Derivatives tamilcanadian, the retrieval method and intermediate products

 

(57) Abstract:

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical. Also described methods of obtaining these compounds and their use as new industrial products for the synthesis of teenillegal derivatives and more specifically cyclic (tamilsexy)amines. 3 S. and 3 C.p. f-crystals, 1 PL.

The invention relates to new derivatives of tamilcanadian, methods for their preparation and to their use as new industrial products for the synthesis of derivatives of teenillegal and, more specifically, cyclic (thienyl-cyclohexyl)amine.

The aim of the invention are compounds of General formula I:

< / BR>
in racemic form or in the form of essentially pure diastereoisomers or enantiomers, where

R represents ceanorhaditis;

the radical of the formula-C(O)A, where a represents a halogen atom; a radical of the formula OR1or who, alkenylphenol or alkenylphenol group, with the alkyl, alkanniny and alkynylaryl radicals optionally substituted by one or more identical or different substituents selected from halogen atoms; hydroxyl; alkoxy; alkylthio; acyl; free, in salt form or esterified with carboxyl; cyano; nitro; amino, optionally substituted by one or more identical or different alkyl radicals;

or cycloalkyl or aryl, and cycloalkyl and aryl radicals optionally substituted by one or more identical or different radicals selected from halogen atoms, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, acyl, free, in salt form or esterified carboxy, cyano, nitro or aminosalicylic, optionally substituted by one or more identical or different alkyl radicals;

the radical of the formula-NR4R5where R4and R5independently represent a hydrogen atom or alkyl, alkanniny or alkynylaryl radical, and alkyl, alkanniny and alkynylaryl radicals optionally substituted by one or more identical or different radicals selected from halogen atoms; hydroxyl; obyazatelno substituted by one or more identical or different alkyl radicals;

or cycloalkyl or aryl, and cycloalkyl and aryl radicals optionally substituted by one or more identical or different radicals selected from halogen atoms, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, acyl, free, in salt form or esterified carboxy, cyano, nitro or amino, optionally substituted by one or more identical or different alkyl radicals;

R' represents 2-thienyl or 3-thienyl radical;

R" represents alkyl, alkanniny or alkynylaryl radical, and alkyl, alkanniny and alkynylaryl radicals optionally substituted by one or more identical or different radicals selected from halogen atoms; hydroxyl; alkoxy; alkylthio; acyl; free, in salt form or esterified carboxy; cyano; nitro; amino, optionally substituted by one or more identical or different alkyl radicals;

or cycloalkyl or aryl, and cycloalkyl and aryl radicals optionally substituted by one or more identical or different radicals selected from halogen atoms, hydroxyl, alkyl, alkenyl, acyl, free, in salt form or these is e same or different alkyl radicals;

cycloalkenyl or cycloalkenyl radical, and cycloalkenyl or cycloalkenyl radicals optionally substituted by one or more identical or different substituents selected from halogen atoms, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, acyl, free, in salt form or esterified with carboxyl, cyano, nitro or amino, optionally substituted by one or more identical or different alkyl radicals;

aryl radical, optionally substituted by one or more identical or different substituents selected from halogen atoms, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, acyl, free, in salt form or esterified with carboxyl, cyano, nitro or amino, optionally substituted by one or more identical or different alkyl radicals;

as well as salts of these compounds with inorganic and organic acids with the exception of compounds in racemic form, in which R represents aminoacyl, R' represents a 2-thienyl radical and R" is a methyl radical.

In the above expressions, the term halogen represents fluorine atom, PI the initial alkyl radical, comprising from 1 to 12 carbon atoms. Preferably, the term alkyl represents a linear or branched alkyl radical having from 1 to 6 carbon atoms and in particular methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, second-boutigny, tert-boutigny, pentelenyi, isopentenyl, sexily, isohexyl radicals.

The term of alkenyl denotes a linear or branched alkanniny radical comprising from 1 to 12 carbon atoms. Preferably the term of alkenyl represents a linear or branched alkanniny radical having from 1 to 6 carbon atoms and, in particular vinyl, allyl, properly, butonly, pettily or exenergy radicals.

The term quinil denotes a linear or branched alkynylaryl radical comprising from 1 to 12 carbon atoms. Preferably, the term quinil represents a linear or branched alkynylaryl radical having from 1 to 6 carbon atoms and, in particular, etinilnoy, prominently, routinely, pantingly or exenergy radicals.

The term alkylthio designates the radicals in which the alkyl radical has the meaning specified above. Preferably Ter the min haloalkyl preferably designates the radicals, in which the alkyl radical has the meaning specified above, substituted by one or more halogen atoms as mentioned above. The term haloalkyl may represent, for example, trifter-methyl triptorelin or bromoethylene radical.

CNS radicals designate radicals in which the alkyl radical has the meaning specified above. Preferred are metaxylene, amoxilina, isopropylaniline or tert-butylaniline radicals.

The expression "cycloalkyl or cycloalkenyl" denotes a saturated or unsaturated hydrocarbon cycle containing from 3 to 7 carbon atoms. Saturated cycloalkyl radicals can be selected from cyclopropenes, cyclobutenes, cyclopentene, tsiklogeksilnogo or cycloheptyl radicals. Unsaturated cycloalkyl radicals can be selected from cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyls, cyclohexadienyl radicals.

The expression "amino, optionally substituted by one or more identical or different alkyl radicals," is aminoacyl, optionally substituted by one or more alkyl radicals as defined vysetrenie, or dialkylamino, such as dimethylamino or diethylamino.

The expression "acyl" refers to acyl radical containing from 1 to 6 carbon atoms, such as, for example, formyl, acetyl, propylaniline, batilly, pentanoyl, hexanoyl, acryloyloxy, crotonoyl or bentely radical.

The expression "aryl" represents an aromatic radical, including cycle or condensed cycles; each cycle may not necessarily include one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. Examples of aryl radicals are phenyl, nattily, thienyl, purely, pyrrolidinyl, imidazolidinyl, personilnya, isothiazolinones, diazolidinyl, isoxazolidine, oxazolidine, peredelnyj, personilnya, pyrimidinyl, benzothiazolyl, benzofuranyl and indolizinyl radicals.

More specifically, the aim of the invention are compounds of General formula I, as described above, in which R represents ceanorhaditis; a radical of the formula-C(O)A, where a is a chlorine atom; a radical of the formula OR1or NR2R3in which R1, R2and R3independently represent a hydrogen atom, alkyl,s carbon and optionally substituted by one or more identical or different radicals, selected from fluorine atoms, chlorine, bromine or iodine, hydroxyl, metaxylene, amoxilina, Isopropylamine, tert-butylaniline, methylthio, ethylthio, propylthio, butylthio, pentylthio, acyl, carboxyl, cyano, nitro, optionally substituted amino, cyclopropenes, cyclobutenes, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl or phenyl groups, and cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptenyl and phenyl radicals optionally substituted;

the radical of the formula-NR4R5in which R4and R5independently represent a hydrogen atom, alkyl, alkanniny or alkynylaryl radical, alkyl, alkanniny and alkynylaryl radicals containing from 1 to 6 carbon atoms optionally substituted by one or more identical or different radicals selected from fluorine atoms, chlorine, bromine or iodine, hydroxyl, metaxylene, amoxilina, Isopropylamine, tert-butylaniline, methylthio, ethylthio, propylthio, butylthio, pentylthio, acyl, carboxyl, cyano, nitro, optionally substituted amino, cyclopropenes, cyclobutenes, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl, phenyl groups, and cyclopropyl substituted;< / BR>
R' represents 2-thienyl or 3-thienyl radical;

R" represents alkyl, alkanniny or alkynylaryl radical,

alkyl, alkanniny and alkynylaryl radicals containing from 1 to 6 carbon atoms and optionally substituted by one or more identical or different radicals selected from fluorine atoms, chlorine, bromine or iodine, hydroxyl, metaxylene, amoxilina, Isopropylamine, tert-butylaniline, methylthio, ethylthio, propylthio, butylthio, pentylthio, acyl, carboxyl, cyano, nitro, optionally substituted amino, cyclopropenes, cyclobutenes, cyclopentyloxy, tsiklogeksilnogo, cycloheptyl, phenyl groups, and cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptenyl and phenyl radicals optionally substituted;< / BR>
cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or cycloheptyl radical, these radicals optionally substituted by one or more identical or different radicals selected from fluorine atoms, chlorine, bromine or iodine, hydroxyl, metaxylene, amoxilina, isopropylaniline, tert-butylaniline, methylthio, ethylthio, propylthio, butylthio, peni, nattily, thienyl, purely, pyrrolidinyl, imidazolidinyl, parasailing, isothiazol, thiazole, isoxazolidine, oxazolidine, peredelnyj, persily, pyrimidinyl, benzothiazolyl, benzofuranyl or indolinyl radical, these radicals optionally substituted by one or more identical or different radicals selected from fluorine atoms, chlorine, bromine or iodine, hydroxyl, metaxylene, amoxilina, isopropylaniline, tert-butylaniline, methylthio, ethylthio, propylthio, butylthio, pentylthio, acyl, carboxyl, cyano, nitro or aminosalicylic, optionally substituted;

as well as salts of these compounds.

A more specific aim of the invention are compounds described below in the examples, in particular, the following connections:

- 2-methyl-1-(2-thienyl)cyclohexane carbonitrile;

- 2-methyl-1-(2-thienyl)cyclohexane carboxylic acid;

- ethyl 2-methyl-1-(2-thienyl)cyclohexane carboxylate;

- 2-methyl-1-(2-thienyl)cyclohexane carboxamide;

- N-[-methyl-((S)-phenylethyl)] -2-methyl-1-(2-thienyl)cyclohexane carboxamide;

- 2-methyl-1-(3-thienyl)cyclohexane carbonitrile;

- 2-methyl-1-(3-thienyl)cyclohexane carboxylic acid;

- 2-methyl-1-(3-t is bontril;

- 2-propyl-1-(2-thienyl)cyclohexane carbonitrile;

- 2-benzyl-1-(2-thienyl)cyclohexane carbonitrile;

- 2-phenyl-1-(2-thienyl)cyclohexane carbonitrile

in racemic form or in the form of essentially pure diastereoisomers or enantiomers.

The aim of the present invention is also a method of obtaining compounds of General formula I, as described above, in which R represents ceanorhaditis or a radical of the formula-C(O)A, where a is a radical of the formula OR1or NR2R3as described above, characterized by the fact that the compound of General formula 1:

R CH2R, 1

in which R and R' mean above, is reacted with a compound of General formula 2;

< / BR>
in which Y and Y' independently represent a deleted group, and R" means specified above, in an inert solvent in the presence of a strong base to form a compound of formula I.

The use of parent compounds in racemic form leads to the formation of compounds of formula I in racemic form. The use of the compounds of formula 2 (R) or (S) form allows you to obtain the compound of formula I in the form of essentially pure enantiomers.

In the compound of formula 2 Y and Y' are removed is 2">

When implementing the above method for this reaction was applied such an inert solvent as acetonitrile, dimethylacetamide or dimethylformamide, preferably dimethylformamide, in the presence of a strong base. A strong base can be selected from such compounds as alkality (such as, for example, methyl-, n-butyl or tert-utility) or one of its derivatives, such as, for example, diisopropylamide lithium (LDA) or hexamethyldisilazane lithium (LiHMDS), alcoholate (e.g., methylate, ethylate, propylate, butyl, tert-butyl, isoamyl or tert-adalat) or hydroxide of an alkali metal. To the specified solvent was then added to the compound of formula 1 in the presence of a strong base at a temperature between -80oC and ambient temperature, preferably between -20oC and 0oC. Then was added the compound of formula 2 at a temperature between -10oC and +10oC, preferably at a temperature slightly above the 0oC. the Reaction mixture is then heated to a temperature of between 20 and 65oWith that was maintained under stirring for from 15 minutes to several hours. The reaction can be followed, for example, chromatography (most suitable: thin-layer, gas is to process a mixture of water and solvent, which is not miscible with water, in order to proektirovanii the reaction product.

Compounds of General formula 1 are commercially available or can be obtained by standard methods known to experts in this field.

Compounds of General formula 2 can be obtained, for example, or by the reaction between the ORGANOMETALLIC compound and valerolactone or one of its derivatives with subsequent restoration by the appropriate substitution of hydroxyl groups, or by reaction between the ORGANOMETALLIC compound of the formula R"-M-Hal and alkyl 4-(halogen formyl)butyrate with subsequent restoration by the appropriate substitution of hydroxyl groups, or by reaction between the ORGANOMETALLIC compound of the formula R"-M-Hal and the corresponding compound of General formula Y-(CH2)4-C(O)Hal with subsequent restoration by the appropriate substitution of hydroxyl group in accordance with the following reaction scheme 1. ORGANOMETALLIC compound, as described above, can be magnetogenesis compound or a compound obtained by exchange between magnetogenesis compound and the halide compound of the metal, such as, e.g. the value of formula 2 can also be obtained in accordance with reaction scheme 2, below, by restoring a ketone of the formula R"C(O)(CH2)2CH= CH where R" has the meaning specified above, followed by the appropriate substitution of hydroxyl groups formed in this way, followed by the conversion of the alkene to the corresponding alcohol, and finally, the appropriate substitution of hydroxyl groups formed in this way.

The compounds of formula 2 in the form of essentially pure enantiomers can be obtained in accordance with reaction scheme 2, for example, by incorporating additional stages for the separation of alcohols of the formula R"C(OH)(CH2)2CH=CH in the form of essentially pure enantiomers, then use the handle of one of the alcohols for the formation of the corresponding compounds 2 to the desired essentially pure form. In this case, when the separation of alcohols in essentially pure form is difficult, alcohol in racemic form may be converted into another compound, enantiomeric form of which is more than just, for example, the alcohol can react with phthalic anhydride, then enantiomers can be separated from formed as a result of this phthalate and phthalate in the form of essentially pure diastereoisomer can build the accordance with reaction scheme 2.

In the presented schemes of reactions 1 and 2 Y, Y' and R" have the meanings specified above, a Hal represents a halogen atom.

Compounds of General formula I, as defined above, where R represents a-NR4R5radical, can be obtained starting from compounds of formula 1, where R represents-C(O)NR2R3radical, used in the standard conditions known to specialists in this field.

Compounds of General formula I, as defined above, where R is an acid, amide or ether function, can also be obtained directly or indirectly by starting with the appropriate compounds of formula I, where each R is ceanorhaditis, used in the standard conditions, well known to the experts in this field, in accordance with the following reaction scheme 3.

Compounds that are the aim of the present invention, can therefore be obtained in racemic form, starting with the original compounds in racemic form. They can also be obtained in the predominant CIS - or transconfiguration between groups R and R". The use of the compounds of formula 2 (R) or (S) form allows you to obtain a single enantiomer over the entire length of the synthesized circuit. More than that is exploring the separation at the stage of the compounds of formula I, where each R is a nitrile, amide or ether may, for example, using nitrilase, hydratase acylase or amide or esterase, respectively. In the case of ether is preferable to apply the esterase pig liver.

Chemical separation may be carried out using a chiral amine at the stage of the compounds of formula I, where R is an acid function. The amine may be selected from chiral amines, known to specialists in this field. It is preferable to apply quinine or-methyl-benzylamine. In the case of separation by quinine, it is preferable to crystallize the salt of the (+) acid. Obtaining (-) acid can be achieved by deposition of its salts with D-(+)-methyl-benzylamine. Similar can be made a separation at the stage of the compounds of formula I, where R represents an amine function, through the use of optically active acids and preferably tartaric acid or a derivative of tartaric acid, such as di-O,O tololing.

Compounds of General formula I, where each R is aminoacyl, are precursors of compounds of formula II:

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where each R and R" have the meanings specified above, a E1and E2connected the other is Anil. Expression heteroseksualci or geteroseksualen denotes a saturated or unsaturated cycloalkyl containing from 3 to 5 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably the heteroatoms are selected from oxygen, sulfur or nitrogen. Examples geterotsiklicheskikh or geterotsiklicheskikh radicals are pyrrolidinyl, imidazolidinyl, pyrazolidinone, piperidinyl, piperazinilnom, morpholinyl, isothiazolinones, diazolidinyl, isoxazolidine, oxazolidine and 1,2,3,6-tetrahydropyridine radicals.

Thus, compounds of General formula II can be obtained by reaction of a corresponding compound of formula I, where R represents aminoacyl, and the compound of the formula Hal-B-Hal, in which Hal represents a halogen atom, and represents the corresponding hydrocarbon chain with 3 to 8 carbon atoms, which is saturated or unsaturated, in standard conditions, well known to specialists in this field. Compounds of General formula Hal-B-Hal commercially available or can be obtained by standard methods, izvestnaia of the invention is also the use of compounds of General formula I, as described above, as new industrial products for the synthesis of teenillegal derivatives and more specifically cyclic (tamilsexy)amines. More specifically, the purpose of this invention is the use of compounds of General formula I, as defined above, where R" is an alkyl radical, for the synthesis of 2-alkyl-(3-thienyl)cyclohexylpiperidine or 2-alkyl-(2-thienyl) cyclohexylpiperidine in racemic form, in the form of essentially pure diastereoisomer or enantiomer. More specifically, the present invention is the use of 2-methyl-1-(2-thienyl)cyclohexylamine in the form of essentially pure enantiomers for the synthesis of 2-methyl-1-(2-thienyl)cyclohexylpiperidine in the form of essentially pure enantiomers, the specified synthesis involving the reaction of 2-methyl-1-(2-thienyl)cyclohexylamine in the form of essentially pure enantiomers with the compound of the formula Hal-(CH2)5-l, in which Hal represents a halogen atom, preferably a chlorine atom, in an inert solvent in the presence of a strong base.

The aim of the present invention is also the use of unsaturated compounds with the General formula I, as described above, as precursors of molecules labeled with radio CLASS="ptx2">

The aim of the present invention are also the compounds of formula 2 in racemic form or in the form of essentially pure enantiomers, as described above, as new industrial products and, in particular, as new industrial products, designed to produce compounds of formula I.

The following examples are presented to illustrate the above methods, however they in no way should be construed as limiting the scope of invention.

Getting 1: (+/-) 1,5-hexanediol

In a 6-liter reaction vessel in a nitrogen atmosphere contribute 560 ml of ethyl 4-acetylbutyrate and then 2.8 l of toluene. In the funnel to add placed 980 ml of 15% by weight solution of tetrahydroaluminate lithium in a mixture of toluene/THF, 1/2.4. Tetrahydroaluminate added dropwise within 2 hours, allowing the temperature to increase gradually to the temperature of reflux distilled. Reaction medium was kept at the temperature of reflux distilled for 3 hours. The reaction vessel was then cooled to a temperature below 15oWith, then very slowly add 110 ml of 5% soda solution and then 250 ml of 15% solution of soda. Conduct stirring for 15 minutes and then add 1 l of methyl tert-butyl ether (MTBE). Rivcoll 2.8 l MTBE. All the filtrates and concentrate obtain 360 g of a very thick oil corresponding to the desired product (Yield = 86%).

Nuclear magnetic resonance (NMR)NMR-13C (Dl3): 21.7; 23.1; 32.1; 38.5; 61.7; 67.3.

Getting 2: (+/-) 1.5-dichlorohexane

Obtaining 2A: starting from compound 3

A 3-liter three-neck vessel in a nitrogen atmosphere contribute 352 g of 1,5-hexandiol and then 1 l of toluene. With careful stirring for 2 hours, added with a dropping funnel 660 ml of thionyl chloride in order to achieve the continuous generation of gas, and leave at a temperature below 40oC. the Reaction medium is gradually brought to a temperature reflux distilled and left under stirring for 1.5 hours. Then distilled off excess thionyl chloride until a temperature vapor 109oC. Then add toluene in an amount equal clubbed volume, again distilled off several ounces, making sure that the temperature of the vapor is always 109-110oC. the Reaction medium was then cooled to 20-25oC and added dropwise to 500 ml of water. Conduct stirring for 15 minutes, after which the two phases are decanted. The organic phase is then washed 3 times with 400 ml saturated aqueous sodium bicarbonate solution (pH= 7) and 500 OE oil is distilled under vacuum. After separation of the first 25 g (because3.75=39-54o(C) receive 292 g of an oil corresponding to the desired product (because3.75= 55-56oC).

NMR-13C(DCl3): 23.9; 25.2; 31.9; 39.4; 44.6; 58.3.

Obtaining 2b: starting from compound 7

Acting similar to the one described below in Receiving 12, 13 and 14 in the manner and using methylmagnesium get the desired product. Analytical characteristics identical to those of the product resulting from the Receipt 2A.

Getting 3: methyl 5-oxooctanoate

In a 250 ml reaction vessel in a nitrogen atmosphere make 2.82 g of magnesium. It is covered with THF and pour in 1 ml of 1-bromopropane. After start of the reaction is added dropwise over 1.5 hours a solution of 9.9 ml of 1-bromopropane in 150 ml of THF. After adding the conduct stirring for 10 minutes, after which the reaction mixture is boiled until the temperature of the reflux distilled for 3 hours and then cooled to a temperature of -80oC. Very slowly for 45 minutes add 17 ml of methyl 4-(chloroformyl)butyrate. Then stirred for 1 hour at -70oS, after which the reaction mixture is allowed slowly to return to the temperature of the 18o(Over 17 hours). The reaction mixture is processed on the next decantation and re-extraction of the aqueous phase with 100 ml of ether. The organic phase is concentrated. The residue is washed with 200 ml of ether, then washed with twice 100 ml of water, dried over magnesium sulfate and concentrated in a rotary evaporator. Thus obtain 20.2 g of an oil corresponding to the expected product.

NMR-13C (CDCl3): 13.5; 17.1; 18.7; 32.8; 41.2; 44.5; 51.3; 173.4; 210.1.

Getting 4: methyl 5-oxogedunin

Proceeding as in 3 and on the basis of 4.5 ml of brometane, obtain 9.2 g of the desired product.

NMR-13C (Dl3): 7.6; 18.8; 32.9; 35.7; 40.9; 51.3; 173.4; 210.5.

Getting 5: (+/-) 1.5 to heptanediol

Acting as Obtaining 1 and on the basis of 5.4 g of methyl 5-exagerate, obtain 4.2 g of the desired product.

NMR-13C (Dl3): 9.9; 21.7; 30.0; 32.3; 36.2; 62.0; 72.8.

Getting 6: (+/-) 1.5 to octandiol

Acting as Obtaining 1 and on the basis of 20.0 g of methyl 5-oxooctanoate, obtain 16.9 g of the desired product.

NMR-13C (Dl3): 14.0; 18.8; 21.7; 32.3; 36.7; 39.5; 62.0; 71.1.

Getting 7: (+/-) 1,5-dichlorethane

In a 100-ml reaction vessel in a nitrogen atmosphere make 20 ml of DMF and then cooled to 0oC. and Then added dropwise within 10 minutes with 5.6 ml of thionyl chloride. Conduct stirring for 25 minutes, then added dropwise within 1.5 hours RxA to 20-25oC. the Reaction medium was then heated at 95oC for 45 minutes and then cooled to 25oC. Add 200 ml of water and extracted three times with 80 ml of diethyl ether. The organic phase is washed twice with 80 ml of water, then dried over potassium carbonate, filtered and concentrated on a rotary evaporator. Obtain 5.0 g of the desired product.

NMR-13C (CDCl3): 10.9; 23.9; 31.4; 32.1; 37.2; 44.7; 65.2.

Getting 8: (+/-) 1,5-dichlorooctane

Proceeding as in Getting 7 and on the basis of 16.5 g of 1,5-octanediol, obtain 11.8 g of the desired product.

NMR-13C (Dl3): 13.5; 19.6; 23.8; 32.1; 37.7; 40.5; 44.7; 63.5.

9: Penta-2-in-1,5-diol

In a 250-ml three-neck vessel consistently contribute 26 ml of but-3-in-1-ol, 55 ml of 30% formaldehyde, 0.41 g of calcium carbonate and, finally, 4.9 g hydrosaline of copper obtained immediately before use according to standard method. Stirred for 10 minutes at 20-25oWith, then within 96 hours at 80oC, then cooled to 20-25oC. the resulting solution was filtered and concentrated. After distillation under vacuum to obtain 15.3 g of the desired product (because0.05=107-109oC).

NMR-13C (Dl3): 22.8; 50.6; 60.6; 79.9; 83.0.

On ml ethyl acetate. Then add 0.65 ml of chloroform and after him 0.71 g of palladium on barium sulfate (5%). Conduct stirring for 5 minutes, after which the installation of clean hydrogen and give one equivalent of hydrogen is absorbed within 6 and a half hours at 20-25oC. the Reaction mixture is filtered on celite with subsequent washing with 50 ml of ethyl acetate and concentrated. Thus obtain 16.4 g of oil, corresponding to the desired product.

NMR-13C (Dl3): 2.35 (m, 2H); 3.61 (t, 2H, CH2); 4.1 (d, 2H, CH2); 4.15 (s, 2H, HE); 5.7 (m, 2H, CH=CH).

Obtaining 11: CIS-1,5-deponent-2-EN

In a 100-ml three-neck vessel contribute 11 ml tribromophenol and cooled to 0oC. for three hours added 16.4 g of CIS the Penta-2-ene-1,5-diol. The temperature slowly give back to 20-25oWith and conduct stirring for 15 hours. Reaction medium was then cooled to 0oWith and within 30 minutes, add 30 ml of water. Stirred for 5 minutes and extracted with twice 30 ml of dichloromethane. The organic phase is washed with 15 ml water, then dried over magnesium sulfate, filtered and concentrated. Thus obtained 35 g of oil corresponding to the expected product with a purity sufficient for use H2C=C); 5.88 (m, 2H, CH=CH).

Obtaining 12: 6-chloro-1-phenylhexane-2-he

In a 250-ml three-neck vessel in an atmosphere of nitrogen load of 10 g of acid chloride of 5-haralanova acid in 50 ml of anhydrous THF. The reaction medium is cooled to -20oWith and added 1.06 g of copper chloride (I). Conduct stirring for 40 minutes, and then for 1.5 hours add 36 ml of 2 M solution of magniloquently in THF. Conduct stirring for 1 hour at -20oWith, then for 1.5 hours the temperature is allowed to return to the 20oC. the Reaction medium is cooled to -10oWith and add 90 ml of 0.4 M hydrochloric acid. Conduct stirring for 20 minutes, after which the aqueous phase is twice extracted with 100 ml of MTBE. The organic phase is washed with twice 50 ml of water, dried over magnesium sulfate, filtered and concentrated. Thus obtain 13.5 g of the desired product.

13: (+/-) 6-chloro-1-phenylhexane-2-ol

In a 250-ml three-neck vessel load 13.1 g of 6-chloro-1-phenylhexane-2-it. The reaction medium is cooled to -5oC and added dropwise within 5 minutes a solution of sodium borohydride (2.18 g) in 15 ml of water. Conduct stirring for 2.5 hours at -5oC, then the temperature allowed to rise to 20oIn emiliania for 10 minutes, followed by three extractions with 80 ml of methylene chloride, drying over magnesium sulfate, filtration and concentration. Thus obtain 12.3 g of the expected product.

Obtaining 14: (+/-) 2,6-dichloro-1-phenylhexane

Proceeding as in Getting 7 and on the basis of 12.3 g of 6-chloro-1-phenylhexane-2-ol and 12.9 g of thionyl chloride, to obtain 13.3 g of the desired product.

Obtaining 15: (+/-) of 1,5-dichloro-1-phenylpentane

Acting as in Obtaining 12, 13 and 14, but using magnicharters instead of benzylacrylamide get the desired product.

Obtaining 16: (+/-) 5-HEXEN-2-ol

In a 250-ml doggedly vessel containing 2 g of LiAlH4and 130 ml of anhydrous ethyl ether in an argon atmosphere is added dropwise under an ambient temperature of 10 g of 5-hexanone dissolved in 20 ml of anhydrous ethyl ether. The mixture is then boiled until the temperature of the reflux distilled for 2 hours. The reaction medium allowed to return to ambient temperature, then cooled in an ice bath. Added dropwise 10 ml of ethanol and then with 20 ml of distilled water. Mixing cease to give to fall educated white precipitate, after which the supernatant transferred into a separating funnel. The phases are separated: the aqueous phase is extracted once with ether (5ml) and the combined form of a light oil.

NMR-1H (Dl3, ppm): 1,0 (d, CH3); 1,4 (m, CH2C=C); 2.0 (m, CH3C=0); 3.1 (s, HE); 3.6 (m, CH-O); 4.9 (m, CH2=C); 5.7 (m, CH=C).

NMR-13C (CDCl3, ppm): 23.0 (CH3); 29.9 (CH2C=C); 38.0 (CH2C-O); 67.0 (CH-O); 114.3 (CH2-C); 138.3 (m, CH=C).

Obtaining 17:5-2-gestiftet

In 100-ml odnogolosy vessel load of 8 g (80 mmol) of 5-HEXEN-2-ol, 12.1 g (80 mmol) of phthalic anhydride and 40 ml of pyridine. The mixture was stirred at ambient temperature for 4 days. Then it is placed in a 500 ml chemical glass 1/3 full of crushed ice and then acidified with chilled on ice concentrated Hcl. Thus obtained solution was twice extracted with chilled on ice chloroform. The combined chloroform phases are washed three times chilled on ice Hcl (2N) and three times chilled on ice saturated NaCl solution, then dried over MgSO4and concentrate. The concentrate is dissolved in a slight excess chilled on ice solution PA2CO3(2 N, 40 ml) and the solution extracted twice with ether. Then it is acidified chilled on ice Hcl (2 N) until the remaining white cloud, and then extracted with chloroform. Organic races provides 16 g of a light oil. This oil is dissolved in 10 ml of petroleum ether, placed overnight in a cold room (7o(C) under mild stirring. A white precipitate is formed very phthalate, which is filtered and dried to obtain 14.3 g of residue (yield 72.3%).

Obtaining 18: division5-2-gestiftet

A mixture of 14 g5-2-gestiftet, 18 g of anhydrous brucine and 200 ml of acetone is boiled to a temperature of reflux distilled in 250-ml-odnogolosy vessel equipped with a condenser to obtain a clear solution. The reaction medium is allowed to cool to ambient temperature. Sediment brucine salt was filtered, dried and recrystallized once from acetone to obtain the mass of 13.6 G. of this salt dissolved in 700 ml of warm ethanol and 30 ml of Hcl (2 N), add 100 ml of distilled water, then cooled solution is extracted four times with ether. The ether phase is washed with Hcl (2 N) and water, dried over MgSO4and concentrate to obtain 5.5 (d) light oil. Oil hydrolyzing 50 ml of NaOH solution (2 N) in 100-ml-odnogolosy vessel and subjected to steam distillation. Obtain 2.2 g of a light oil, characterized as (+)-5-HEXEN-2-ol. []D=+12.2o(C=2.99; Et2O).

(-)-5-HEXEN-2-ol get PU Fallen in the brucine salt was filtered, dried and treated in the same way as in the previous case, to obtain 2.5 g of the product, []D=-11.1o([S]=2.5; Et2O).

NMR-1H (Dl3, ppm): 1.0 (d, CH3); 1.4 (m, CH2C=C); 2.0 (m, CH2C=O); 3.1 (s, HE); 3.6 (m, CH-O); 4.9 (m, CH2=C); 5.7 (m, CH=C).

NMR-13C (CDCl3, ppm): 23.0 (CH3); 29.9 (CH2C=C); 38.0 (CH2C-O); 67.0 (CH-O); 114.3 (CH2=); 138.3 (m, CH=C).

Obtaining 19: (+)-5-chloro-1-hexene

In a 100-ml three-neck vessel equipped with a condenser, thermometer and additional funnel, was placed 2.5 g (25 mmol) of (-)-5-HEXEN-2-ol and 10 ml of carbon tetrachloride and added dropwise a solution of 8 g of triphenylphosphine in 10 ml of dichloromethane. The mixture is stirred overnight at 25o, Then cooled to ambient temperature and concentrate. Adding pentane (20 ml), precipitated f3RO, which is filtered, and the filtrate concentrated. The concentrate is diluted with pentane and placed in an ice bath for one hour and again filtered. The filtrate is then passed through silica gel, elwira pentane. After concentrating obtain 1.3 g of the product. NMR-1H analysis and force the optical rotation indicate that the product obtained using the configuration of inversion, dei is H (Dl3, ppm): 1.50 (d, CH3); 1.80 (m, CH2C=C); 2.20 (m, CH2C-Cl); 4.0 (m, CH-Cl); 5.1 (m, CH2=C); 5.7 (m, CH=C).

20: (+)-5-chloro-1-hexanol

In a 50 ml three-neck vessel under argon was placed 1 g of (+)-5-chloro-1-hexene and 10 ml of anhydrous ether, and then the mixture is cooled in an ice bath. Added dropwise 0.5 ml NR3:S(CH3)2(10:10.2 M) followed by stirring for one hour at ambient temperature. The reaction medium is then oxidised at 0-5oWith 4 ml of NaOH (3 N), and then 8 ml of H2O2(30%) and the mixture is stirred for one hour at ambient temperature. Then decanted and the aqueous phase is extracted three times with ether. The combined organic phases are washed with distilled water, dried over MgSO4and concentrate to obtain 0.7 g (60.8% (+)5-chloro-1-hexanol. []D=+14.2o(=2.96; Et2O).

NMR-1H (CDCl3, ppm): 1.45 (d, CH3); 1.52 (m, 2CH2); 1.60-1.70 (m, CH2C-Cl); 3.16 (s, HE); 3.57 (t, CH2O); 4.1 (m, CH-Cl).

Getting 21: (+)-1.5-dichlorohexane

Working conditions are identical used for the synthesis of 5-chloro-1-hexene using 400 mg (2.93 mmole) of (+)-5-chloro-1-hexanol, 3 ml of dichloromethane, 1 g (3.81 mmole) of triphenylphosphine and 3 ml of carbon tetrachloride. In Konecna>1H (CDCl3, ppm): 1.50 (d, CH3); 1.60-1.85 (m, 6H, CH2); 3.53 (t, 2H, CH2-Cl); 4.1 (m, CH-Cl).

Example 1:

(+/-) CIS-2-methyl-1-(2-thienyl)cyclohexane carbonitrile

430 g of potash (85%) in 1.7 l of DMF contribute in the reaction vessel with a capacity of 6 liters Reaction medium was then cooled to -20oAnd add a solution of 191 g of 2-trilaterally in 0.7 l of DMF while cooling. So the temperature does not exceed -15oC. After the completion of this first phase immediately add a solution of 250 g of 1,5-dichlorohexane in 0.5 l of DMF for 1 hour, allowing the temperature to rise to -5oC. After these two additions, remove the cooling bath and allow to rise the temperature to 20-25oC for 40 minutes. When these conditions hold swing over 4.5 hours, after which the DMF is removed under vacuum. The resulting environment is mixed with 1.5 l of water and extracted twice with 500 ml of heptane. The organic phase is twice washed with 500 ml of water, dried over magnesium sulfate, filtered and the resulting solution concentrated. Thus obtained greenish oil after distillation under vacuum gives 267 g of a colorless oil corresponding to the desired product (because2.1=90-100oC).

NMR-13C (CDCl3): 18.0; 23.7; 25.4; 32.0; 41.2; 42.8; 48.1; 120.1; 124.4; 125.Il-1-(2-thienyl)cyclohexanecarbonitrile in 1 l of diethylene glycol contribute in the reaction vessel 4 HP After homogenization for 5 minutes with vigorous shaking add 2.4 kg of a 60% aqueous solution of potash. Then shaken at 170oWith in 24 hours. The reaction medium is cooled to 20-25oC, then diluted to 1 l of water, and pour it in 6.5 l of water and twice washed with 3 l of dichloromethane. During strong shaking reaction medium is acidified by adding 2.5 l of concentrated hydrochloric acid. At temperatures below 30oWith Wednesday extracted twice 3 l of dichloromethane. The organic phase is re-extracted twice with 2 liter soda (the first portion contains 78 g 99% soda, and the second 2 g). The organic phase is removed. The aqueous phase is acidified by adding 1 l of hydrochloric acid (containing 230 ml of concentrated hydrochloric acid) followed by extraction twice with 2 l of dichloromethane. The organic phase is washed with 2 l of water, treated with soot and magnesium sulfate, filtered and concentrated. Whitish solid is crystallized from 1.65 l of heptane with shaking. After filtration and washing with heptane collected 178 g of solids corresponding to the desired product (So pl.=109oC).

NMR-13C (CDCl3): 16.1; 21.2; 22.1; 29.0; 31.5; 37.4; 52.5; 124.8; 125.4; 126.5; 146.5; 180.9.

Example 3:

(+) CIS-2-methyl-4 g of quinine dissolved in 2.1 l of warm acetone. These two solutions are mixed and the temperature slowly give back to 20-25oWith and spend shaken at this temperature for 3 hours. The reaction mixture was filtered washing with a small amount of acetone. The resulting solution was then concentrated. The obtained salt is recrystallized from 860 ml of acetone. Acid isolated from a salt thereof, selected processing 10% hydrochloric acid and extraction with dichloromethane. The organic phase is concentrated after drying over magnesium sulfate and filtered. Thus collected 8.8 g of the desired (+) acid (So pl.= 109oC). []D20=+70.95 (ethanol 0.8%)

NMR-13C (Dl3): identical to the compound of Example 2.

Example 4:

(-)CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid

The first filtrate obtained upon receipt in example 3, concentrated until dry. Acid isolated from a salt thereof, selected processing 10% hydrochloric acid and extraction with dichloromethane. The organic phase is concentrated. 11.9 g of the selected acid and 6.1 g of D (+) -methyl-benzylamine in order dissolved in MTBE at the temperature of reflux distilled. The temperature slowly give back to 20-25oC, then stirred for 3 hours. React the si MTBE/EtOH followed by filtration and acid isolated as described above. Thus assembled 4.0 g of the desired (-) acid (So pl.: 109oC). []D20=-72.1 (ethanol 0.8%).

This (-)acid can also be obtained in the reaction of (+)-1,5-dichlorohexane with 2 trilateration at the operating conditions of example 2.

NMR-13C (Dl3): identical to the compound of example 2.

Example 5:

ethyl(+/-) CIS-2-methyl-1-(2-thienyl)cyclohexanecarboxylate

In a 250 ml reaction vessel dissolve 2.5 g of (+/-) CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid in 60 ml of toluene. Then add 3 ml of thionyl chloride for 15 minutes. The reaction mixture is allowed to become uniform within 5 minutes, and then gradually brought to reflux distilled, checking out with the formation of gas (1 hour). The reaction medium is stirred at a temperature of reflux distilled for 2 hours. The excess thionyl chloride is then distilled off until the vapor obtained by 108-110oWith, followed by toluene. Add 60 ml of ethanol and the remaining toluene is removed by distillation of the toluene/ethanol azeotrope to vapour at 77-78oC. At 20-25oTo add a solution of 1.5 g ethanolate sodium in 50 ml of ethanol for 20 minutes. The reaction medium give to be homogeneous within 5 minutes and then boil with the reverse was built in adicheskie phases are washed with 10 ml of water, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. Thus obtain 2.36 g of an oil corresponding to the desired product.

NMR-13C (Dl3): 12.3; 13.9; 21.8; 22.4; 29.3; 32.1; 38.1; 52.7; 60.5; 123.8; 124.8; 126.2; 147.6; 174.0.

Example 6:

ethyl(+/-)TRANS-2-methyl-1-(2-thienyl)cyclohexanecarboxylate

Proceeding as in example 1, but using 3 g of ethyl 2-thiopheneacetic instead of 2-trilaterally, obtain 1.3 g of the desired compound. His identify by comparing the structures of the compounds obtained basic hydrolysis, with the structures of the compounds of example 2.

Example 7:

(-)CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid

In a 100-ml three-neck vessel consistently make 50 ml phosphate buffer (pH 7), 0.15 ml of a solution of 1 g of ethyl(+/-)CIS-2-methyl-1-(2-thienyl)cyclohexanecarboxylate in propan-2-OLE and 0.46 mg of the crude drug esterase from pig liver. Reaction medium was then carefully stirred for 72 hours at 40oSince then cooled to 20-25oWith filtration on Sephadex and alkalization by adding 20 ml of 5% soda. Shaken out three times with 100 ml of MTBE. The organic phase is washed with 100 ml of water. The combined aqueous phase is then acidified with 100 ml of water, dried over magnesium sulfate, filter and concentrate to extract 0.4 g of the desired compound.

NMR-13C (Dl3): identical to the compound of example 4.

Example 8:

(+)CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid

The first phase MTBE obtained in preparation example 1, dried over magnesium sulfate, filtered and concentrated. The oil obtained is then washed with 2 ml of ethylene glycol followed by homogenization. After that add 4.8 g of 60% potash in water. Conduct stirring for 17 hours at 170oSince then cooled to 20-25oWith, then add 15 ml of water. The reaction medium is washed with twice 10 ml of dichloromethane and then acidified with 5 ml of concentrated hydrochloric acid and extracted twice with 10 ml dichloromethane. All organic phases are washed with 100 ml of water, dried over magnesium sulfate, filtered and concentrated to retrieve 0.45 g of the desired compound.

NMR-13(Dl3):identical to the compound of example 3.

Example 9:

(+/-)CIS-2-methyl-1-(2-thienyl)cyclohexanecarboxylic

A 2-liter reaction vessel in a nitrogen atmosphere dissolve 59 g of CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid in 600 ml of toluene. Then within the field to reflux distilled, controlling the formation of gas (4 hours). The excess thionyl chloride is then distilled off to obtain vapor at 108-110oC. Under these conditions, the reaction medium is cooled to 10oWith, then blow through it the ammonia with a very high speed without cooling. The temperature is allowed to rise to 65oAnd then to decrease to 20-30oC. After completion of the absorption of ammonia conduct stirring for 1 hour and then Tegaserod environment by blowing with nitrogen and add 600 ml of water. Two phase is decanted and the aqueous phase re-extracted with 300 ml of toluene. All organic phases are washed with twice 250 ml of water and environment focus. The resulting brownish solid is crystallized from 360 ml of heptane to obtain 52 g of the desired substance (So-square=100oC).

NMR-13C (Dl3): 15.8; 20.5; 21.9; 29.0; 30.2; 36.2; 52.4; 124.3; 124.8; 126.9; 148.8; 177.1.

Example 10: (+/-) CIS-2-methyl-1-(2-thienyl)cyclohexylamine

In a 1-liter three-neck vessel dissolve 60 g of potash in 240 ml of water. The reaction medium is cooled to 0oC. Simultaneously, add 7 ml of bromine. After homogenizing for 10 minutes fast (7 minutes) add a solution of 20.5 g of CIS-2-methyl-1-(2-thienyl)cyclohexanecarboxylate and 0.5 g of one-deputizing sulfate tetrabutylammonium 100 ml of water and the reaction medium was concentrated to highlight the intermediate isocyanate.

In the second 1-liter three-neck vessel dissolve 71 g of sodium (99%) in 170 ml of water. The reaction medium is cooled to 20-25oC. Fast (4 minutes) add a solution of 23.2 g of the intermediate isocyanate and 0.5 g of one-deputizing of tetrabutylammonium sulfate in 210 ml of MTBE. The reaction medium is stirred under these conditions for 7 hours, after which the two phases are decanted. The aqueous phase is extracted with 170 ml of MTBE. The organic phase is washed with 70 ml of water. The organic phase is extracted with twice 200 ml of acidified water (and the first portion contains 100 ml of 5% hydrochloric acid, and the second 1 ml). The aqueous phase is washed with 100 ml of MTBE and then alkalinized by adding 170 ml of 5% soda and extracted with twice 200 ml of MTBE. The organic phase is washed with 100 ml of water, dried over magnesium sulfate, filtered and concentrated. Thus obtain 17.2 g of an oil corresponding to the desired amine.

NMR-13C (Dl3): 15.9; 22.1; 25.9; 30.2; 41.7; 56.9; 121.1; 122.5; 126.5; 157.4.

Example 11: (+) CIS-2-methyl-1-(2-thienyl)cyclohexylamine

3.0 g (+/-) CIS-2-methyl-1-(thienyl)cyclohexylamine and 2.3 g (-) tartaric acid dissolved in a minimum amount of warm 95% aqueous ethanol. The reaction mixture is then stirred for 12 hours at 20-25oWith, and then filter the times from ethanol 95. The solid is washed with water and produce amine by adding 5% ash. Amin then extracted with ethyl ether, dried over magnesium sulfate and concentrated. This way obtain 0.25 g of the desired product. []D20=+14.7 (methanol 2%).

NMR-13C (Dl3): identical to the compound of example 10.

Example 12: (-) CIS-2-methyl-1-(2-thienyl)cyclohexylamine

Concentrate the various filtrates obtained in preparation example 11. Amin allocate according to the Protocol described above. Then it is crystallized with the use of (+) tartaric acid in a minimum amount of warm ethanol 95. The reaction medium is then stirred for 12 hours at 20-25oWith, and then filtered washing with a small amount of ethanol and petroleum ether. The obtained crystals are recrystallized three times from ethanol 95. The solid is washed with water and produce amine by adding 5% ash. Amin then extracted with ethyl ether, dried over magnesium sulfate and concentrated. This way obtain 0.31 g of the desired product. []D20=-15.5 (methanol 2%).

NMR-13C (CDCl3): identical to the compound of example 10.

Example 13:

(+/-) CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidineoC for 20 hours, then cooled to 25-30oWith and handle the addition of 300 ml of water and 100 ml of MTBE. Two phase decanted. The aqueous phase is again extracted with 150 ml of MTBE. The organic phase is washed with 100 ml of water. The organic phase is extracted with twice 150 ml of acidified water (with the first portion contains 40 ml of 5% hydrochloric acid, and the second 10 ml). The combined acidic aqueous phases are washed with 100 ml of MTBE and separate the organic phase. The aqueous phase is alkalinized by adding 70 ml of 5% soda and twice extracted with 100 ml of MTBE. Extraction the organic phase is washed with 50 ml of water, treated with soot and magnesium sulfate, filtered on clasele and concentrate. In this way collect 7.5 g of residue which is crystallized from 150 ml of methanol. In the find 5.9 g of a white solid corresponding to the desired molecule (the So-square=81-82oC).

NMR-13C (Dl3): 14.0; 19.4; 23.1; 25.1; 27.0; 29.5; 30.1; 33.9; 46.0; 52.7; 122.1; 124.0; 125.9; 144.7.

Example 14:

(+/-)CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidine hydrochlorination in nitrogen atmosphere quickly add a solution of 5 g (+/-) CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidine in 45 ml of MTBE. After the addition stirring is continued for 3 hours, then filtered and dried at a pressure of 1 Torr (1 mm RT.CT.) at 45oC. in This way gather 5.4 g of the desired product (So pl.=230-1oC).

NMR-13C (CDCl3): 15.8; 17.8; 22.1; 22.3; 22.5; 26.5; 30.2; 35.4; 46.7; 48.9; 72.9; 127.2; 127.6; 130.1; 136.9.

Example 15:

(+)CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidine hydrochloride

15A. Chemical separation

17.53 g (+/-) CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidine and 12.7 g (-) di-O, O'-Dalwallinu acid are dissolved separately in minimum amount of hot isopropanol. These two solutions are mixed, the temperature slowly give back to 20-25oC and then stirred for 4 hours. The reaction medium is filtered with washing a small amount of isopropanol and heptane. The solid is washed with water and produce amine by adding 5% ash. The amine is extracted with MTBE, dried under magnesium sulfate and concentrated. The concentration of the enantiomer (+) measured by chiral column HPLC and crystallization procedure is repeated three more times, bringing the number of (-) di-O, O'-Dalwallinu acid to the source of the stoichiometric ratio. Thus obtained 3.2 g of amine (+) with a predominance of enantiomer boea 14, which allows to obtain 3.6 g of the desired product (So pl.=230-1oC).

NMR identical to that of the product of example 14.

15b. Chemical synthesis of

Acting, as indicated at getting in examples 9, 10, 13 and 14, and using 23.2 g (+) CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid, obtain 18.2 g of the desired (+) hydrochloride (So pl.=230-1oC). []24D=+33.0.

NMR identical to that of the product of example 14.

Example 16:

(-)CIS-2-methyl-1-(2-thienyl)cyclohexylpiperidine hydrochloride

16A. Chemical separation

The first filtrate obtained upon receipt in example 15A, concentrate and conduct the crystallization procedure using (+) di-O,O'-Dalwallinu acid, under the same conditions as before, three times in a row. After joining hydrogen chloride allocate 3.7 g of the desired compound (So pl.=230-1oC).

NMR identical to that of the product of example 14.

16b. Chemical synthesis of

Acting, as indicated at getting in examples 9, 10, 13 and 14, and using 11.5 g of (-)CIS-2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid, obtain 8.1 g of the desired (-) hydrochloride (So pl.=230-1oC).

NMR identical to that of the product of example 14.

[]24D=- 32.3.

Thin liquid chromatography (TLC) (SiO260F254, hexane /diethyl ether 5/5, manifestation in the UV, the relative mobility (Rf=0.66).

Example 18:

(+/-) CIS-2-methyl-1-(3-thienyl)cyclohexanecarbonitrile

In a 500-ml three-neck vessel placed 43 g of potash in 160 ml of DMF. The reaction medium is cooled to -10oAnd dropwise within 30 minutes, add a solution of 17.6 g of 3-trilaterally is giving 30 minutes at -10oTo add a solution of 24.7 g of 1,5-dichlorohexane in 40 ml of DMF. Conduct stirring for 15 minutes and the temperature of the reaction medium to give back to 20-25oC for 1.5 hours. This was followed by stirring for 18 hours at 25oWith and then for 4 hours at 60oC. After distillation, the DMF under vacuum, the temperature is allowed to return to 20-25oAnd pour it in 1 l of water. Extracted first 600 ml and then 400 ml of heptane. The organic phase is washed with 400 ml of water and then 400 ml of a solution of sodium chloride. The resulting solution was dried over magnesium sulfate, filtered and concentrated. After distillation under vacuum to obtain 15.2 g of a colorless oil corresponding to the desired product (because0.08=114-120oC).

NMR-13C (Dl3): 17.9; 23.5; 25.2; 34.7; 39.1; 40.7; 47.8; 121.2; 121.3; 124.7; 126.6; 142.1.

Example 19: (+/-) CIS-2-methyl-1-(3-thienyl)cyclohexanecarbonyl acid

On the basis of 15.0 g (+/-) CIS-2-methyl-1-(3-thienyl)cyclohexanecarbonitrile and acting the same way as described under getting in example 2, after crystallization from 4 volumes of heptane obtain 11.6 g of the desired compound.

TLC (SiO260F254, diethyl ether, the manifestation in the UV, Rf=0.7).

Example 20:

(+/-) CIS-2-methyl-1-(3-thienyl)cyclohexane the Ohm, as described under getting in example 9, after crystallization from 5 volumes of heptane obtain 12.0 g of the desired compound.

NMR-13C (Dl3): 16.0; 21.2; 22.1; 29.1; 30.8; 35.6; 52.1; 121.4; 126.1; 126.9; 145.1; 177.5.

Example 21: (+/-) CIS-2-methyl-1-(3-thienyl)cyclohexanamine

On the basis of 11.6 g (+/-) CIS-2-methyl-1-(3-thienyl)cyclohexanecarboxylate and acting the same way as described under getting in example 10, to obtain 6.9 g of an almost colorless oil, corresponding to the desired connection.

NMR-13C (Dl3): 15.2; 15.9; 21.9; 26.1; 30.1; 40.3; 41.8; 56.3; 118.9; 125.2; 125.5; 152.4.

Example 22:

(+/-) CIS-2-methyl-1-(3-thienyl)cyclohexylpiperidine

On the basis of 5.7 g (+/-) CIS-2-methyl-1-(3-thienyl) cyclohexanamine and acting the same way as described under getting in example 13, after crystallization from 14 volumes of methanol obtain 5.9 g of the desired compound.

NMR-13C (Dl3): 13.7; 19.6; 23.0; 25.1; 27.0; 28.8; 29.3; 32.7; 46.0; 62.2; 120.8; 123.1; 127.8; 141.1.

Example 23:

(+/-) CIS-2-methyl-1-(3-thienyl)cyclohexylpiperidine hydrochloride

On the basis of 0.7 g (+/-) CIS-2-methyl-1-(3-thienyl)cyclo-hexylpyridine and acting the same way as described under getting in example 14, to obtain 0.62 g of the desired hydrochloride (so pl.=230oC).

N2-thienyl)cyclohexyl]-1,2, 3,6-tetrahydropyridine

On the basis of 11.51 g (+/-) CIS-2-methyl-1-(2-thienyl)cyclohexanamine and 35 g of CIS-1,5-deponent-2-ene and acting the same way as described under getting in example 13, to obtain 15.2 g of a beige solid, which is purified by chromatography on 500 g of aluminum (Merck 90) (elution with heptane). So get 4.81 g of the desired compound.

NMR-13C (CDCl3): 14.1; 19.4; 23.0; 27.3; 29.4; 29.9; 34.4; 42.1; 44.5; 62.9; 122.6; 124.5; 124.8; 126.0; 126.5; 143.6.

Example 25: (+/-) [CIS-2-methyl-1-(2-thienyl)cyclohexyl]-1,2,3, 6-tetrahydropyridine hydrochloride

On the basis of 0.24 g (+/-) [CIS-2-methyl-1-(2-thienyl)cyclohexyl]-1,2, 3, 6-tetrahydropyridine and acting the same way as described under getting in example 14, to obtain 0.2 g of the desired compound (So pl.=182-184oC).

Example 26:

(+/-) CIS-2-ethyl-1-(2-thienyl)cyclohexanecarbonitrile

Acting in the same way as described under getting in example 1, but from 4.8 g of 1,5-dichlorethane instead of 1,5-dichlorohexane, obtain 2.8 g of the desired product.

NMR-13C (CDCl3): 10.1; 22.3; 23.1; 23.9; 26.8; 41.4; 46.9; 47.9; 118.9; 123.0; 123.7; 125.0; 143.8.

Example 27:

(+/-) CIS-2-propyl-1-(2-thienyl)cyclohexanecarbonitrile

Acting in the same manner as described in example 1, but from 5.1 g of 1,5-dichloro is 25.4; 28.9; 33.9; 42.0; 47.1; 47.8; 120.5; 124.4; 125.2; 126.4; 145.3.

Example 28:

(+/-) CIS-2-benzyl-1-(2-thienyl)cyclohexanecarbonitrile

Acting in the same manner as described in example 1, but using 2,6-dichloro-1-phenylhexane instead of 1,5-dichlorohexane get the desired product.

Example 29:

(+/-)CIS-2-phenyl-1-(2-thienyl)cyclohexanecarbonitrile

Acting in the same manner as described in example 1, but using 1,5-dichloro-1-phenylpentane instead of 1,5-dichlorohexane get the desired product.

Using the method mentioned above can be obtained also the following compounds, which are also part of the invention and which form the preferred connection:

1. Derivatives tamilcanadian General formula I

< / BR>
in racemic form or in the form of pure diastereoisomers or enantiomers, where R represents ceanorhaditis; a radical of the formula-C(O)A, where a represents a halogen atom, a radical of the formula OR1or-NR2R3where R1, R2and R3independently represent hydrogen or alkyl group, optionally substituted by phenyl; or aminoacyl;

R' represents 2-thienyl or 3-thienyl radical; R" is alkyl, or salts of these compounds, excluding analny radical and R" is a methyl radical.

2. The compound of General formula I, as defined in paragraph 1, in racemic form, in the form of essentially pure diastereoisomers or enantiomers, representing a compound selected from the group including:

2-methyl-1-(2-thienyl)cyclohexanecarbonitrile;

2-methyl-1-(2-thienyl)cyclohexanecarbonyl acid;

ethyl 2-methyl-1-(2-thienyl)cyclohexanecarboxylate;

2-methyl-1-(2-thienyl)cyclohexanecarboxylic;

N-[-methyl-((S)-phenylethyl)]-2-methyl-1-(2-thienyl)cyclohexanecarboxylic;

2-methyl-1-(3-thienyl)cyclohexanecarbonitrile;

2-methyl-1-(3-thienyl)cyclohexanecarbonyl acid;

2-methyl-1-(3-thienyl)cyclohexanecarboxylic;

2-methyl-1-(3-thienyl)cyclohexylamine;

2-ethyl-1-(2-thienyl)cyclohexanecarbonitrile;

2-propyl-1-(2-thienyl)cyclohexanecarbonitrile;

2-benzyl-1-(2-thienyl)cyclohexanecarbonitrile;

2-phenyl-1-(2-thienyl)cyclohexanecarbonitrile.

3. The method of obtaining compounds of General formula I, as described in one of paragraphs. 1 or 2, where R represents ceanorhaditis or-CO(A), as specified in paragraph 1, characterized in that the compound of General formula (1)

R CH2R,

where R and R' have the meanings specified in paragraph 1,

subjected to interaction with the compound of General formula (2)


4. The method according to p. 3 obtain the compounds of formula I in the form of essentially pure enantiomers, characterized in that the obtained in racemic form of the compound of formula I is separated into the enantiomers.

5. Compounds of General formula (I) under item 1 or 2 as intermediate products for the synthesis of teenillegal derivatives and, more specifically, cyclic (tamilsexy)amines.

6. The compound of the formula (2) as specified in paragraph 3, in which Y and Y' is halogen, in racemic form as intermediate products in the synthesis of compounds of formula I on p. 1.

 

Same patents:

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

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The invention relates to the field of chlorinated organic synthesis, in particular, to a method of obtaining hexachlorethane, which is used in the process of casting aluminum parts

The invention relates to the chlorination of paraffin

The invention relates to techniques for the chlorination of paraffin hydrocarbons with gaseous chlorine
The invention relates to a technology for organochlorine products, namely the method for producing a solid chloroparaffin brand HP-1100, used as additives to polymeric materials to reduce their Flammability

The invention relates to the production of tertiary butyl chloride, used as intermediate in organic synthesis
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The invention relates to the field of synthesis of halide Akilov, which are used as solvents and as intermediates in the industries of organic synthesis, for example in the synthesis of CHLOROSILANES

The invention relates to methods of chlorination of paraffins, widely used in polymer compositions as plasticizers in the production of building materials, paints and varnishes, synthetic films and leathers, rubber industry, as well as ontamarama additives to various polymers
The invention relates to methods for monochloramine of primary alcohols

FIELD: chemical technology.

SUBSTANCE: invention relates to technology manufacturing halide-substituted hydrocarbons, in particular, to stabilization of halogenated paraffins that are used as plasticizers, antipyrenes and special additives for polymeric materials and rubber mixtures, and in leather industry and in manufacturing depressants and lubricants also. Method is carried out by addition of stabilizing system comprising epoxy-compound and chelate compound forming chelate with iron ions. Stabilizing system comprises additionally acceptor of hydrogen chloride as a stabilizing agent that represents aliphatic carboxylic acid ketene comprising carbon number in chain in the ranges (C10-C23) and alkaline-earth metal of the 2-d group of periodic system in the following ratio of components as measured for the parent halogenated paraffin, wt.-%: chelate compound, 0.03-0.50; acceptor of hydrogen chloride as a stabilizing agent, 0.05-0.30; epoxy-compound, 0.20-0.80. Addition of indicated components of stabilizing system to halogenated paraffin is carried out simultaneously or successively at temperature in the ranges 40-90oC. Stabilizing system can comprise additionally also antioxidant - a stabilizing agent of phenol type representing sterically hindered di- or trialkylphenol or its derivative, or their mixtures taken in the mount 0.01-0.15 wt.-%. Addition of indicated antioxidant - stabilizing agent is carried out before blowing or steaming acid mixtures at temperature in the ranges 40-90oC in common or separately with chelate compound. Halogenated paraffin represents chlorinated paraffin with mass part of chlorine in the ranges 12-75%. Invention provides enhancing quality of stabilized halogenated paraffins by indices "color index" and "mass part of acids", reducing consumption norm of epoxy-compound.

EFFECT: improved stabilizing method.

8 cl, 1 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to manufacturing chloro-containing hydrocarbons, in particular, tert.-butyl chloride used for preparing addition agents and as activator for dehydrogenation catalysts. Method for preparing involves interaction gaseous isobutylene and hydrogen chloride in the presence of catalyst in the amount 0.02-0.3 wt.-% of parent reagents mass. Water is used as a catalyst. Process is carried out at volume rate of feeding reagents from 1400 h-1 to 1500 h-1, at temperature from 0oC to -5oC and in the mole ratio isobutylene : hydrogen chloride = (1.01-1.015):1 in the bubbling reactor. Method provides elevating yield of tert.-butyl chloride up to 99.2-99.5 wt.-%.

EFFECT: improved preparing method, enhanced yield.

2 cl, 1 tbl, 4 ex

FIELD: industrial organic synthesis.

SUBSTANCE: invention is dealing with production of chlorohydrocarbons exhibiting plasticizing properties in polymer compositions in production of synthetic building materials, varnishes and paints, artificial films and leathers, in rubber industry, and as fire-retardant additives in polymers. Process comprises chlorination of waste obtained in production of C14-C32 fraction by ethylene-α-olefin oligomerization. Chlorination is accomplished in two steps: addition chlorination at 35-55°C followed by substitution chlorination at 40-105°C. Chlorohydrocarbons thus obtained can, in particular, be used as secondary plasticizer in polyvinylchloride compositions.

EFFECT: reduced expenses due to using production waste.

4 tbl, 30 ex

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