (100 ml) is heated under reflux for 6 hours. The resulting solution was extracted with chloroform. The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, and then extracted with dichloromethane. Extracts containing dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, and then evaporated in vacuum.

After distillation of Gex-5-andnew acid (9,9 g) as a colourless liquid (so Kip. 66-67oWith, 0.6 mm Hg).

(V). A mixture containing Gex-5-IP acid (1 g) and chloride thionyl (1,95 ml) in benzene (25 ml) is heated under reflux for 3 hours. The resulting solution is cooled and then evaporated in vacuum. Resulting from this galoyanized dissolved in simple ether and then added dropwise to a thoroughly stirred solution containing 3-oxymethyl-3-n-propyloxy (162 g) and pyridine (0.8 ml) in dry ether (20 ml). The reaction mixture was stirred at room temperature for 16 hours. Then the organic layer by drying over anhydrous magnesium sulfate, and then it evaporated in vacuum. The residue is purified by chromatography on silica, with its preliminary elution with hexane containing 1% triethylamine. After elution by the mixture hexane: ether to obtain ( 3-propyloxy-3-yl)metrex-5-inat (1,33 g) as a colourless oil.

Gas-liquid chromatography (GLC): OV-17 at 175oWith creates a single peak.

NMR spectrum:1H (ppm from TMS in CDCl3, integral, multipletness): 4,45 4H, s; 4,20, 2H, S; 2,8-0,8, 14 N, m

(VI). To the thoroughly stirred solution of (3-propyloxy-3-yl) methyl ester Gex-5-invoi acid (1,33 g) in dry dichloromethane (25 ml) was added athirat of boron TRIFLUORIDE ( 0,18 ml) at -70oC. the mixture is Then warmed to room temperature for 16 hours. Then add triethylamine (0,28 ml), and then the solvent evaporated in vacuum. The remainder is divided into layers between diethyl ether and water. The organic layer is separated and before drying it over anhydrous magnesium sulfate washed with water and brine. The solvent is evaporated in vacuo, and the residue is purified column chromatography on alumina with elution with a mixture of 1:6 dichloromethane: hexane saturated with ammonia. Get 1-(Penta-4-inyl)- 4-propyl-2,6,7-trixaicin the oWith gives a single peak.

Example II. 1-(Gex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane.

The solution methanesulfonanilide (23,7 ml) in dry dichloromethane (25 ml) was added dropwise to a solution containing Gex-5-in-1-ol (the product Lancaster Synthesis, 25 g) and triethylamine 47,3 ml) in dichloromethane (300 ml) and thoroughly mixed in a nitrogen atmosphere at -70oC. the resulting mixture was gradually warmed to room temperature for 16 hours. The mixture is then washed with water, diluted hydrochloric acid, saturated sodium bicarbonate solution and brine, followed by drying over anhydrous magnesium sulfate and evaporation in vacuo. Get Gex-5-inimicality in the form of oil (43,6 g), used without purification.

NMR spectrum: 1H (ppm from TMS in CDCI3, integral, multipletness), I, Hz): 4,15, 2H, t I Hz 6; 3,0,MN,s; 2,4-1,4, 7 H, m

(II) a Mixture consisting of Gex-5-inimitableness (43,6 g) and potassium cyanide (24 g) in 20% aqueous ethanol (150 ml), heated under reflux for 4 hours and then stirred at room temperature overnight. Add water (600 ml) and the reaction mixture extracted with diethyl ether. The organic extracts washed with water, the distillation 6-cyan-1-hexyne (20,1 g) as a colourless oil (so the TRC. 82-95oC, 15 mm Od).

IR spectrum (liquid film): 3340, 2990, 2920, 2330, 2160, 1485, 1450, 1355, 670 cm-1.

(III). Using the procedure described in stage (IV) of example 1, 6-cyan-1-hexyne in turn hept-6-andnew acid (so Kip. 78-82oWith, 0.75 mm Od).

IR spectrum (liquid film): 3340, 2980, 2160, 1730, 1435, 1310, 1255, 955, 660 cm-1.

(IV). Using the procedure described in stages (V) and (VI) of example 1, 1-(Gex-5-inyl)-4-propyl-2,6,7-dioxabicyclo-[ 2.2.2]octane is obtained from hept-6-invoi acid and 3-oxymethyl 3-n-propylacetate.

GC: OS-17 175oWith gives a single peak.

In a similar way we obtain also the following link:

1-(Oct-7-inyl)-4-propyl-2,6,7-dioxabicyclo[2.2.2] octane of Oct-7-in-1-ol (see patent UK 969816, Chem. Abs. 1965 1571f ).

Example III. 1-(Penta-4-inyl)-4-propyl-3-trifluoromethyl-2,6,7 - dioxabicyclo[2.2.2]octane

(I). A mixture consisting of Gex-5-invoi acid (1 g) and chloride taanila (1695 ml) in benzene (25 ml) is heated under reflux for 2.5 hours. The resulting solution is cooled and evaporated in vacuum. So produced acid chloride dissolved in dry diethyl ether (5 ml) and added dropwise to the solution containing 3-(1-e (20 ml). The reaction mixture was stirred at room temperature overnight. Then washed with water, diluted hydrochloric acid, saturated sodium bicarbonate solution and saline. The organic layer is separated and dried over anhydrous magnesium sulfate, followed by evaporation it in a vacuum. The residue is purified by chromatography on silica, previously washing out his hexane containing 1% triethylamine. After gradient elution with a mixture of hexane: ether to obtain 2,2,2-Cryptor-1-(3-propyloxy-3-yl)ethylhex-5-INOUT (1.2 g) as a colourless oil.

GC: OS-17 175oWith gives a single peak.

NMR spectrum:1H (ppm from TMS in GDCl3the integral multipletness) 4,8-4,1,53, m; 2,7-0,8, 14 N, m

(II). Using the procedure described in stage (VI) of example 1, from 2,2,2-Cryptor-1-(3-propyloxy-3-yl)ethylhex-5-enoate get 1-(Penta-4-inyl)-4-propyl-3-trifluoromethyl-2, 6,7-dioxabicyclo[2,2,2] octane in the form of a crystalline substance of white color.

GC: OS-17 170oWith gives a single peak.

Similarly from hept-6-invoi acid and 3-(1 - hydroxy-2,2,2-triptorelin)-3-n-propylacetate get the following connection:

1-(Gex-5-inyl)-4-propyl-3-trifluoromethyl-2,6,7-dioxabicyclo[ 2,2,2] dimethyl sulfoxide (12 ml) in dry dichloromethane (4.0 ml) was added to the solution thoroughly mixed oxalicacid (7,4 ml) in dichloromethane (25 ml) at -70oC in nitrogen atmosphere. Then the resulting mixture is stirred for another 5 minutes at -70oFrom before to it is added dropwise over 10 minutes a solution of 3-oxymethyl-3-n-propyl-oxetane (10.0 g) in dichloromethane (25 ml). The resulting mixture is stirred for further 30 minutes, after that add pure triethylamine (54 ml) for approximately 30 minutes. The reaction mixture is heated to room temperature within 3 hours after it was poured into water. The organic layer is separated and the aqueous layer was additionally extracted with dichloromethane. The combined organic extracts are washed with diluted hydrochloric acid, saturated sodium bicarbonate solution and saline. The resulting organic layer is dried over anhydrous magnesium sulfate, followed by evaporation in vacuum. Get 3-formyl-3-n-propyloxy (10,5 g) (see application for Europatent N 216624) as a yellow oil.

(II). A mixture consisting of Gex-5-invoi acid (1 g) and chloride taanila (1,95 ml) in benzene (25 ml) is heated under reflux for 3 hours. The resulting solution is cooled and then evaporated in vacuum. The resulting acid chloride is added to a thoroughly stirred solution of 3-formyl-3-n-prop is the right time (and 0.61 g) in water (1 ml). The resulting mixture was vigorously stirred for 16 hours at room temperature. After that, the reaction mixture is washed with water, saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the residue is purified column chromatography on silica pre-elute with hexane containing 1% triethylamine. After gradient elution by the mixture hexane:simple ether get 1-cyano-( 3-propyloxy-3-yl)metrex-5-INOUT in the form of a colorless oil (1.2 g).

GC: OS-17 175oWith gives a single peak.

NMR spectrum: 1H(ppm from TMS in DI3, integral, multipletness) of 5.6, 1H, C, 4.75 V-4,4, 4H, m; 2,8-0,9, 14 N, m

(III). Athirat of boron TRIFLUORIDE (0.25 ml) was added to a solution of 1-cyano-1-(3-propyloxy-3-yl)metrex-5-inat (0.5 g) in dry dichloromethane (10 ml) with stirring the mixture at -70oC in nitrogen atmosphere. The resulting solution is heated to room temperature over night. Then add triethylamine (0,38 ml) and the solvent evaporated in vacuum. The remainder is divided into layers between diethyl ether and water. The organic layer is separated and washed with water and saline races is via on silica with elution with a mixture of dichloromethane: saturated ammonia hexane 1:4. Get 1-(Penta-4-inyl)-4-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane-3-carbonitrile in the form of an oil (0.25 g).

GC: OS-17 175oWith gives a single peak.

Similarly receive the following connections:

1-(Gex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[2,2,2]octane-3 carbonitril

4-n-butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2,2,2]Octan-carbonitril

4-tert-butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2,2,2]- Octan-C-carbonitril (getting 2-tert-butyl-2-oximation-1,3-diol (see I. Ozoe, M. Eto, Agric.Biol. Chem. 1982, 46, page 411).

4-Cyclopropylmethyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[ 2,2,2] octane-3-carbonitrile, 1-(Gex-5-inyl)-4-phenyl-2, 6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile, 1-(Gex-5 - inyl)-4-ISO-butyl-2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile and 1-(Gex-5-inyl)-4-(2-methylprop-2-enyl)-2,6,7-dioxabicyclo[ 2,2,2]octane-3-carbonitrile obtained from 3-cyclopropylmethyl-C-formyloxyethyl, 3-formyl-Z-phenyloxirane, 3-formyl-3-isobutylketone and 3-formyl-3-(2-methylprop-2-enyl), oxetane, respectively. According to the method described in example 5 (except that instead of tetrahydrofuran as a solvent in stage (I) use toluene), 3-cyclopropylmethyl-3-formyloxy, 3-formyl-Z-phenyloxirane, 3-formyl-3-isobutylketone and 3-formyl-3-(2-methylp the issue. 50, 1985), diethyl ether of phenylmalonate acid (Aldrich), diethyl ether of isobutylamino acid (Beilstein, 2, 683) and diethyl ether 2-methylprop-2-animalanimal acid ( see. W. I. Doran, I. Amer. Chem.Soc. 1937, 59, 1965).

Example V 4-Cyclohexyl-1-(Penta-4-inyl)-2,6,7-dioxabicyclo [2.2.2] octane

(I). Diethyl ether cyclohexylamino acid (18.7 g). (see Beilstn, 9, page 739) was added to a thoroughly stirred suspension of sodium hydride (4.8 g, 50% dispersion in oil) in dry tetrahydrofuran (50 ml) under nitrogen atmosphere. The mixture is heated under reflux, with stirring for 1 hour. The mixture is cooled and added benzylcarbamoyl ether (13,9 g) (product of company Sigma Chemical Company) in dry tetrahydrofuran (50 ml), and then the reaction mixture is heated under reflux, with stirring for 3 hours. Next, the mixture is cooled and poured into water. The aqueous layer was extracted with simple ether. The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. Receive diethyl ether-2-benzoyloxymethyl-2-cyclohexylmethanol acid (30 g) as a brown oil which is used without further purification.

(II). Diethyl ether 2-benzoyloxymethyl-2-cyclohexylmethanol acid (2 g) was added nod for 12 hours at room temperature. Carefully add water (5 ml) and this mixture is stirred for 10 minutes. Add 10% solution of sulfuric acid (10 ml) and the mixture is then extracted with simple ether. The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica with elution with a mixture of ether:hexane 1:1. Get 2-benzoyloxymethyl-2-cyclohexylprop-1,3-diol as a colourless oil (1.0 g).

(III). 2-Benzoyloxymethyl-2-cyclohexyl-propane-1,3-diol (5.5 g) in dry diethyl ether (50 ml) was added to liquid ammonia (200 ml) at -70oC. To the thoroughly stirred solution was added sodium (2.5 g). Stirring is continued at -70oC for 1 hour. The mixture is heated to 0oWith and gently introduce solid ammonium chloride (15 g). From the reaction mixture to remove ammonia in a stream of nitrogen. For the destruction of the remaining sodium to a stirred mixture was added methanol (25 ml). Then add dichloromethane (400 ml) and the mixture filtered. The filtrate is evaporated in vacuum. Get 2-cyclohexyl-2-oximation-1,3-diol as a colourless solid (3.2 g).

(IV). A mixture of 2-cyclohexyl-2-oximation-1, 3 diode (3,76 g), ethyl ester of carboxylic acid (2,42 m for 20 minutes. The installation is switched to the mode of distillation. The ethanol is removed by distillation (78-80oWith a pressure of 760 mm Hg). After you remove all of the ethanol, the residue is distilled under reduced pressure. The result is 3-cyclohexyl-3-oxytetracyclin ( see application for Europatent N 216624) as a colourless oil.

(V). Using the procedure described in stage (V) and (VI) of example 1, from Gex-5-invoi acid and 3-cyclohexyl-3-oxitetraciclina receive a 4-cyclohexyl-1-(Penta-4-inyl)-2,6,7 - dioxabicyclo[2,2,2] octane.

GC: OS -17 at 230oWith gives a single peak.

Similarly from hept-6-invoi acid get 4-cyclohexyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2,2,2] octane.

Example VI. 4-tert-butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2,2,2]octane

Method 1.

In accordance with the method described in stage (VI) of example 1, get 4-tert-butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[ 2,2,2] octane of hept-6-invoi acid and H-tert-butyl-3-oxitetraciclina ( 2-tert-butyl-2-oximation-1, 3-diol get method I. Ozoe and M. Eto, Agric. Biol. Chem. 1982, vol. 46, page 411).

GC: OS-17 230oWith gives a single peak.

Method 2.

A mixture of 2-tert-butyl-2-oximation-1, 3-diol (0.75 g) and trimethylboron ether ablaut one drop of concentrated hydrochloric acid, and the mixture is heated to about 135oWith a stream of nitrogen for 10 minutes. The mixture is then cooled and chromatographic on alumina, using as eluent a mixture of dichloromethane: saturated ammonia hexane 1:6.

Receive a 4-tert-butyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo [ 2,2,2]octane in the form of colorless crystals (0,38 g, recrystallized from hexane)

In a similar way we obtain a 1-(Gex-5-inyl)-4-phenyl-2, 6,7-dioxabicyclo[2,2,2]octane 2-oxymethyl-2-phenylpropane-1, 3-diol (prepared according to the procedure described in example V, diethyl ether 2-phenylmalonate acid).

Example VII. 4-tert-butyl-1-(6-trimethylsilyloxy-5-inyl)- -2,6,7-dioxabicyclo[2,2,2] octane

n-Utility (0,31 ml, 6M solution in hexane) was added to a thoroughly stirred solution of 4-tert-butyl-1-(hex-inyl)-2,6,7-dioxabicyclo[2,2,2] octane (100 mg) in dry tetrahydrofuran (4.0 ml) at 0oC in nitrogen atmosphere. The reaction mixture was stirred at 0oC for 15 minutes. Then add trimethylsilane (63 μl) and the resulting mixture is heated to 20oC for 2 hours. Add the water and found water the mixture is extracted with simple diethyl ether. The ether extracts are washed with brine and dried over b is Woelm TSC), using as eluent a mixture of dichloromethane:saturated ammonia hexane 1:6.

Receive a 4-tert-butyl-1-(6-trimethylsilyloxy-5-inyl)- 2,6,7-dioxabicyclo[2,2,2]octane in the form of colorless crystals ( 60 mg) (so pl. 87-90,5oC).

GC: OS-17 230oWith gives a single peak.

Example VIII. 1-(4-Ethynylcyclohexanol)-4-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane

(I). To a mixed solution containing dimethyl ether of 1,4-cyclohexanedicarboxylic acid (20 g, Aldrich) in methanol (50 ml) was added to a solution of potassium hydroxide (7,3 g) in methanol (75 ml). The reaction mixture is heated under reflux for 16 hours. After cooling, the solvent is evaporated in a rotary evaporator. The residue is dissolved in a simple ether with water and extracted to remove neproreagirovavshikh source complex diapir. The aqueous layer was acidified with diluted hydrochloric acid and re-extracted with simple ether. The ether extracts are washed with saline and dried. After evaporation in vacuo get a solid substance. Cleaning provides recrystallization from ethyl acetate to yield 4-methoxycarbonylaminophenyl acid (6.2 g), so pl. 90,9oC.

(II). Chloride thionyl (3,65 ml) preballet ml). The reaction mixture is heated to irrigation under mild conditions in an oil bath for 4 hours. The resulting solution is cooled and then evaporated in vacuum. Resulting from this galoyanized re-dissolved in benzene with subsequent evaporation in a vacuum. The exiting product is used in the next stage without additional purification.

IR spectrum (liquid film): 1790 (s), 1720 (s) cm-1.

(III). A solution of zinc borohydride (67 ml of a 0.35 M solution) and tetramethylethylenediamine (TMEDA) are sequentially added to the thoroughly stirred solution containing 4-methoxycarbonylaminophenyl (1,02 g) in tetrahydrofuran (THF) (18 ml) at 0oC. the Reaction mixture was stirred at 0oC for 30 minutes. Then the organic layer was washed with diluted hydrochloric acid and brine before drying over anhydrous magnesium sulfate, and then evaporated in vacuum. Get a 4-hydroxymethylglycinate in the form of a semi-crystalline oil.

IR spectrum (liquid film: 3400 (s, W), 1720 (C) cm-1.

GC: OS-17 at 110oC gives 2 peak (CIS-, TRANS-isomers of about 1:1).

(IV). Dimethyl sulfoxide (0,65 ml) in dry dichloromethane (5 ml) emiliania in the treatment of 5 minutes added dropwise a solution, contains 4-oxyethylenenitrilo (0.64 g) in dichloromethane (5 ml). The reaction mixture is stirred for 30 minutes at -70oC. Then added triethylamine (2,60 ml) and then the reaction mixture is heated to room temperature within 3 hours. After pouring this mixture into water ( 100 ml) the organic layer was washed with diluted hydrochloric acid before drying over magnesium sulfate. In the process of evaporation in a vacuum get methyl ester 4-formyltetrahydrofolate acid (0,58 g) in a mixture of CIS and TRANS isomers.

IR spectrum (liquid film): 1720 cm-1(C).

GC: OS-17 120oWith gives only 1 peak.

Mass spectrum (MS), chemical ionisation: M+1, 171.

(V). The solution containing tetrabromomethane (1.66 g) in dry dichloromethane (10 ml) was added to a stirred solution of triphenylphosphine (2,62 g) in dry dichloromethane (10 ml) under cooling. To the resulting orange solution was added a solution containing methyl ester 4-formyltetrahydrofolate acid (0.85 grams) in dry dichloromethane (10 ml) in a stream of nitrogen. The reaction mixture was stirred at room temperature overnight. The solvent is removed in vacuum. The residue is stirred mechanically with hexane in toadie of the methyl ester of 4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (1,15 g) as a mixture of CIS - and TRANS-isomers.

IR spectrum (liquid film): 1722 cm-1.

GC: OV at 155oC gives two peaks.

Mass spectrum: chemical ionization (2 maximum voice /MS), both M+1, 325.

(VI). Methyl ester of 4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (1,15 g) was added to a mixed solution of potassium hydroxide (297 mg) in methanol (2 ml). After mixing, the solvent evaporated in vacuum. The remainder is divided into layers diethyl ether and water. The aqueous layer was separated and acidified with diluted hydrochloric acid. After extraction with diethyl ether to obtain a solution, which is washed with saline, and then dried over anhydrous sulfate Magnum. After evaporation in vacuo receive a 4-(2,2-dibromovinyl) cyclohexanecarbonyl acid (0,86 g) as a colourless solid.

IR-spectrum (paste Nujol): 1690 (s), cm-1.

(VII). Chloride thionyl (of 0.67 ml) was added to a stirred solution of 4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (0,86 g) in dry benzene (25 ml). The reaction mixture is heated to gentle irrigation in olive bath for 4 hours. The resulting solution is cooled and then evaporated in vacuum. The resulting galoyanized re-dissolved in benzene, and then CLASS="ptx2">

IR spectrum (liquid film): 1790 (C) cm-1.

(VIII). Chloride 4-(2,2-dibromovinyl)cyclohexanecarbonyl (0,91 g) in dry dichloromethane (5 ml) was added to a cooled ( 0oC) a solution containing 3-propyl-3-oxytetracyclin (0,406 g) and pyridine (of 0.64 ml) in dry dichloromethane (10 ml) in a stream of nitrogen. The reaction mixture is heated to room temperature with stirring overnight. Then add dichloromethane. The organic phase is then washed with diluted hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the residue is purified column chromatography on silica gel, conducting preliminary elution with a mixture of hexane with 1% triethylamine. After elution by the mixture hexane: simple ether (3: 1) get 3-propyloxy-3-ymetray ester of 4-(2,2-dibromovinyl) cyclohexanecarboxylic acid (0.6 g) as a mixture of CIS - and TRANS-isomers.

IR spectrum (liquid film): 1772 (C) cm-1.

Mass spectrum (chemical ionization: 2 peak in voice/MS in the ratio of 3:1, both M+1, 423.

(IX). Athirat of boron TRIFLUORIDE (40 mil) was added to a stirred solution of 3-propyloxy-3-Ismailov the ü warmed to room temperature for 16 hours. Then added triethylamine (0.6 ml). The organic layer was washed with brine before drying over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the residue is purified column chromatography on alumina with elution with a mixture of dichloromethane: hexane, saturated with ammonia, 3:7. Get 1-[4-(2,2-dibromovinyl) cyclohexyl] -4-propyl-2,6,7-dioxabicyclo[2,2,2]octane in the form of a colorless oil (0.34 g).

IR spectrum (liquid film): 1060, 1020 cm-1.

Mass spectrum, chemical ionization, 2 peak in voice/MS in the ratio of 3:1, both M+1, 423.

(X). n-Utility (1.6 ml of a 1.1 M solution in hexane) was added at -70oTo a solution of 1-[4-(2,2-dibromovinyl)cyclohexyl]-4-propyl-2,6,7-dioxabicyclo[2,2,2]octane (0.25 g) in dry tetrahydrofuran (5 ml) in a stream of nitrogen. After heating to room temperature for 2 hours, add a simple ether (about 25 ml). The ether solution is washed with saline and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum and the residue is purified column chromatography on alumina with elution with a mixture of 3:7, dichloromethane:saturated ammonia hexane. Get 1-(4-ethynylcyclohexanol)- 4-propyl-2,6,7-dioxabicyclo[2,2,2]octane as a colourless oil"ptx2">

(I). Using the procedure described in stage (VIII) of example VIII, and using as starting material 4-(2,2 - dibromovinyl)cyclohexanecarbonitrile and 3-tert-butyl-3-oxytetracyclin receive 3-tert-butylacetyl-3-ymetray ester of 4-(2,2-dibromovinyl)cyclohexanecarbonyl acid in the form of a mixture of CIS - and TRANS-isomers.

(II). According to the method described in stage (IX) of example VIII, 3-tert-butylacetyl-3-Eletropaulo ester of 4-(2,2-dibromovinyl) cyclohexanecarbonyl acid get as a mixture of qixi TRANS-isomers of 4-tert-butyl-1-[4-(2,2-dibromovinyl)cyclohexyl] -2,6,7-dioxabicyclo[2,- 2,2]octane as a colourless oil.

(III). In accordance with the method described in stage (X) of example VIII, and using as starting material 4-tert-butyl-1-[4-(2,2-dibromovinyl)cyclohexyl] -2,6,7-dioxabicyclo[ 2,2,2] octane, receive a 4-tert-butyl-1-(4-ethynylcyclohexanol)- 2,6,7-dioxabicyclo[2,2,2] octane in the form of a colourless solid, (so pl. 125,9-131,8o(C) as a mixture of CIS - and TRANS-isomers.

Both CIS-and TRANS-form 4-tert-butyl-1-(4-ethynylcyclohexanol)- 2,6,7-dioxabicyclo[2,2,2]octane receive the following procedure:

(a) CIS - and TRANS-methyl ester 4-(2,2-dibromovinyl)cyclohexanecarbonyl acid

The chromatograph is about acid (example VIII, stage (V) ) on silica gel, using as eluent a mixture of simple ether (10% ): hexane, gives separate forms of CIS - and TRANS-methyl 4-(2,2-dibromovinyl) cyclohexanecarboxylate in the form of colourless oils.

(b) CIS-4-(2,2-dibromine)cyclohexanecarbonyl acid

CIS-methyl ester 4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (4 g) is heated under reflux in a solution containing Hydrobromic acid (48%, 20 ml) and acetic acid (40 ml). After heating for 4 hours, the solvent evaporated under reduced pressure. Then add water (50 ml) and the resulting mixture is extracted with diethyl ether. The ether extracts are additionally extracted with sodium bicarbonate solution. Then the resulting aqueous layer is acidified and again extracted with simple ether. Esterified layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation receive CIS-4-(2,2-dibromovinyl)cyclohexanecarbonyl acid (3.6 g) as a pale yellow oil.

(C) TRANS-4-(2,2-dibromovinyl)cyclohexanecarbonyl acid

TRANS-methyl ester 4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (4,2 g) is stirred in a solution of potassium hydroxide (1,09 g) in methanol (50 ml) in t is stragiht simple diethyl ether. The aqueous layer was then acidified with hydrochloric acid. After re-extraction of simple ether the organic layer was washed with brine and dried over anhydrous magnesium sulfate. In the evaporation obtain TRANS-4-(2,2-dibromovinyl) cyclohexanecarbonyl acid (3.6 g) in the form of oil is pale yellow in color.

(IV). CIS - and TRANS-4-(2,2-dibromovinyl)cyclohexanecarbonyl acid is further converted into CIS - and TRANS-4-tert-butyl-1-( 4-ethynylcyclohexanol)-2,6,7-dioxabicyclo[2,2,2] octane, respectively, using the methods described in stages (VII), (VIII) and (X) example (VIII).

4-tert-butyl-1-(4-ethynylcyclohexanol)-2,6,7-dioxabicyclo[ 2,2,2]octane

Method 2.

(I). Diisopropylamine (44,7 ml) dissolved in dry tetrahydrofuran (400 ml) and then cooled to -78oWith a stream of nitrogen with mechanical stirring. Add a solution of n-utility in hexane (1.6 M, 197 ml). After stirring at -78oC for 10 minutes, add a solution containing dimethyl cyclohexane-1,4-dicarboxylic acid (56,6 g, Lancaster) in dry tetrahydrofuran (200 ml). After stirring for 30 minutes at -78oTo introduce the solution of acetyl chloride (22.5 ml) in tetrahydrofuran (200 ml). The reaction mixture is gradually heated the IRNA extracts washed with water, saturated sodium bicarbonate solution, diluted hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to obtain a colorless oil, which slowly distilled to yield dimethyl ether 1-acetylcyclohexanone-1,4-dicarboxylic acid (23.3 g, so pl. 114-120oC at a pressure of 0.4 mm Hg).

IR spectrum (liquid film): 1740, 1710 cm-1.

(II). Dimethyl ether 1-acetylcyclohexanone-1,4-dicarboxylic acid (23.3 g) was added to a solution containing concentrated hydrochloric acid (253 ml) in ethanol (126 ml). After boiling under reflux for 10 hours, the reaction mixture was poured into water and then extracted with dichloromethane. The organic layer is then washed with saturated sodium bicarbonate solution and saline. After drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. Get methyl ester 4-acetylcyclohexanone acid in the form of a colorless oil. The resulting product was then purified by distillation (so Kip. 138-145oC at a pressure of 14 mm Od).

IR spectrum (liquid film): 1730, 1710 cm-1.

(III). According to the method described in stage (II) primeryayut methyl ester of 4-(1-chloranil)cyclohexanecarbonyl acid.

IR spectrum (liquid film): 1730 cm-1.

(IV). In accordance with the method described in stage (III) of example XVIII, and using as starting material methyl ester of 4-(1-chloranil)cyclohexanecarbonyl acid, receive a 4-(1-chloranil)cyclohexylmethanol.

(V). According to the method described in stage (IV) of example XVIII, and using as starting material 4-(1-chloranil) cyclohexylmethanol, receive a 4-ethynylcyclohexanol.

IR spectrum (liquid film): 3420, 3290 cm-1< / BR>
Mass spectrum (collision of electrons): M+1, 139.

(VI). Using the procedure described in stage (V) of example XVIII, and as starting material 4-ethynylcyclohexanol, receive a 4-ethynylcyclohexanol acid.

IR-spectrum (paste Nujol): 3290, 1705 cm-1.

Mass spectrum (collision of electrons): M+1, 153.

According to the method described in example 1, using as starting material 4-ethynylcyclohexanol acid and 3-tert-butyl-3-oxytetracyclin, receive a 4-tertbutyl-1-( 4-ethynylcyclohexanol)-2,6,7-dioxabicyclo[2,2,2] octane.

In accordance with the procedure described in example IV, and using as the source material,6,7-dioxabicyclo [2,2,2]octane-3-carbonitrile.

Example x 4-tert-butyl-1-(3,3-dimethylbutan-1-inyl)-2,6,7 - dioxabicyclo[2.2.2]octane

(I). According to the method described in stage (VIII) of example VIII, and using as starting material 4,4-dimethyl-2-pentenoate and 3-tert-butyl-3-oxytetracyclin receive ( 3-tert-butylacetyl-3-yl)methyl 4,4-dimethylpent-2-inat in the form of a solid substance.

GC: OS-17 180oWith gives a single peak.

(II). In accordance with the method described in stage (IX) of example VIII, and using as starting material (3 - tert-butylacetyl-3-yl)methyl 4,4-dimethylpent-2-inat, receive a 4-tert-butyl-1-(3,3-dimethylbutan-1-inyl)-2,6,7-dioxabicyclo [2,2,2]octane in the form of colorless crystals (so pl. 204-206oC).

GC: OS-17 180oWith gives a single peak.

In accordance with the procedure described in example IV, and using as starting material 3-formyl-3-n-propyloxy and 3-isobutyl-3-formyloxy, get 1-(3,3-dimethylbutan-1-inyl)- 4-n-propyl-2,6,7-dioxabicyclo[2,2,2] octane-3-carbonitrile and 4-isobutyl-1-(3,3-dimethylbutan-1-inyl)-2,6,7 - dioxabicyclo[2,2,2]octane-3-carbonitrile.

Using a similar methodology, E-1-(3,3-dimethylbutan-1-ethyl)- 4-n-propyl-2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile and TRANS-1-(2-tert-butylcyclohexyl)-4-n-propyl-the-2-tert-butylcyclohexanecarboxylic acid ( see E. L. Foreman I. Amer. Chem Soc. 1940, vol. 62, page 1438 and clerks and other hem. Abs. 70:78062, respectively).

Using a similar technique of 4,4-dimethylpentane acid (see G. M. whitesides, etc. I. Amer. Chem. Soc. 1967 howled. 89, page 1135) receive a 4-tert-butyl-1-(3,3-dimethylbutyl)- 2,6,7-dioxabicyclo[2,2,2] octane and 1-(3,3-dimethylbutyl)- 4-n-propyl-2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile.

Example XI. 1-(Gex-5-inyl)-4-n-propyl-2-oxa-6,7-diabetico [2,2,2]octane

(I). The stirred solution of 6-cyanogens-1-in (4.0 g) (synthesis: see example II, stage II) in dry methanol (30 ml) and dry diethyl ether saturated with hydrogen chloride, and the solution temperature kept in the range of -10 -0oC. the Reaction solution was diluted with dry diethyl ether (120 ml) and incubated at -20oWith in 24 hours. The obtained white crystalline product is filtered and dried in vacuum to yield methyl ester hydrochloride kinagat-6-sludge acid.

(II. Dry methanol (33 ml) was added the hydrochloride methylimine-6-hinata ( of 38.4 g) in a stream of dry nitrogen. Then enter hexane (750 ml) and the resulting mixture is stirred at 20oC for 6 hours. The mixture was kept overnight for settling, and the supernatant hexane solution providing desantirovanie the(25,0 g).

(III). In accordance with the methodology described in Europatent N 216625, and using as starting material trimethylated-6-inat and 2-oxymethyl-2-n-propylparaben-1,3-dithiolo ( synthesis are also described in the mentioned patent) receive 1- (Gex-5-inyl)-4-n-propyl-2-oxa-6,7-diabetico[2,2,2]octane.

In addition, 2-oxymethyl-2-n-propylparaben-1,3-dithiolo get but the following method:

(I). 3-n-propyloxy-3-ylmethylphosphonate obtained from 3-oxymethyl-3-n-propylacetate and methanesulfonanilide using the method described in stage (I) of example II.

(II). The solution benzylmercaptan (25,0 ml) in dry dimethylformamide (100 ml) stirred at 0oWith a stream of nitrogen. Sodium hydride (6.0 g, 80% dispersion in oil) was added to this mixture, followed by stirring it at 0oC for 1 hour. Add 3-n-propyloxy-3-ylmethylphosphonate ( 10 g) and the resulting mixture was stirred at 0oC for 1 hour. The mixture is then heated under reflux with stirring for 6 hours. The mixture is cooled and poured into water. The aqueous phase is extracted with diethyl ether.

The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. The remainder of the chromium(benzyldimethyl)pentane-1-ol as a pale yellow oil (15.6 g).

Mass spectrometry (chemical ionization); M+l, 361.

(III). 2,2-di-(benzyldimethyl)pentane-1-ol (8.0 g) in dry diethyl ether (150 ml) was added to liquid ammonia (500 ml), stirred in nitrogen atmosphere at -70oC. Then added in small portions sodium (8.0 g) and the resulting mixture was stirred at -70oC for 3 hours. The mixture is heated to 20oWith and add solid ammonium chloride (20 g). To remove excess sodium cautiously added methanol (100 ml). Then add water, and the aqueous mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. Get 2-oxymethyl-2-n-propylparaben-1,3-dietil in the form of a colorless oil (4.6 g).

Similarly, 4-n-butyl-1-(GEK-5-inyl)-2-oxa-6,7-diabetico[2,2,2]octane, 4-tert-butyl-1-(Gex-5-inyl)- 2-oxa-6,7-diabetico[2,2,2] octane, 4-isobutyl-1-(Gex-5 - inyl)-2-oxa-6,7-diabetico[2,2,2]octane, 1-(Gex-5-inyl)- -4-phenyl-2-oxa-6,7-diabetico[2,2,2]octane and 4-cyclopropyl-1-( Gex-5-inyl)-2-oxa-6,7-diabetico[2,2,2] octane, respectively, received from trimethylboron ether orthocept-6 - silt acid and 2-n-butyl-2-oximation-1,3-dithiol, 2-tert-butyl-2-oximation-1,3-dithiol, 2-isobutyl-2-oximation-1, 3-ditio. 1-Gex-5-inyl-4-n-propyl-2,6,7-trimebutina [2.2.2]octane

Method 1.

Athirat of boron TRIFLUORIDE (0,20 ml) was added to a mixed solution containing 2-mercaptomethyl-2-n-propylparaben-1,3-dithiolo ( 0,30 g) (synthesis described in example XXXI) and timetravel ether orthocept-6-invoi acid (0,30 g) in dry dichloromethane (10 ml) at 20oC in nitrogen atmosphere. The mixture is then stirred at 20oC for 5 hours and add triethylamine (1.0 ml). Add the water, and the aqueous mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuum. The remainder chromatographic on alumina, using as eluent a mixture of dichloromethane:saturated ammonia hexane 1:10. Volatile impurities (methylhept-6-inat) removed in vacuum (130oWith the pressure of 10 mm Od).

As a result of recrystallization of the residue from hexane get 1-(Gex-5-inyl)-4-n-propyl-2,6,7-trimebutina[2,2,2] octane in the form of a colourless solid (10 mg).

Method 2.

The solution containing timetravel epirote-6-invoi acid (6.0 g) in dry methanol (24 ml), stirred at 0oC in nitrogen atmosphere. Add 2-mercaptomethyl-2-n-propylparaben-1,3-dithiolo ( 3.0 g) in dry methanol (10 m is added dry triethylamine (3.0 ml). Then add water (100 ml) and the mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The remainder chromatographic on alumina with elution with a mixture of dichloromethane: saturated ammonia hexane 1:10. Volatile components are removed under vacuum ( 130oWith the pressure of 0.5 mm Od). The remainder vykristallizovyvalas from hexane. Get 1-(Gex-5-inyl)-4-n-propyl-2,6,7-trimebutina [2,2,2] octane in the form of colorless crystals (from 0.90 g).

Using a similar methodology (method 2), receive a 4 - ethyl-1-(Gex-5-inyl)-2,6,7-trimebutina[2,2,2] octane and 4-isobutyl-1-(Gex-5-inyl)-2,6,7-trimebutina[2,2,2]octane from trimethylated-6-hinata and 2-ethyl-2-mercaptomethyl-1,3-dithiol and 2-isobutyl-2-mercaptomethyl-1,3-dithiol, respectively.

Example XIII. 4-n-propyl-1-[2-(prop-2-initio)ethyl]-2,6,7 - dioxabicyclo-[2,2,2]octane

(I). A solution of 3-mercaptopropionic acid (15 ml) in dry dimethylformamide (250 ml) stirred at 0oC in nitrogen atmosphere. Sodium hydride (10.2 g, 80% dispersion in oil) is carefully added to a given solution, and the mixture is then stirred at 40oC for 1 hour. The mixture is cooled to 0oWith, and injected dropwise bromine of propargyl (60 g, 80% in toluene). Smvdu. The aqueous mixture is extracted with diethyl ether, and the extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum. The oil obtained (30 g) (containing mainly prop-2-inyl-3-(prop-2-initio)propenal) was added to a solution of sodium hydroxide (8.0 g) in water (100 ml) with methanol (100 ml) and the mixture is then stirred at 20oWith in 24 hours. The mixture is extracted with diethyl ether, and the aqueous layer was acidified with hydrochloric acid. The acidified mixture is extracted with diethyl ether, and the ether extracts dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum. Get 3-(prop-2-initio)propionic acid in the form of a red oil (12.0 g), which is used without further purification.

(II). 4-n-propyl-1-[5-(prop-2-initio)ethyl]-2,6,7-dioxabicyclo[ 2,2,2] octane is obtained from 3-(prop-2-initio)propionic acid and 3-oxymethyl-3-n-propylacetate according to the method described in example 1.

4-tert-butyl-1-[2-(prop-2-initio)ethyl] -2,6,7-dioxabicyclo[ 2.2.2] octane is obtained from 3-(prop-2-initio)propionic acid and 3-tert-butyl-3-oxymethylnitrobenzene according to the method described in example 1.

4-n-propyl-1-[2-(prop-2-initio)ethyl]-2,6,7-dioxabicyclo[2,2,2]octane-- 3-carbonitrile and get the>/P>Example XIV. 4-n-propyl-1-[2-(prop-2-ynyloxy)ethyl] -2,6,7 - dioxabicyclo[2,2,2]octane

(I). 3-(prop-2-ynyloxy)propionic acid is obtained from propargilovyh alcohol and ethyl ester of 3-bromopropionic acid by the procedure similar to the synthesis of 3-(but-3-in-1 yloxy)propionic acid as described in example XIX.

(II). 4-n-propyl-1-[2-(prop-2-ynyloxy)ethyl] -2,6,7-dioxabicyclo[ 2,2,2]octane is obtained from 3-(prop-2-ynyloxy)propionic acid and 3-oxymethyl-3-n-propylacetate according to the method described in example 1.

4-tert-butyl-1-[2-(prop-2-ynyloxy)ethyl] -2,6, 7-dioxabicyclo[2,2,2] octane is obtained from 3-(prop-2-ynyloxy) propionic acid and 3-tert-butyl-3-oxitetraciclina according to the method described in example 1.

4-n-propyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6 7 trioxane-cyclo[2,2,2]octane-3-carbonitrile obtained from 3-(prop-2-inyl-hydroxy)propionic acid and 3-formyl-3-nitrophenoxide according to the method described in Example IV.

Example XV. 1-(but-3-Unlocker)-4-n-propyl-2,6,7-trioxa-bicyclo[2,2,2]octane

(I). 2-(but-3-ynyloxy)acetic acid get them but-3-in-1-ol and ethylbromoacetate by the method similar to the synthesis of 3-(but-3-enyloxy)propionic acid (example XIX).

(II). 1-(but-3-Unlocker)-4-n-propyl-2,2,7-trioxepane in example I.

4-tert-butyl-1-(but-3-Unlocker)-2,6,7-dioxabicyclo-[2,2, 2]octane is obtained from 2-(but-3-ynyloxy) acetic acid and 3-tert-butyl-3-oxitetraciclina according to the method described in example I.

1-(but-3-Unlocker)-4-n-propyl-2,6,7-dioxabicyclo[2,2, 2]octane-3-carbonitrile obtained from 2-(but-3-ynyloxy) acetic acid and 3-formyl-3-n-propyl-oxetane according to the method described in example IV.

Example XVI. 4-tert-butyl-1-(hept-6-inyl)-2,6,7-dioxabicyclo [2,2,2]octane

(I). Sodium (1.2 g) is dissolved in dry ethanol (200 ml). Add diethyl ester of malonic acid (7.8 ml) and the resulting mixture is stirred for 30 minutes, and then add Gex-5-inimicality (9.0 g). The mixture is stirred and heated under reflux for 1 hour. The mixture is cooled and evaporated in vacuum. Poured into water and the aqueous layer was extracted with diethyl ether. The ether extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum. The crude ester was added to a solution containing an aqueous solution of sodium hydroxide ( 100 ml of 15% solution) and methanol (50 ml) and the resulting mixture is stirred at 20oWith in 24 hours. The mixture is extracted with diethyl ether. Water-base layer packgoat 2- (Gex-5-inyl)malonic acid as a colourless solid (4.5 g), which is used without further purification.

(II). A mixture of 2-(Gex-5-inyl)malonic acid ( 2.2 g) and cuprous oxide (60 ml) in dry acetonitrile (40 ml), stirred and refluxed under nitrogen atmosphere for 6 hours. The solvent is evaporated in vacuum. Add 5% aqueous solution of hydrochloric acid, and the aqueous mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuum. Receive Oct-7-andnew acid oil (1.5 g), which is used without further purification.

(III). 4-tert-butyl-1-(hept-6-inyl)-2,6,7-dioxabicyclo[2,2,2]octane is obtained from Oct-7-invoi acid and 3-butyl-3-oxitetraciclina according to the method described in example 1.

1-(hept-6-inyl)-4-n-propyl-2,6,7-dioxabicyclo-[2,2,2] octane is obtained from Oct-7-invoi acid and 3-oxymethyl-3-n-propylacetate according to the method described in example 1.

Example XVII. 1-(Gex-5-inyl)-4-(prop-2-enyl)-2,6,7-dioxabicyclo[ 2,2,2]octane-3-carbonitrile

(I). The Penta-4-enal obtained from the Penta-4-EN-1-ol (supplied by Aldrich company) according to the method described in stage (I) of example IV.

(II). 2-Oxymethyl-2-(prop-2-enyl)propane-1,3-diol is obtained from the Penta-4-enala as described in example I, stage (vannoy in examples I and IV.

1-(Gex-5-inyl)-4-(prop-2-enyl)-2,6,7-dioxabicyclo [2,2,2] octane-3-carbonitrile get from hept-6-invoi acid and 3-formyl-3-(prop-2-enyl)oxetane according to the method described in example IV.

Similarly, using as starting material 2-(but-3-ynyloxy)acetic acid (example XV) and 3 - formyl-3-(prop-2-enyl)oxetan, get 1-(but-3-Unlocker)- 4-(prop-2-enyl)-2,6,7-dioxabicyclo[2,2,2]octane-3 - carbonitrile.

Similarly, using as source material Gex-5-EN-1-ol obtain 4-(but-3-enyl)-1-(Gex-5-inyl)-2,6,7-dioxabicyclo [2,2,2] octane-3-carbonitrile.

Triol is obtained from 2-(but-3-enyl)-2-oximation-1,3 - diol, triacetate by transesterification with sodium methoxide in methanol with impurities, which is cleaned in the following way.

A mixture of crude 2-(but-3-enyl)-2-oximation-1,3-diol ( 4.5 g), acetone (30 ml) and para-toluenesulfonic acid (0.25 g) is heated under reflux in an apparatus of the Dean-stark for 7 hours. The mixture is then cooled and washed with aqueous sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate, the solvent evaporated in vacuum. The remainder chromatographic on silica, using ka is escitalo oil.

Mass spectrum (chemical ionization): M+1, 201.

A mixture of 5-(but-3-enyl)-2,2-dimethyl-5-oxymethyl-1,3 - dioxane (0,80 g) and Amberlite "15" (0.50 g) in methanol (100 ml) with water (1.0 ml) is refluxed, carefully stirring for 6 hours. This mixture is filtered and the filtrate evaporated in vacuum. Get 2-(buta-C-enyl)- 2-oximation-1,3-diol as a colorless oil (0.6 g), which solidified upon storage.

4-(but-3-enyl)-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[2,2,2] octane-3-carbonitrile get from hept-6-invoi acid and 3-(butyl-3-enyl)-3-formylacetate according to the method described in example IV.

Example XVIII. 4-tert-butyl-1-(4-metrex-5-inyl)-2,6,7 - dioxabicyclo[2,2,2]octane

(I). A mixture of diethyl-2-acetyl-2-methylhexan-1,6-dioate ( 16.0 g) (see Chem. Ber. 1980, vol. 113, page 451), hydrochloric acid (100 ml) and ethanol, heated under reflux for 4 hours. Then the mixture is cooled, diluted with water and alkalinized with sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether. The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum.

Ethyl ester 5-methyl-6-exogamous acid obtained as a colorless oil (7,3 g), which is, and the aqueous mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuum.

5-Methyl-6-oxalatebuy acid is obtained as a yellow oil (8.5 g).

(II). A mixture consisting of patalenitsa phosphorus (3.0 g), dry pyridine (4.0 ml) and benzene (30 ml) was stirred at 25oC in nitrogen atmosphere. Ethyl ester 5-methyl-6-exogamous acid (1.0 g) dissolved in benzene (3.0 ml), was added to this mixture and then the mixture is refluxed with stirring for 3 hours. The mixture is cooled and poured into ice water. The aqueous layer was extracted with diethyl ether. The ether extracts are washed and hydrochloric acid, sodium bicarbonate solution and finally with water. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The obtained oil (800 mg) contains ethyl ester of 6-chloro-5-methylhept-6-ene acid (70%) and ethyl ester of 6-chloro-5-methylhept-5-ene acid (30%), which is used without further purification.

Mass spectrum (chemical ionization). In combination with gas-liquid chromatography. The presence of two components (a 2:1 ratio). M+1 for both komponentov 205.

is tmosphere nitrogen. A mixture of ethyl-6-chloro-5-methylhept-6-Anata and ITIL-chloro-5-methylhept-5-Anata (4.0 g) in dry diethyl ether (20 ml) was added and the resulting mixture was stirred in nitrogen atmosphere for 2 hours. Add aqueous sodium hydroxide solution (10 ml, 10%), being careful. Pop-up the ether layer is removed by decantation, and the residue was washed with diethyl ether (2 x 50 ml). The combined ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The resulting oil (3.5 g) consists of 6-chloro-5-methylhept-6-EN-1-ol ( 50% ) and E and Z-isomers of 6-chloro-5-methylhept-6-EN-1-ol ( 50%), which is used without further purification.

(IV). A mixture of 6-chloro-5-methylhept-6-EN-1-ol and E and Z-isomers of 6-chloro-5-methylhept-5-EN-1-ol (2.8 g) was stirred in dry tetrahydrofuran (50 ml) at 0oC in nitrogen atmosphere. Add n-utility (43 ml of 1.6 M solution in hexane) and the resulting mixture is stirred for 4 hours at 20oC. Add the ice water and the mixture extracted with diethyl ether. The ether extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuum. The oil obtained chromatographic on silica using as eluent a mixture of diethyl ether one peak.

Mass spectrum (chemical ionization). Gaseous ammonia as the ionizing gas M+18, 144.

(V). A solution of 5-methylhept-6-in-1-ol (1.0 g) in dry dimethylformamide (9.0 ml) was stirred at 20oWith and added pyridinium a bichromate (10,5 g) caution. The mixture is stirred for 24 hours at 20oC. was Added diethyl ether (50 ml), and the supernatant was separated by decantation. The residue was washed with additional portions of diethyl ether (10 x 50 ml). The ether extracts are washed with 0.5 N. hydrochloric acid and then with water. Then the ether extracts dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuum.

5-Methyl-hept-6-andnew acid is obtained as a light brown oil (0,80 g), which is used without further purification.

(VI). 4-tert-butyl-1-(4-metrex-5-inyl)-2,6,7-dioxabicyclo[ 2,2,2] octane is obtained from 5-methylhept-6-invoi acid and 3-tert-butyl-3-oxitetraciclina according to the method described in example 1.

1-(4-Metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] -octane-3-carbonitrile obtained from 5-methylhept-6-invoi acid and 3-formyl-3-n-propylacetate according to the method described in example IV.

Example XIX. 1-[2-(but-3-enyloxy)-ethyl] -4-the mixed solution of but-3-in-1-ol (16.2 g, to 0.23 mole, Lancaster) in dry toluene (200 ml). After stirring for 2 hours at 25oTo add a solution containing ethyl ester 3-bromopropionic acid (20,8 g, 0,115 mole, Lancaster). The reaction mixture is stirred and heated under reflux for 7 hours. With a sudden cooling of the cooled reaction mixture into water, extraction by a simple ether, washing with salt solution, dried over anhydrous magnesium sulfate, followed by evaporation receive the ethyl ester of 3-(but-3-enyloxy) propionic acid (17.8 g).

(II). Ethyl ester of 3-(but-3-enyloxy)propionic acid ( 17,4 g) is stirred overnight with a solution of sodium hydroxide (150 ml, 2M). After simple extraction with ether, the aqueous layer was acidified with concentrated hydrochloric acid. The desired acid is obtained by extraction with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation receive 3-(but-3-enyloxy) propionic acid (8.8 g) as a colourless oil.

1-[2-(but-3-ynyloxy)ethyl] -4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane is obtained from 3-(but-3-enyloxy)propionic acid and 3-oxymethyl-3-n-propylacetate according to the method described in example 1.

Ispolin-1-ol (supplied by company "Lancaster Synthesis"), get 1-[1- (but-3-ynyloxy)ethyl]-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] octane.

Example XX. 1-(7-Meloxicam-5-inyl)-4-n-propyl-2,6,7 - dioxabicyclo[2,2,2]octane

(I). A mixture of 7-chloro-1-meloxicam-2-in (8.0 g) and sodium cyanide (5.0 g) dissolved in dimethylformamide (20 ml) and water (20 ml) was stirred at 80oWith over 7 hours. The mixture is cooled and diluted with water. The aqueous mixture is extracted with diethyl ether. The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. Get 7-cyano-1-meloxicam-2-in the form of a yellow oil (6.0 g).

Mass spectrum (chemical ionization): M+1, 152.

(II). A mixture of 7-cyano-1-meloxicam-2-in (6.0 g) and an aqueous solution of sodium hydroxide (100 ml, 2 BC) is refluxed for 16 hours. Then the mixture is cooled and extracted with a simple diethyl ether. Water-alkaline solution is acidified with hydrochloric acid, and the aqueous layer was extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. Get 8-metakit-6-andnew acid as a colorless oil (6.0 g).

1-(7-Meloxicam-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] octane is obtained from 8-metakit-6-invoi acid is,7 - dioxabicyclo[2,2,2]octane

(I). Hydrochloride methyl ester 5-bromopentanoate ( so pl. 89o(C) is obtained from 5-bangaloreindia according to the method described in stage (I) of example XI.

(II). Trimethyl 5-bromooctadecane (colorless liquid, so Kip. 108-110oC, a pressure of 16 mm Hg) is obtained from the hydrochloride of methyl-6-bromopentanoate according to the method described in stage (II) of example XI.

(III). 1-(4-Bromobutyl)-4-tert-butyl-2,6,7-dioxabicyclo [2.2.2] octane (so pl. 111-115o(C) is obtained from 5-bromooctadecane and 2-tert-butyl-2-oximation-1,3-diol according to the method described in method 2 of example VI.

Mass spectrum (chemical ionization): M+1, 307, 309.

(IV). To a mixed solution containing anhydrous liquid ammonia (70 ml) and dry diethyl ether (20 ml), add sodium (0.1 g) at -70oC in nitrogen atmosphere. After 10 minutes, to the resulting dark blue solution was added nitrate iron (15 mg). The reaction mixture, which turns green, bring up to temperature -30oWith and add small amounts of additional amounts of sodium (0.75 g). The mixture is stirred for 30 minutes at -30oWith gain methylpropylamine (2.2 g). The mixture is stirred for another hour at -30oWith and added 1-(4-bromobutyl)-4-tert-butyl-2,6,7-trio is ribault solid ammonium chloride (1.7 g), and then methanol (5 ml) and the reaction mixture is brought to room temperature. Add water (20 ml) and the aqueous mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The remainder chromatographic on alumina, using as eluent a mixture of dichloromethane saturated with ammonia hexane 1:9.

4-tert-butyl-(7-meloxicam-5-inyl)-2,6,7-dioxabicyclo[ 2,2,2] octane obtained as a colorless solid (so pl. 47-49oWith, recrystallized from hexane)

Example XXII. But-3-inyl-4-n-propyl-2,6,7-dioxabicyclo [2,2,2]octane-1-carboxylate

(I). Chloride, oxalyl (4.3 ml) was added to a stirred solution of but-3-in-1-ol (3.5 g) in dry dichloromethane (75 ml) at 0oC. the resulting solution was stirred at 0oC for 30 minutes and then added dropwise to the mixed solution containing 3-oxymethyl-3-n-propyloxy (6.4 g) and dry pyridine (30 ml) in dry dichloromethane (75 ml). The mixture is stirred for 24 hours at 20oC., water is Added, and the aqueous mixture extracted with diethyl ether. The ether extracts washed with 5% hydrochloric acid, saturated sodium bicarbonate solution and at the end of the water. The ether extracts are dried over betw aeternum by elution with 1% triethylamine in hexane), and by elution with a mixture of 1:1 diethyl ether:hexane. Get the but-3-inyl (3-n-propyloxy-3-yl)Metrocall in the form of a colorless oil (7.0 g).

(II). But-3-injuly ester of 4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane-1-carboxylic acid derived from but-2-inyl(3 - n-propyloxy-3-yl)methylacetate according to the method described in example 1.

Example XXIII. N-(prop-2-inyl)-4-n-propyl-2,6,7-trixibelle [2,2,2] octane-1-carboxamide

(I). Ethyl ester of 4-n-propyl-2,6,7-dioxabicyclo [2,2,2]octane-1-carboxylic acid is obtained from 3-oxymethyl-3-n-propylacetate and ETHYLACETYLENE (supplied by the firm Aldrich ) by the procedure described in example 1 (colorless solid, so pl. 70oC).

Mass spectrum (chemical ionization): M+1, 231.

(II). A solution containing ethyl ester of 4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane-1-carboxylic acid (0.12 g) and 2-provisionin (0.5 ml), and methanol (20 ml) maintained at 20oC for 4 days. The solution is evaporated in vacuum. The remainder chromatographic on alumina, using as eluent a mixture of dichloromethane:saturated ammonia hexane 2:3.

N-(prop-2-inyl)-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] octane-1-carboxamide obtained as a pale yellow solid (0.12 g).

(II). A mixture of ethyl 2-n-4-n-propyl-2,6,7 - dioxabicyclo[2,2,2] Oct-1-yl acetate (0,48 g) and sodium hydroxide (0.35 g) in methanol (10 ml) and water (2.0 ml) is stirred at a temperature of 20oC for 3 hours. Add granulated carbon dioxide (10 ml) and the mixture is then evaporated to dryness. Crude 2 - 4-n-propyl-2,6,7-dioxabicyclo[2,2,2] oxt-1-yl sodium acetate is used without additional purification.

(III). A mixture consisting of 2 - 4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] Oct-1-yl acetate (1.0 g) and methyl of propargyl (1.8 ml of 80% solution in toluene, supplied by the firm Aldrich) in dry dimethylformamide (30 ml), stirred at 20oWith in 24 hours. Add the water, and the aqueous mixture extracted with simple diethyl ether. The ether extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo, the residue chromatographic on silica (pre-suirvey a mixture of dichloromethane:hexane containing 3% triethylamine, 1:3) and elute with a mixture of dichloromethane and 3% triethylamine in hexane 1:3. Prop-2-inyl 2-n-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] Oct-1 - yl acetate obtained as a colorless solid (0.45 g).

Example XXV. 1-(but-3-initimate)-opisannoi in stage (I) of example 1.

(II) 2-(but-3-initio)acetic acid

Method A.

Thioglycolic acid (6.0 g) was added to a mixed solution of sodium hydroxide (8.0 g) in ethanol (50 ml). Added but-3-inimicality (7,4 g) and the mixture stirred at 20oWith in 24 hours. The reaction mixture was poured into water and the aqueous mixture extracted with diethyl ether. The aqueous alkaline extracts are acidified with hydrochloric acid and the mixture extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The oil obtained is stirred in dry dimethylformamide (100 ml) and added anhydrous sodium carbonate (15 g). Add methyl iodide (7.0 ml) and the reaction mixture is then stirred at 20oWith in 3 days. Add the water, and the aqueous mixture extracted with diethyl ether. The ether extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuum and the residue chromatographic on silica with elution with a mixture of diethyl ether:hexane 1:4. Get the methyl ester of 2-(but-3-initio)acetic acid as a colorless oil (1.2 g) (as impurity is present in a minor amount of methyl ester of 2-(but-3-in-1 ylthio) propionic acid). See amerivault within 24 hours at 20oC. Add the water, and the aqueous mixture extracted with diethyl ether. The aqueous alkaline extracts are acidified with hydrochloric acid and then extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuum. Get 2-(but-3-initio)acetic acid as a colorless oil (0.5 g). There is a small amount of 2-(but-3-initio)propionic acid.

2-(but-3-in-1 ylthio)acetic acid

Method C.

2-(but-3-initio)acetic acid is obtained from thioglycolic and but-3-inimitableness according to the method described in stage (I) of example XIII.

(III). 1-(but-3-initimate)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] octane is obtained from 2-(but-3-initio)acetic acid and 3-oxymethyl-C-n-propylacetate according to the method described in example 1.

4-tert-butyl-1-(but-3-initimate)-2,6,7-dioxabicyclo[ 2,2,2] octane is obtained from 2-(but-3-initio)acetic acid and 3-tert-butyl-3-oxitetraciclina according to the method described in example 1. There is a small amount of 4-tert-butyl-1-[ 1-(but-3-inyl-1 ylthio)ethyl]2,6,7-dioxabicyclo [2,2,2]octane.

Example XXVI. N-(prop-2-inyl)-2-(4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] Oct-1-yl)ndimethylacetamide

To p is EP XXIV) in methanol (5 ml) was added 2-Propylamine (2.0 ml), and then sodium cyanide (20 mg). The mixture is stirred for 12 hours at 70-80oC. was Added water and the mixture extracted with ethyl acetate. An ethyl acetate extracts are dried over anhydrous sulfate of magic and evaporated in vacuum. The residue is purified by chromatography on silica using gradient elution with a mixture of ethyl acetate:hexane with 1% triethylamine.

N-(prop-2-inyl)-2-(4-n-propyl-2,6,7-dioxabicyclo [2,2,2] Oct-1-yl)ndimethylacetamide obtained as yellowish oil (122 mg).

GC: OS-17 245oWith gives a single peak.

Example XXVII. 1-(1-metrex-5-inyl)-4-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane

(I). Using strictly the same technique described in stage (I) of example II, Penta-4-inimicality (37,8 g) is obtained from methanesulfonanilide (22 ml), triethylamine (44 ml) and Penta-4-in-1-ol (obtained by synthesis Lancaster 20)

(II). A solution of diethyl ether methylmalonic acid (produced by Aldrich Chemical Company, 35,6 ml) in dry tetrahydrofurane (200 ml) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 9,1 g) in tetrahydrofuran (50 ml) under nitrogen atmosphere. When you finish the introduction, the mixture is heated with irrigation in mild conditions for 1 hour, and then cooled the th mixture is heated to gentle irrigation for another 2 hours. All the used solvent is then distilled off in vacuum and the residue is divided into layers diethyl ether and water. The organic phase is separated and washed with water and brine before drying over anhydrous magnesium sulfate and evaporation under reduced pressure. After distillation of diethyl ether 2 - methyl-2-(Penta-4-inyl)malonic acid (45,8 g) as a colourless oil (so Kip. 92-97oWith the pressure of 0.5 mm Hg).

GC: OS-17 programming in the range of 120-210oWith gives a single peak.

(III). A mixture of diethyl ether 2-methyl-2- (Penta-4-inyl)-malonic acid (11 g) and potassium hydroxide (15 g) in 95% ethanol (150 ml) is heated under reflux for 4 hours, then brought to room temperature for 15 minutes. All solvent is distilled off in vacuo, and the residue is dissolved in water. The resulting aqueous layer washed with dichloromethane, acidified with concentrated acid to pH 1 and then extracted with fresh dichloromethane. The organic extracts are washed with saline, dried over anhydrous magnesium sulfate and evaporated in vacuum. Get 2-methyl-2-(pent-inyl)malonic acid as a pale yellow oil (6.7 g).

(IV). A mixture consisting of 2-methyl-2-(Penta-4-inyl)malonic sour the s 4.25 hours. The solvent is removed under reduced pressure, to the residue was added water, and then for the hydrolysis of salts of copper sufficient amount of concentrated hydrochloric acid. The resulting aqueous phase is extracted with diethyl ether, and the organic extracts washed with water and brine. Dried over anhydrous magnesium sulfate and evaporated in vacuum. Get 2-methylhept-b-andnew acid (3.6 g) as a colorless oil after distillation (so Kip. 150-165oC, 0.5 mm Hg)

(V). According to the method described in stage (V) and (VI) of example 1 from 2-methylhept-6-invoi acid and 3-oxymethyl-3-n-propylacetate get 1-(1-metrex-5-inyl)-4-propyl-2, 6,7-dioxabicyclo[2,2,2]octane.

GC: OS-17 200oWith gives a single peak.

Similarly obtained, in addition, the following connection:

4-tert-butyl-1-(1-metrex-5-inyl)-2,6,7-dioxabicyclo [2,2,2]octane.

In accordance with the procedure described in example IV, get 1-(1-metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane-3-carbonitrile.

Example XXVIII. Methyl 7-(4-n-propyl-2,6,7-dioxabicyclo [2,2,2]Oct-1-yl)hept-2-inat

(I). n-Utility (5,2 ml, 1.6 M solution in hexane) was added to a solution containing hept-6-andnew acid (0.5 g) in dry then it is carbonated is C for 0.25 hour, adding methyl ether harpalinae acid. The resulting solution was stirred at -70oWith another 0.5 hour, and then warmed to room temperature for 0.5 hours. Then add water (5 ml), and the whole of the solvent used is distilled off under reduced pressure. The residue is diluted with water and extracted with diethyl ether. The aqueous phase is separated, acidified to pH 1 with concentrated hydrochloric acid, and then extracted with dichloromethane. The combined dichloromethane extracts are washed with brine followed by drying over anhydrous magnesium sulfate and evaporation in vacuo. The residue is purified by distillation (at a slow boil, pressure of 0.5 mm Hg). At a temperature of 220oWith distilled 1-methyl ether of 1,8-Oct-2-indicolite in the form of a brown oil (183 mg).

Mass spectrum (sample) (chemical ionization): M+1, 185.

(II). According to the method described in stage (V) and (V1) of example 1 from 1-methyl ether of 1,8-Oct-2-indicolite and 3-oxymethyl-3-n-propylacetate get methyl ester 7-(4-propyl-2, 6,7-dioxabicyclo[2,2,2]Oct-1-yl)hept-2-invoi acid.

Example XXIX. 1-(Gex-5-inyl)-3-methyl-4-n-propyl-2-oxa-6,7 diabetico[2,2,2]octane

(I). A solution of 2,2-di-(benzyldimethyl)-pentane-1-ol (the I (1.8 g) and anhydrous sodium acetate (0.11 g) in dry dichloromethane (25 ml) at 0oWith a stream of nitrogen. The reaction mixture is heated to 20oC, and then stirred for 2 hours. Add dry diethyl ether, and the resulting mixture is stirred for 30 minutes. The ether extracts decanted and the residue is washed with additional portions of diethyl ether. The combined ether extracts dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuum. The residue is purified on silica with charcoal, while elution with diethyl ether. Receive 2,2-di-(benzyldimethyl)pentanal in the form of a pale yellow oil (0.27 g).

Mass spectrum (chemical ionization): M+1, 359.

(II). A solution of 2,2-di(benzyldimethyl)pentanal (of 3.54 g) in dry diethyl ether are added dropwise to the solution containing minimalized (obtained from methyl iodide) ( 1.2 ml) and magnesium (0,48 g) in dry diethyl ether (6% ml). The reaction mixture is refluxed for 2 hours and then cooled. Add saturated aqueous solution of ammonium chloride. The mixture was then stirred for 30 minutes and extracted with diethyl ether. The ether extracts dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuum. Receive 3,3-di-(benzyldimethyl) hexane-2-od in the-4-n-propyl-2-oxa-6,7-diabetico [2,2,2]octane is obtained from 3,3-di-(benzyldimethyl)hexane-2-ol according to the method described in example XI.

Example XXX. 1-(2-metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]-octane-3-carbonitrile

(I). 1-4-Dimethylcyclohex-1-ene (12 g) (see Beilstein, 5, 74) is dissolved in dry dichloromethane (120 ml) and the resulting solution was stirred at -70oC. After the solution is passed a stream of ozone for 3 hours. Then the solution is allowed a little bit to warm up, and then poured into a solution of hydrogen peroxide in water (600 ml of 3% solution). Dichloromethane is removed in vacuo, and the mixture is vigorously stirred at 20oWith in 48 hours. Next, the mixture is alkalinized with a saturated solution of sodium bicarbonate, and the aqueous mixture extracted with diethyl ether. The aqueous solution is acidified with 10% hydrochloric acid, and then extracted with diethyl ether. After drying over anhydrous magnesium sulfate, both ether extract evaporated in vacuum. Both contain residue of an organic acid and aldehyde. United precipitation (3.5 g) was stirred in dry dimethylformamide (30 ml) and added bichromate pyridinium a (17.4 g). The mixture is stirred at 20oWith in 24 hours, and then diluted with diethyl ether (50 ml). The ether extracts decanted, and the black precipitate was washed repeatedly by a large amount of diethyl ether. United broadcasting the al is removed in vacuum, you will receive 3-methyl-6-oxalatebuy acid as a yellow oil (2,45 g).

Mass spectrum (chemical ionization): M+1, 159.

(II). 3-Methyl-6-oxalatebuy acid (2,45 g) is stirred in dry dimethylformamide (60 ml) at 20oWith, and then add anhydrous sodium bicarbonate (1.64 g). Added dropwise to ethyliodide (5,4 ml) and the resulting mixture is refluxed with stirring for 2 hours. The mixture is cooled, poured into water and the aqueous mixture extracted with diethyl ether. The ether extracts are washed with saturated aqueous sodium thiosulfate, water, and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuum and the residue is purified by chromatography on silica using as eluent a mixture of diethyl ether:hexane 1:4. Get the ethyl ester of 3-methyl-6-exogamous acid as an orange oil (2.0 g).

Mass spectrum (chemical ionization): M+1, 187.

(III). Using the procedure described in example XVIII, of the ethyl ester of 3-methyl-6-exogamous acid get 3-methylhept-6-andnew acid.

(IV). 1-(2-Metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]Octan-C-carbonitrile obtained from 3-methylhept-6-invoi acid according to the method the op is Il-3-(prop-2-enyl)oxetan (see example XVII) according to the procedure described in example IV, receive 1-(2-metrex-5-inyl)-4-(prop-2-enyl)-2,6,7-dioxabicyclo[ 2,2,2]octane-3-carbonitrile.

Example XXXI. 1-(but-3-Unlocker)-4-n-propyl-2,6,7 - dioxabicyclo[2.2.2]octane

(I). Methanesulfonanilide (74,0 g) are added dropwise within 30 minutes to a solution of 2-oxymethyl-2-n-propylparaben-1, 3-diol (28,0 g) in dry pyridine (200 ml) under nitrogen atmosphere at 0oC. the Mixture is heated to room temperature. After stirring for 18 hours the mixture was poured into water (200 ml) and extracted with chloroform (2 x 200 ml). The chloroform extracts washed with water (2 x 100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuum to yield solid brown color. This product is stirred in a simple diethyl ether (200 ml) to obtain 2-oxymethyl-2-n-propylparaben-1,3-diol trimethylsulfonium in the form of a white solid (70,0, so pl. 103,6oC).

(II). Trithiocarbonate sodium (18.0 g) in water (25 ml) was added to a solution containing trimethylsulfonium 2-oxymethyl-2-n-propylparaben-1, 3-diol (12.0 g) in dimethylformamide (100 ml). The mixture is heated under reflux (130oC) for 4 hours and then cooled to room temperature. what the notes (50 ml). The mixture is extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a brown liquid. Add hexane (200 ml) and the mixture is then washed with water (3 x 50 ml). Dried over anhydrous magnesium sulfate and after evaporation receive oil amber (6.8 g). Crude oil (6.4 g) in diethyl ether (10 ml) was added dropwise to a suspension of lithium aluminum hydride (3.0 g) in diethyl ether (100 ml) at a speed sufficient to maintain the irrigation. After the introduction of lithium aluminum hydride, the mixture is stirred for further 1 hour, and then carefully add water (3 ml). Enter diluted sulfuric acid (3 ml) and added water (3 ml). The mixture is filtered, the solids washed with diethyl ether (50 ml), and then the combined extracts dried over anhydrous magnesium sulfate. After evaporation in vacuo get 2-mercaptomethyl-2-n-propylparaben-1,3-diol as a pale yellow oil (5.3g).

(III). Hydrogen chloride (gas) is bubbled through a suspension of paraformaldehyde (4.3 g) but-3-in-1-Ola (10.0 g) (company Aldrich) and dry dichloromethane (30 ml) at -20oC for 30 minutes. The mixture is heated to room temperature, and then stirred for further 18 hours. Add cold water (30 prostoy CHLOROTHALONIL ether but-3-inila liquid amber (14.2 g).

(IV). A mixture of 2-mercaptomethyl-2-n-propylparaben-1,3-dithiol ( 2.3 g) and teeterboro ether orthomorphisms acid (1,74 g) is heated in dry toluene containing paratoluenesulfonyl (5 mg) and ethanol obtained by distillation. After cooling, add toluene (15 ml) and the resulting mixture washed with water (2 x 10 ml). After drying over anhydrous magnesium sulfate and evaporation in vacuo receive light yellow oil. The oil obtained is extracted with diethyl ether (50 ml) and the extracts evaporated in vacuo to yield a white solid. After purification by chromatography on alumina, elwira a mixture of dichloromethane saturated with ammonia hexane 1:10, receive a 4-n-propyl-2,6,7-trimebutina[2,2,2]octane in the form of a white solid (0.33 g, so pl. 139oC).

Mass spectrum (chemical ionization): M+1, 207.

(V). n-utility (0.3 ml, 1.6 M solution in hexane) was added to a solution of 4-n-propyl-2,6,7-trimebutina[2,2,2] octane (0.1 g) in dry tetrahydrofuran (5 ml) at -70oC in nitrogen atmosphere. The solution is stirred for 30 minutes and add a simple CHLOROTHALONIL ether but-3-inila (0,58 g) in dry tetrahydrofuran (2.0 ml), the reaction mixture is heated to 20oC. Add water (10 ml), and then the resulting mixture extracted with dietro is OK purified by chromatography on alumina with elution with a mixture of 1:10 dichloromethane:saturated ammonia hexane.

Get 1-(but-3-Unlocker)-4-n-propyl-2,6,7-trimebutina [2,2,2] octane in the form of a waxy solid (0,032 g).

Example HHH. 1-[(E/Z)-Gex-3-EN-5-inyl]-4-propyl-2,6,7 - dioxabicyclo[2,2,2]octane-3-carbonitrile

(I) a Mixture of (E/Z)-5-bronet-4-ene acid is obtained from the diethyl ester of malonic acid and 1,3-dibromopropane (mixture of isomers, the company Aldrich Chemical Company according to the method described in example XVI, stage (I) and (II).

(II). According to the method described in stages (II) and (III) of example IV, from (E/Z)-5-bronet-4-ene acid and 3-formyl-Z-n-propylacetate get 1-[(E/Z)-4-brombach-3-enyl] -4 - propyl-2,6,7-dioxabicyclo[2,2,2] octane-3-carbonitrile (in the form of oil).

GC: OS-17 230oWith gives a single peak.

Mass spectrum: M+1, 316, 318.

(III). A mixture of 1-[(E/Z)-4-brombach-3-enyl]-4 - propyl-2,6,7-dioxabicyclo[2,2,2] Octan-3-carbonitrile (500 mg), trimethylsilylacetamide (0.45 ml), bis-triphenylphosphorane dichloride (30 mg) and copper iodide (5 mg) in dry diethylamine (10 ml), stirred at room temperature under nitrogen atmosphere for 4 hours. Then the solvent is removed in vacuum. The residue is dissolved in diethyl ether and washed with water and brine before drying over anhydrous magnesium sulfate and pack the orders containing 15% saturated with ammonia in dichloromethane. Receive a 4-propyl-1-[(E/Z)-6-(trimethylsilyl) Gex-3-EN-5-inyl] -2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile in the form of a pale yellow oil (365 mg).

GC: OS-17 250oWith gives two peaks (E/Z-isomers).

(IV). The tetrabutylammonium fluoride (1.1 ml of 1M solution in tetrahydrofuran) was added to a stirred solution of 4-propyl-1-[( E/Z)-6-(trimethylsilyl)Gex-3-EN-inyl] -2,6,7-dioxabicyclo[ 2,2,2]Octan-3-carbonitrile (293 mg) in tetrahydrofuran (5 ml). The resulting mixture was stirred at room temperature for 1 hour, and then remove the solvent under reduced pressure. The remainder is divided into phases diethyl ether and water. The organic phase is separated, washed with water and then evaporated in vacuum. The residue is purified column chromatography on alumina with elution with hexane containing 15% saturated ammonia dichloromethane. Get 1-[(E/Z)- Gex-3-EN-8-inyl]-4-propyl-2,6,7-dioxabicyclo[2,2,2]Octan-carbonitrile in the form of a colorless oil (143 mg).

GC: OS-17 250oWith gives a single peak.

In a similar manner from 1-[(E/Z)-4-brombach-3-enyl] -4 - propyl-2,6,7-dioxabicyclo[2,2,2] Octan-3-carbonitrile and the desired terminal acetylene (given in parentheses) obtained sostoi methylpropyloxy ether).

1-[(E/Z)-7-oxysept-3-EN-5-inyl] -4-propyl-2,6,7-dioxabicyclo[ 2,2,2] Octan-C-carbonitril (propargilovyh alcohol).

Example XXXIII. 4-tert-butyl-1-[(E)-Gex-1-EN-5-inyl]-2,6,7 - dioxabicyclo[2,2,2]octane-3-carbonitrile

(I). According to the method described in example IV, stage (I), Penta-4-in-1-ol (company Aldrich Chemical Company) make the Penta-4-Inal. The crude product is purified by distillation at a slow boil (oven temperature <65oWith the pressure of 15 mm Hg).

GC: OS-17 at 80oWith 1 gives the peak.

(II). A mixture of Penta-4-Inal (1.2 g) and (carboxymethyl)triphenylphosphorane (5,1 g) in dichloromethane (20 ml), stirred at room temperature for 2.5 hours. The solution is evaporated under reduced pressure, and the residue is extracted with hexane. The insoluble product are filtered and after evaporation of the solvent receives a yellow oil. Ethyl ester of (E)-hept-2-EN-6-invoi acid is obtained as colorless oil after distillation at a slow boil (oven temperature 155oC, 15 mm Hg).

GC: OS-17 120oWith gives two peaks (95:5).

(III). A solution of ethyl ester of (E)-hept-2-EN-6-invoi acid (1.8 g) in 50% aqueous solution of methanol containing 5% sodium hydroxide, stirred at temperature environmental camp. The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and re-extracted with dichloromethane. These organic extracts are washed with saline, dried over anhydrous magnesium sulfate and after evaporation in vacuo get isomer (E)-hept-2-unit-6-invoi acid as a white solid (1.3 g).

(IV). According to the method described in example IV, stage (II) and (III) from 3-tert-butyl-3-formylacetate and (E)-hept-2-EN-6-invoi acid get 4-tert-butyl-1-[(E)-Gex-1-EN-5-inyl] 2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile.

GC: OS-17 at 220oWith gives two peaks (95:5).

Example IV. 4-n-propyl-2,6,7-dioxabicyclo[2,2,2]octane-1 carboxaldehyde of oxime prop-2-Unilever

(I). A solution containing ethyl ester 4-propyl-2,6,7- -dioxabicyclo[2,2,2] octane-1-carboxylic acid (5,0 r) (example XXIII) in anhydrous tetrahydrofuran (10 ml) and added dropwise to a stirred suspension of lithium aluminum hydride (1.86 g) in dry diethyl ether (160 ml) at 0oC in nitrogen atmosphere. The resulting mixture was stirred at 0oC for 1.5 hours and then at room temperature for 2.5 hours. Added dropwise with cooling an aqueous solution of sodium hydroxide (25 ml of 10% solution). The aqueous phase extragere, and then evaporated in vacuum.

The residue, 1-oxymethyl-4-propyl-2,6,7-dioxabicyclo [2,2,2] octane is obtained in the form of a white crystalline solid product (3.4 g, so pl. 100-101oC).

Mass spectrum (chemical ionization): M+1, 189.

(II). 4-Propyl-2,6,7-dioxabicyclo[2,2,2] octane-1-carboxaldehyde obtained from 1-oxymethyl-4-propyl-2,6,7-dioxabicyclo[ 2,2,2]octane according to the method described in example IV,step (I).

4-Propyl-2,6,7-dioxabicyclo[2,2,2] octane-1-carboxaldehyde receive in the form of a white solid (1.7 g, so pl. 117 - 118oC).

Mass spectrum (chemical ionization): M+1, 187.

(III). A solution containing 1-carboxaldehyde 4-propyl-2, 6,7-dioxabicyclo[2,2,2]octane (1.0 g) in 1,2-dimethoxyethane ( 15 ml) was added to a stirred mixture consisting of hydrochloric hydroxylamine (1.51 g) and sodium carbonate (to 2.29 g) in water (10 ml), at 20oC. Stirring is continued for 12 hours.

The resulting mixture was diluted in diethyl ether, then the organic layer is washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated in vacuum. The residue, 4-propyl-2,6,7-dioxabicyclo[2,2,2] octane-1-carboxaldehyde receive in the form of white smolis Himicheskaya ionization): M+1, 202.

(IV). To a stirred solution containing 4-propyl-2, 6,7-dioxabicyclo[2,2,2]-octane-1-carboxaldehyde (0.52 g) in dry methanol (10 ml), added propylbromide (of 0.44 ml of 80% solution in toluene), and then sodium methylate (0,141 g). The mixture is stirred at 20oWith in 12 hours. The mixture was then poured into water and the resulting aqueous phase is extracted with diethyl ether. The ether extracts washed with water, brine and dried over anhydrous magnesium sulfate, and then pair off in vacuum. The residue, a yellow oil, purified by chromatography on silica (treated pre-hexane with 1% triethylamine), using as eluent a mixture of 4:1 ethyl acetate: hexane with 1% triethylamine.

4-Propyl-2,6,7-dioxabicyclo[2,2,2] octane-1-carboxaldehyde of oxime prop-2-injuly ether obtained as a white crystalline solid (of 0.085 g, so pl. 73-74oC).

Example V. 2-(4-n-propyl-2,6,7-dioxabicyclo[2,2,2]Oct-yl)Etherboot-2-inat

(I). A solution of ethyl ester of 2-(4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] Oct-1-yl) acetic acid (5.0 g) (example XXIV) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (1.8 g) in dry diethyl ether (100 ml) at 0

GC: OS-17 at 210oWith gives a single peak.

(II). To a stirred solution of 1-(2-oxyethyl)-4-propyl-2, 6,7-dioxabicyclo[2,2,2] octane (0.5 g) in dry dichloromethane (20 ml) at 0oWith added 4-dimethylaminopyridine (55 mg), and then detrolbuy acid (210 mg). The mixture is stirred for 5 minutes at 0oWith, then portions (100 mg) added dicyclohexylcarbodiimide (520 mg) for 2 hours. Stirring is continued at 20oWith in 12 hours. Add the water, and the aqueous mixture extracted with dichloromethane. The organic extracts are washed with 10% sodium bicarbonate solution, water, brine, dried over anhydrous magnesium sulfate and evaporated in vacuum. The rest get in the form of a resin, which is purified by chromatography on silica with a preliminary washing with hexane containing 1% triethylamine in the elution mixture is to obtain in the form of a white crystalline solid (0,266 mg, so pl. 80-81oC).

Example VI. 1-(Gex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2] octane

(I). The solution trimethylsilylacetamide (12.0 g,Aldrich) in dry tetrahydrofuran (100 ml) stirred at 0oWith a stream of nitrogen, and added dropwise n-utility (76.5 ml, 1.6 M solution in hexane). The solution is stirred for 30 minutes and add a solution of 1-chloro-Z-iodopropane (25,0 g) in dry tetrahydrofuran (75 ml). The reaction mixture is heated to 20oC and stirred for 18 hours. The resulting mixture was poured into water and the aqueous mixture extracted with diethyl ether. The ether extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo, and the residue is distilled. Get 5-chloro-1-trimethylsilyl-1-in in the form of a colorless oil (12.7 g, so pl. 67-72oC, 15 mm Od).

(II) a Mixture of 5-chloro-1-trimethylsilyl-1-in ( 13.5 g) and patriotica (29 g) in butanone (100 ml) is heated under reflux for 10 hours. The solvent is then evaporated in vacuo, and the residue is divided into phases diethyl ether and water. The organic phase is separated, washed with water and brine, then dried over anhydrous magnesium sulfate. The solvent is removed at reduced pressure in the solution in hexane) are added dropwise to a stirred solution of N, N-dimethylhydrazone acetone (2.6 g) (see R. H. Wiley and others, G. Org. Chem. vol. 22, page 204, 1957) in dry tetrahydrofuran (40 ml) at -70oWith a stream of nitrogen. The resulting solution was stirred for 30 minutes and added dropwise a solution containing 5-iodine-1-trimethylsilyl-1 in (8.1 g) in dry tetrahydrofuran (30 ml). The reaction mixture was stirred at -70oC for 1 hour, warmed to 0oC and stirred for further 2 hours. The reaction mixture is cooled to -70oC and added dropwise second portion of n-utility (19 ml, 1.6 M solution in hexane). The mixture is stirred at -70oC for 15 minutes, warmed to 0oC and stirred for 30 minutes. Add a solution containing 5-iodomethyl-2,2-dimethyl-5-n-propyl-1, 3-dioxane (9.0 g, Europatent N 216625) in dry tetrahydrofuran (30 ml). The resulting mixture was stirred at 0oC for 30 minutes, and then 48 hours at 20oC. the Solvent is distilled off in vacuo, and the residue poured into water. The aqueous mixture is extracted with diethyl ether and then the ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. After chromatographic separation of the residue on silica using as eluent diethyl ether:hexane 1:9, receives a yellow malox-1-in the ratio of 3:1 (1.4 g). The above mixture in tetrahydrofuran (25 ml) and hydrochloric acid (50 ml, 1N. the solution is intensively stirred at 20oC for 1 hour. The tetrahydrofuran is removed in vacuo, and the residue extracted with diethyl ether. The ether extracts are dried over magnesium sulfate, and the solvent evaporated in vacuum. Receive a 4-n-propyl-1-(6-trimethylsilyloxy-5-inyl)- 2,6-dioxabicyclo[2,2,2] octane as a colourless oil ( 1.6 g), which is used without further purification.

Mass spectrum (chemical ionization): M+1, 309.

(IV). A solution of tetrabutylammonium fluoride (1.0 M solution of 4.0 ml) was added to a stirred solution of 4-n-propyl-1-(6 - trimethylcyclohex-5-inyl)-2,6-dioxabicyclo[2,2,2] octane in dry tetrahydrofuran (40 ml) at 20oC, and the resulting mixture is stirred for 1 hour. The solvent is evaporated in vacuo, and the residue extracted with diethyl ether and water. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. After chromatography on alumina with elution of a mixture of dichloromethane:saturated ammonia hexane 1: 9, get 1-(Gex-5-inyl)-4-n-propyl-2,6-dioxabicyclo[2,2,2]octane in the form of a colorless oil (0.45 g).

Example sheets xxx VII. 1-[(Z)-1-fluoro-3,3-dimethylbutan-1-enyl] -4-propyl-2, 6,7-dioxabicyclo[2,2,2]OK what Osvita (30 ml) is heated to 150oWith the apparatus, adapted to fractional distillation to stop the formation of brometane. After distillation of the residue under reduced pressure to obtain ethyl ester diethylphosphonoacetate acid as a colourless oil ( 9,05 g, so Kip. 80-88oWith the pressure of 0.1 mm Hg).

(II). A solution of n-utility (4.8 ml, 1.6 M solution in hexane) was added to a mixed solution of Diisopropylamine (1.1 ml) in tetrahydrofuran (15 ml) at 0oC in nitrogen atmosphere. The mixture was incubated at 0oC for 0.5 hours, and then cooled to -70oWith, adding to the solution ethyldiethanolamine (1.7 g) in tetrahydrofuran (5 ml). After 0.5 hours at -70oC, add the net trimethylacetaldehyde (0,76 ml) and the resulting mixture is warmed to room temperature for 5 hours. Then add water (5 ml), and the solvent evaporated in vacuum under reduced pressure. The remainder is divided into layers diethyl ether and water. The organic layer was separated, washed with water, 10% hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum. Get ethyl ester (2)- 2-fluoro-4,4-dimethylpent-2-ene acid as a pale green oil (1.0 g).

GC: OS-1R-4,4-dimethylpent-2-Anata get (Z)-2 - fluoro-4,4-dimethylpent-2-envoy acid.

(IV). According to the method described in example IV, stage (II) and (III) of 3-formyl-3-n-propylacetate and (Z)-2-fluoro-4,4-dimethylpent-2-ene acid to obtain 1-[(Z)-1-fluoro-3,3-dimethylbutan-enyl] - -4-propyl-2,6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile.

GC: OS-17 250oWith 1 gives the peak.

Example VIII. 4-Ethoxymethyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo[ 2,2,2]Octan-C-carbonitril

(I). To a stirred solution of 5,5-di-(oxymethyl)-2,2 - dimethyl-1,3-dioxane (5.0 g) (Beilstein 19, 11, 93) in dry dimethylformamide (50 ml) in a nitrogen atmosphere at 20oWith added sodium hydride (0.68 g, 80% dispersion in oil). The mixture was stirred at 80oC for 2 hours and cooled. Add ethyliodide (4.4 g) in dry dimethylformamide (40 ml) and the reaction mixture is heated at 110oC for 3 hours. The mixture was then cooled and poured into water. The aqueous mixture is extracted with diethyl ether. The ether extracts are washed with saline, dried over anhydrous magnesium sulfate and evaporated in vacuum. Receive 2,2-dimethyl-5-ethoxymethyl-5-oxymethyl-1,3 - dioxane in the form of a pale yellow oil (1.2 g), which is used without further purification.

(II). A mixture of 2,2-dimethyl-5-ethoxymethyl-5-oxymethyl-1, 3-dioxane (15.0 g) and Amberlyst "15" (3.0 g) in methanol (500 ml) the rat then evaporated in vacuum.

Get 2-ethoxymethyl-2-oximation-1,3-diol in the form of a viscous oil (10.5 g), which is used without further purification.

(III). 4-Ethoxymethyl-1-(Gex-5-inyl)-2,6,7-dioxabicyclo [2,2,2] Octan-C-carbonitrile obtained from 2-ethoxymethyl-2-oximation-1, 3-diol according to the method described in example IV. Similarly receive 1-(Gex-5-inyl)-4-methoxymethyl-2, 6,7-dioxabicyclo[2,2,2]octane-3-carbonitrile.

Example XXXIX. 4-tert-butyl-1-(Gex-5-inyl)-2,6-dioxa-7 - diabetico [2,2,2] octane

4-tert-butyl-1-(Gex-5-inyl)-2,6-dioxa-7-diabetico [2,2,2]octane is obtained from trimethylboron ether orthocept-6-invoi acid and 2,2-di(oxymethyl)-3,3-dimethylbutan-1-thiol (see description for Europatent N 216625) according to the method described in this patent.

Example XI. 1-(3-metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]Octan-C-carbonitril

(I). 2-Methylpent-4-inimicality obtained from 2-methylpent-4-in-1-ol according to the method described in example II, stage (I).

(II). A solution of diethylmalonate (46 g) in dry toluene (500 ml) stirred at 0oC in nitrogen atmosphere. Add sodium hydride (8.6 g of 80% dispersion in liquid paraffin), being careful, and then the mixture was stirred at 100oWith 1 hour. The mixture is cooled and added 2-methyl is ATEM mixture is cooled, pour in the water, and the aqueous mixture extracted with diethyl ether. The ether extracts washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuum. Excess diethylmalonate removed by distillation under reduced pressure, and the residue is purified by chromatography on silica with elution with 7.5% solution of diethyl ether in hexane. Diethyl ether (2-methylpent-4-inyl)malonic acid obtained as a colorless oil (6.5 g).

GC: OS-17 160oWith gives a single peak.

Mass spectrum (chemical ionization): M+1, 241.

4-Methylhept-6-andnew acid is obtained from diethyl ether (2-methylpent-4-inyl)of malonic acid by the procedure described in stages (III) and (IV) of example XXVII.

1-(3-Metrex-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] Octan-C-carbonitrile obtained from 4-methylhept-b-invoi acid and 3-formyl-3-n-propyl-oxetane according to the method described in example IV.

Using the stage (II) and (III) of example XXX, and as the source of the product (3)-4-methyl-6-oxalatebuy acid (see G. Am. Chem.Soc. vol. 85, page 937, 1963) receive (S)-4-methylhept-6-andnew acid.

1-[(S)-3-metrex-5-inyl]-4-n-propyl-2,6,7-dioxabicyclo[ 2,2,2]Octan-C-carbonitrile obtained from (S)-4-methylhept-6-invoi acid pgcet 4-isobutyl-1-(3-metrex-5-inyl)-2,6,7 - dioxabicyclo[2,2,2] Octan-C-carbonitrile.

Example LI. 1-(tert-butylthioethyl)-4-n-propyl-2,6,7 - dioxabicyclo[2,2,2]Octan-C-carbonitril

In accordance with the stages (I) and (II) of example XIII, using as starting material tert-butylthio and ethyl ether bromoxynil acid, receive tert-butylthiourea acid.

1-(tert-butylthioethyl)-4-n-propyl-2,6,7-dioxabicyclo[2,2,2] octane-3-carbonitrile obtained from tert-butylthiourea acid and 3-formyl-3-n-propylacetate according to the method described in example IV.

Example LII. 1-(hept-5-inyl)-4-n-propyl-2,6,7-dioxabicyclo [2,2,2]octane

A solution of n-utility (1.7 ml, 1M solution in hexane) are added dropwise to a stirred solution of 1-(Gex-5-inyl)-4 - n-propyl-2,6,7-dioxabicyclo[2,2,2] octane (0.65 g) in dry tetrahydrofuran (25 ml) at 0oWith a stream of nitrogen. The mixture was stirred at 0oC for 15 minutes, then add methyl iodide (0,18 ml). The reaction mixture was stirred at 0oC for 1 hour and then evaporated in vacuum. The remainder is divided into layers diethyl ether and water. The ether extracts dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuum. The residue is purified by chromatography on alumina with elution with a mixture of 1: 10 dichloromethane:saturated ammonia, gexo substances (0.26 g) (containing 15% of 2-(Gex-5-inyl)-4-n-propyl-2, 6,7-dioxabicyclo[2,2,2]octane.

Example LIII. 4-(2,2-Dichlorocyclopentane)-1-(Gex-5-inyl)- 2,6,7-dioxabicyclo[2,2,2]octane

(I). Triacetate 2-oxymethyl-2-(prop-2-enyl)propane-1,3 - diol (2.2 g) (example XVII) is heated to 130oWith under stirring. Add trichloracetic sodium (5.0 g) for 2 hours and then the reaction mixture is heated to 155oWith in 24 hours. The ether extracts dried over anhydrous magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica with elution with a mixture of diethyl ether-hexane 1:4.

Get 2-(2,2-dichlorocyclopentane)-2-oximation-1, 3-diol triacetate as a colourless oil (1.4 g).

Mass spectrum (chemical ionization): ammonia as the ionizing gas, M+18, 372.

(II). In accordance with the procedure described in example 1, stage (I), triacetate 2-(2,2-dichlorocyclopentane)-2 - oxymethyl-propane-1,3-diol get 2-(2,2-dichlorocyclopentane)- 2-oximation-1,3-diol.

(III). According to the method described in example VI, method 2, from 2-(2,2-dichlorocyclopentane)-2-oximation-1,3-diol and trimethylol ether orthocept-6-invoi acid get 4-(2,2-dichlorocyclopentane)-1-(Gex-5-inyl)-2,6,7-trioxa the Ilan KEO 20,00

Xylene 67,50

Bottled guaiacol 2,50

Just 100,00

2. Wettable powder

The compound of formula (I) 25,00

Attapulgite 69,50

Isopropylbenzenesulfonyl sodium 0,50

Sodium salt of condensed naphthalenesulfonate 2,50

Bottled oxytrol 2,50

Just 100,00

3. Dust (powder)

The compound of formula (I) 0,50

Bottled guaiacol 0,10

Talc 99,40

Just 100,00

4. Bait

The compound of formula (I) 40,25

Ice sugar 59,65

Bottled oxytrol 0,10

Just 100,00

5. Lacquer

The compound of formula (I) 0,1

Butyl butoxide 0,5

Bottled guaiacol 10,1

Reference to ha white spirit 92,0

Just 100,00

6. Aerosol

The compound of formula (I) 0,30

Bottled guaiacol 0,10

1,1,1-trichloroethane 4,00

Neponese kerosene 15,60

Arctan 11/12, 50:50 mixture 80,00

Just 100,00

7. Spray (solution for spraying)

The compound of formula (I) 0,1

Bottled guaiacol 0,1

Xylene 10,0

Neponese kerosene 89,8

Just 100,00

8. Spray with the reinforcing action

The compound of formula (I) 0,1

Butyl butoxide 0,5

Bottled guaiacol 0,1

Xylene 10,1

Nepah the market illustrate the pesticidal activity of the compounds of formula (I).

Test the action of solutions for spraying

The activity of compounds of the invention were tested by dissolving the claimed compounds in acetone (5%), and then breeding the resulting solution in a mixture of water: Synperonic (94,5:0,5%) to obtain an aqueous emulsion. Then this solution is used for the treatment of the following pests-insects.

Musca domestica

20 females placed in cartoony cylinder with mesh on both sides. Through the mesh on insects sprayed with the solution containing the tested compound. After 48 hours at 25oTo assess mortality.

These compounds exhibit activity when <1000 ppm: 4, 5, 14, 20, 21, 22, 24, 25, 26, 28, 32, 43, 44, 45, 50, 53, 54, 56, 69, 71, 72, 76, 77, 82, 88, 89.

The following compounds exhibit pesticidal activity when the <200 ppm: 6, 9, 10, 11, 12, 13, 15, 16, 17, 29, 30, 31, 33, 34, 46, 47, 48, 52, 57, 58. 59, 60, 61, 62, 63, 64, 65, 68, 74, 75, 78, 79, 80, 81, 83, 84, 85, 90. Sitophilus granaris and Tribolium castaneum 20 adult Sitophilus and Tribolium added to 10 g of wheat grain which is pre-treated with 2 ml of a solution containing the proposed connection. Mortality was assessed after 6 days at 25oC.

The following compounds exhibit pesticidal activity against Sitophilus granaris when < 1000 ppm: 7, 10, 19,22, 23, 2�ode < 200 ppm: 3, 4, 5, 6, 9, 12, 14, 15, 16, 17, 29, 30, 31, 33, 34, 45, 47, 48, 53, 54, 57, 58, 60, 61, 62, 68, 72, 74, 75, 76, 77, 78, 79, 80, 81.

These compounds exhibit activity against Tribolium castaneum dose of < 1000 ppm: 4, 6, 10, 14, 17, 33, 53, 57, 58, 65, 71, 76, 79, 82, 84.

These compounds exhibit activity as pesticides against Tribolium castaneum when the < 200 ppm: 9, 12, 15, 16, 34, 46, 63, 74, 75.

Myzus persicae

10 adults Myzus placed on the plate leaf Chinese cabbage. After 24 hours, leaf plate sprayed with the solution containing the tested compound. Mortality was assessed after 2 days at 25oC.

The following compounds exhibit pesticidal activity at the dose of < 1000 ppm: 4, 9, 17, 37, 46, 53, 56, 60, 71, 77, 78, 79, 80, 81, 84.

The following compounds exhibit pesticidal activity at a dose of < 200 ppm: 6, 45, 47, 48, 57, 58, 59, 62, 63, 74, 75, 76.

Plutella xylostella

7 larvae of Plutella sprayed with a solution containing the test compound and placed on a leaf of Chinese cabbage, which is sprayed in a similar manner the test compound, and which is allowed to dry. Alternatively, 8-10 larvae of Plutella placed on the leaf and sprayed with the solution containing the tested compound. The percentage mortality calculated in 2 days PR is 4, 35, 48, 55, 56, 58, 59, 65, 68, 71, 75, 77, 78, 79, 80, 81, 83, 85, 87.

These compounds exhibit activity at the dose of < 200 ppm: 9, 12, 13, 46, 47, 57, 74.

Tetranychus urticae

Plate leaves that contain a mixed population of Tetranuchus urticae, are sprayed with a solution of the test compound. mortality assessed after 2 days at 25oC.

These compounds exhibit activity at a dose of < 1000 ppm: 78, 81, 83, 90.

The following compounds exhibit pesticidal activity at a dose of < 200 ppm: 60, 80.

Additional tests on the effect of solution for spraying

Pesticide activity proposed compounds was investigated additionally. Compounds are dissolved in acetone (75%) and then add water. The below solution used for spraying the following insect pests: Aphis fabae

Mixed populations of Aphis fabae felt the leaves of the nasturtium.

The following compounds exhibit pesticidal activity at a dose of < 1000 ppm: 4, 6, 13, 16, 17, 25, 26, 29, 30, 31, 33, 46, 47, 50, 54, 63, 65.

Macrosteles fascifrans

Imago Macrosteles fascifrans felt wheat germ.

These compounds exhibit activity at a dose of < 1000 ppm: 6, 9, 13, 16, 17, 23, 25, 26, 29, 31, 33, 34, 46, 47, 64, 65, 68.

Tetranych dose < 1000 ppm: 5, 9, 16, 30, 33, 31, 46, 47, 50, 65, 68.

Diabrotica undecimpunctata in the third stage of development is tested on filter paper.

The following compounds exhibit pesticidal activity at a dose of < 1000 ppm: 3, 4, 5, 6, 13, 16, 17, 23, 25, 26, 29, 30, 31, 33, 34, 46, 47, 53, 63, 65, 68.

Tests for local use

The proposed activity of the compounds against nearestterminal females ordinary flies Musca domcstica (WRL-line) shows the local application to the test insect of a solution containing the test compound and butyl butoxide in butanone. Mortality was assessed after 48 hours.

The following compounds exhibit pesticidal activity at a dose of 1 μg: 9, 10, 11, 12, 13, 15, 17, 29, 30, 31, 33, 34, 47, 52, 63, 64, 68, 83, 84, 85.

The proposed activity of the compounds against shot male Periplaneta americana demonstrated the local application to the test insect of the solution containing the tested compound in butanone. Mortality was assessed after 6 days.

These compounds exhibit activity at a dose of < 50 µg: 2, 6, 16, 17, 25, 31, 39, 83.

Pesticide activity proposed compounds against shot male Blattelba germanica demonstrated CLASS="ptx2">

Mortality was determined after 6 days.

The following compounds exhibit pesticidal activity at a dose of < 5 μg: 6, 9, 12, 14, 15, 16, 17, 20, 29, 30, 31, 33, 34, 45, 46, 48, 56, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 71, 72, 74, 75, 83 84, 90.

Nematocidal activity

Meloidogyne incognita

Selected compounds of the invention were analyzed on a just hatched nematode Meloidogyne incognita 2. The test solution contains a mixture of 1% acetone 100 ppm Tritons-100. Nematocidal activity determined after 24 hours.

These compounds exhibit activity at a dose of < 100 ppm; 6, 16, 17, 26.

Toxicity relative to mammals

The toxicity of the proposed compounds set during oral intubation mouse Cbarles River CDL, starving 3 hours. Empatheia compound is administered in the form of solutions in DMSO at a dose of 200 mg/10 ml/kg, 20 mg/10 ml/kg and 2 mg/10 ml/kg Toxicity determined 14 days after admission.

The following compounds exhibit toxicity with LD50200 mgkg-1.

17, 60.

The following compounds exhibit toxicity with LD50in the range of 20-200 mgkg-1.

16,75

The results of comparative tests of the compounds of the present invention (corresponding Evropeyskaya V shows the values of ppm (parts per million), in which connections are active.

(A). Except for compounds 9, 83 and 14, all connections in the application Europatent N 300297 are active against cycatki, however, none of the compounds in the foregoing patents (European patent office N 211598, 216624 and 216625) does not show this activity.

(In). All connections in Europatent N 300297 are active against bean aphid, however, only two compounds in the foregoing patents show this kind of activity.

(C). All connections in Europatent N 300297 are active against a flea dinosau, but only some connections in the previous patents show this activity. In the secondary test compounds Europatent N 300297 generally are more active.

Di Diabrotica undecimpunctata (blaska Donousa)

MA Macrostiles fascifrans (Cicada)

Ar Aphis fabae (aphid bean)

Ty Tetranychus urticae (clasic spider bimaculated)

Sg Sitophilus granaris adults (calandrini)

TC Tribolium castaneum adults (flour hrusak)

Px Plutelia xylostella larvae (cabbage moth)

Mr Myzus persicae adults (peach aphid)

VD Blattella germanica adults (cockroach red)

Md Musca domesfica adults (fly room)

(U) designerware on us researchsurvey. TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT

Derivatives of heterobinuclear formula

< / BR>
where Y and Y1O or S;

Z CH2O or CH2S;

R1hydrogen;

R2hydrogen or C1-C3-alkyl, unsubstituted or substituted by a halogen atom or cyano;

AH contains from 4 to 20 carbon atoms, where X is hydrogen, straight or branched C2-C12-alkyl, unsubstituted or substituted C1-C6-quinil, C1-C6-alkynylamino, C1-C6-alkylalcohol, C1-C6-alkyloxybenzoic or C1-C6-alkyloxyalkyl group; C2-C6alkenyl, unsubstituted or substituted by a halogen atom; C2-C12alkenyl, unsubstituted or substituted by a hydroxy-group, C1-C6-alkoxygroup or Si(CH3)3group; C1-C6-alkyloxyalkyl; N-(C1-C6quinil)-carbarnoyl or N-(C1-C2quinil)acetaminophe;

R C1-C6-alkyl, unsubstituted or substituted C2-C6-alkyloxy, C2-C6alkenyl, C3-C1O or S, Z is CH2O or-CH2S, R1hydrogen, R2hydrogen or C1-C3alkyl, unsubstituted or substituted by a halogen atom or cyano, R C1-C6alkyl, unsubstituted or substituted C1-C6alkoxygroup; C2-C6alkenyl; C3-C6-cycloalkyl, unsubstituted or substituted by a halogen atom, X is hydrogen, straight or branched C2-C12-alkyl, unsubstituted or substituted C1-C6-quinil or C1-C6-alkylcarboxylic group, C2-C12alkenyl, unsubstituted or substituted C1-C6-alkoxygroup or Si(CH3)3group;

07.10.87 when X, Y, Y1, Z, R, R1and R2have the above values, And C2-C6alkenyl, unsubstituted or substituted by a halogen atom;

26.04.88 when X, Y, Y1, Z, R, R1and R2have the above values, And C2-C6alkenyl, unsubstituted or substituted by a hydroxy-group; C2-C6alkyloxyalkyl; N-(C1-C6-quinil)carbamoyl or N-(C1-C6-quinil)acetaminophe.

21.07.88 for other values of A.

 

Same patents:

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The invention relates to a method for production of new chemical compounds having pesticidal activity

FIELD: organic chemistry, insecticides.

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FIELD: agriculture.

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FIELD: agriculture.

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EFFECT: invention enables to implement the specified assignment.

14 cl, 3 tbl, 2 ex

FIELD: chemistry.

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1 cl, 1 tbl

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10 cl, 7 tbl, 6 ex

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11 cl, 2 tbl, 8 ex

FIELD: chemistry.

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26 cl, 17 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) or to their salts:

,

where: R1 or R2, independently represents a group consisting of R1, R2, N and/or O selected from the groups:

,

Z1 represents hydrogen or hydroxyl; Z2 represents hydrogen or hydroxyl; Z3 represents C6-C10aryl; Z4 represents C1-C6alkoxy. The invention also refers to a method for producing the compounds according to any of claims 1-4, as well as to application of the compounds.

EFFECT: preparation of new biologically active compounds which exhibit anticancer activity.

12 cl, 10 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for synthesis of 13-(N-Boc-β-isobutylserinyl)-14β-hydroxybaccatin III-1,14-carbonate (I) , in which carbonylation of 1,14-hydroxy groups of the baccatin backbone is carried out using bis(trichloromethyl carbonate) and the 7-hydroxy group is protected by a trichloroacetyl group. The invention also relates to novel intermediate compounds of formula VII and VIII.

EFFECT: simple process.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of ketal compounds, for example having formula where R1 denotes hydrogen or a carbon atom of a levulinate fragment; R2 denotes hydroxyl, an oxygen atom of glycerine or an oxygen atom of an esterified glycerine fragment and "p" denotes an integer from 1 to 100, from glycerine and levulinic acid and esters thereof, and use thereof.

EFFECT: improved method.

17 cl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 2,3,5,6-tetraoxabicyclo[2.2.1]heptanes of formula I where R is adamantyl, unsubstituted or substituted benzyl, unsubstituted or substituted C1-C6 alkyl, wherein the substitutes can be CN, COOMe, COOEt or a CH2=CH group, R1 is a lower alkyl or hydrogen, R2 is a C1-C6 alkyl, which can be used in polymer chemistry, as well as in medicine and pharmacology. The method involves reaction of the corresponding β-diketones of general formula II where R, R1 and R2 have values given above, with hydrogen peroxide in the presence of an acid catalyst which is phosphomolybdic acid, in a medium of an organic solvent - acetonitrile, with molar ratio β-diketone: hydrogen peroxide: phosphomolybdic acid 1:3-5:0.1-0.3.

EFFECT: method increases safety and simplifies the process of producing end products and increases output thereof.

10 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, more specifically to new 4,7-dimethyl-2-(2,4,5-trimethoxyphenyl)-3,4,4a,5,8,8a-hexahydro-2H-4,8-epoxychromen of formula possessing high analgesic activity, and may be used in medicine.

EFFECT: compound possess low toxicity and is synthetised from the available natural compound α-pinene.

1 cl, 4 ex, 2 tbl

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