Dimethyl(3-arival-3-enyl)amino compounds and methods for their production

 

(57) Abstract:

Describes new compounds - dimethyl(3-arival-3-enyl)amino compounds of the formula I, in which R1is C1-C5-alkyl, a R2means N or C1-C5-alkyl, or R1and R2both together represent - (CH2)2-4-, -(CH2)2-CHR7or - CH2-CHR7- CH2-, R3means N or C1-C5-alkyl, R4means H, HE, C1-C4-alkyl, C1-C4-alkyl, OR8, CF3, R5represents H, HE, C1-C4-alkyl, -O-C1-C4-alkyl, CHF2, CF3, OR8and R6means H, HE, C1-C4-alkyl, -O - C1-C4-alkyl, CF3, OR8provided that two of the radicals R4, R5or R6are H, or R4and R5both together means - CH=C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OR10)= CH-, provided that R4is H, R7means C1-C8-alkyl, R8means CO6H4-R11, R9means N or C1-C4-alkyl, R10means N, R11mean OS(O)-C1-C is tomarow or racemates, provided that the exception is the racemate of compounds of formula I in which R1and R2both together represent -(CH2)3-, R3, R4and R3mean N and R5is OCH3. The compounds possess analgesic activity. Describes how they are received. 3 S. and 3 C.p. f-crystals, 1 table.

The present invention relates to dimethyl(3-arival - 3-enyl)amino compounds, method of their production and to the use of these compounds for medicines.

Treatment of chronic and nechanicky painful States plays in medicine important role. Currently, worldwide there is a great need for more and not only due to the use of opioid drugs are highly effective obezbolivajuschem treatment. The urgent need to implement practical measures targeted, taking into account individual patient treatment of chronic and nechanicky painful conditions, and must be taken into account successful and satisfactory for patients treating their pain, is reflected in a recent numerous scientific publications on the application is for many years for pain treatment, although they cause a number of side effects, such as an irresistible craving and mental dependency, depression, breathing, inhibitory effects on the gastro-intestinal tract and constipation. For this reason, their use is permissible only when proper precautions, in particular the special regulations, especially in cases, for example, when drugs are prescribed for a long period of time or in high dosage (see Goodman, Gilman's "The Pharmacological Basis of Therapeutics", published by Pergamon Press, new York, 1990).

Tramadolhydrochlorid, he (1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol, hydrochloride, is among the main effective analgesic funds special place because it is an active substance has a strong analgesic effect without causing unlike opioids known side effects (see Journ. Pharmacol. Exptl. Ther. 267, 331 (1993)). Tramadol is a racemate and consists of equal amounts of (+)-and (-)-enantiomers. In vivo this active substance forms a metabolite O-desmethyltramadol, also presented in the form of a mixture of enantiomers. Studies have shown that both enantiomers of tramadol and enantiomers of metabolites is built in the framework of the invention, the task consisted in the development and creation of analgesic action of substances, designed for the treatment of severe pain and do not cause any side effects typical of opioids. In addition, the created substance were not required to have properties conducive as it is observed in some cases during treatment with tramadol, the manifestation of side effects, such as nausea and vomiting.

It was found that the requirements set forth in the creation of new substances that meet certain dimethyl(3-arival-3-enyl)amines. These substances differ a pronounced analgesic effect, significantly higher than its effectiveness tramadol.

The subject of the invention in accordance with this are the dimethyl(3-arival-3-enyl)amino compounds of the formula I

< / BR>
in which R1is C1-C5the alkyl, a R2means H or C1-C5alkyl, or R1and R2both together represent -(CH2)2-4-, -(CH2)2-CHR7or-CH2- CH7R-CH2-, R3means H or C1-C5alkyl, R4means H, HE, C1-C4alkyl, O-C1-C4alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8, R5represents H, HE, C1-C4alkyl, O-C1-Calkyl, O-C1-C4alkyl, O-benzyl, CF3, O-CF3, Cl, F or OR8provided that two of the radicals R4, R5or R6are H, or R4and R5both together means-CH=C(R9)-O - or-CH=C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OR10)=CH-, provided that R4is H, R7means C1-C8alkyl, C3-C8cycloalkyl, O-C1-C4alkyl, O-benzyl, CF3, Cl or F, R8means CO-C1-C5alkyl, PO(O-C1-C4alkyl)2, CO-C6H4-R11, CO(O-C1-C5alkyl), CO-CHR12-OTHER13, CO-NH-C6H3-(R14)2or represents unsubstituted or substituted meridiabuy, teenlove, tiazolului or phenyl group,9means H or C1-C4alkyl, R10means H or C1-C3alkyl, R11means OC(O)-C1-C3alkyl in the ortho - position or CH2-N(R15)2in the meta - or para-position, where R15is C1-C4the alkyl or both radicals R15together with N form a 4-morpholinyl radical, R12and R13are identical or different and denote H, C1-C14means H, HE, C1-C7alkyl, O-C1-C7alkyl, phenyl, O-aryl, CF3, Cl or F, provided that both of the radical R14are identical or different, in the form of their bases and/or salts of physiologically acceptable acids, in the form of enantiomers or racemates, provided that the exception is the racemate of compounds of formula I in which R1and R2both together represent -(CH2)3-, R3, R4and R6mean H and R5is OCH3.

The preferred dimethyl(3-arival-3-enyl)amino compounds correspond to the formula I, where R1is C1-C3the alkyl, and R2means H or C1-C3alkyl, or R1and R2both together represent -(CH2)2-4- or -(CH2)2-CHR7, R3means H or C1-C3alkyl, R4means H, HE, CF3, Cl, F or OR8, R5represents H, HE, C1-C4alkyl, O-C1-C4alkyl, O-benzyl, CHF2, CF3, Cl, F or OR8and R6means H, HE, O-C1-C4alkyl, O-benzyl, CF3, Cl, F or OR8provided that two of the radicals R4, R5or R6are H, or R4and RR6both together means-CH=CH-C(OR10)=CH-, provided that R4is H, and R7means C1-C4alkyl, CF3, Cl or F.

Especially preferred dimethyl(3-arival-3-enyl)amino compounds of the formula I, in which R1is CH3or C3H7and R2represents H, CH3or CH2CH3or R1and R2both together means -(CH2)2-3- or -(CH2)2-CHR7, R3means H, CH3or CH2CH3, R4means H or HE, R5means H, HE, OCH3, CHF2or OR8and R6means H, HE or CH3provided that two of the radicals R4, R5or R6are H, or R4and R5both together represent-CH= C(CH3)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OH)=CH-, provided that R4is H, and R8is a CO-C6H4-R11where R11means OC(O)-C1-C3alkyl in the ortho-position.

The most preferred are dimethyl(3-arival-3-enyl) amino compounds, where R1is CH3and R2means H or CH3or R1and R2SUB>, R4means H, R5means HE or OR8, R6is H and R8is a CO-C6H4-R11where R11means OC(O) -CH3in the ortho-position.

Another object of the invention is a method of producing dimethyl(3-arival-3-enyl)amino compounds of the formula I, in which R1is C1-C5the alkyl, and R2means H or C1-C5alkyl, or R1and R2both together represent -(CH2)2-4-, -(CH2)2-CHR7or-CH2-CHR7-CH2-, R3means H or C1-C5alkyl, R4means H, C1-C4alkyl, O-C1-C4alkyl, O-benzyl, CF3, O-CF3, Cl or F, R5represents H, C1-C4alkyl, O-C1-C4alkyl, O-benzyl, CHF2, CF3, O-CF3, Cl or F, and R6means H, C1-C4alkyl, O-C1-C4alkyl, O-benzyl, CF3, O-CF3, Cl or F, provided that two of the radicals R4, R5or R6are H, or R4and R5both together means-CH=C(R9)-O - or-CH=C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OR10)=CH-, provided that R is Kil, O-benzyl, CF3, Cl or F, R9means H or C1-C4alkyl, and R10means H or C1-C3alkyl, with the exception of the compounds of formula I in which R1and R2both together means -(CH2)3-, R3, R4and R6are H and R5represents OCH3, characterized in that dimetilaminometil formula II

< / BR>
interaction with the ORGANOMETALLIC compound of formula III

< / BR>
in which Z denotes MgCl, MgBr, MgI or Li, transform into a tertiary alcohol of the formula IV

< / BR>
then dehydration with the obtained compounds of formula I.

Interaction-dimetilaminokhalkona connection Grignard reagent of the formula III in which Z denotes MgCl, MgBr or MgI, or with an organolithium compound of formula III can be carried out in simple aliphatic ether, for example diethyl ether and/or tetrahydrofuran at temperatures from -70oC to +60oC. Interaction with the connection of the Grignard reagent may be conducted with or without additives additives Explorer reaction, preferably 1,2-dibromethane. Organolithium compounds of the formula III can be obtained by the coupling of compounds of formula III in which Z denotes Cl, Br or J, the thou of the formula IV can be degidratiruth using acids, first of all, formic acid or hydrochloric acid, at temperatures in the range of 0oC to 100oC.

Another object of the invention is a method of producing dimethyl(3-arival-3-enyl)amino compounds of the formula I, in which R1is C1-C5the alkyl, and R2means H or C1-C5alkyl, or R1and R2both together represent -(CH2)2-4-, -(CH2)2-CHR7or-CH2-CHR7-CH2, R3means H or C1-C5alkyl, one of the radicals R4, R5or R6IT means, while the two other radicals are H, R7means C1-C8alkyl, C3-C8cycloalkyl, O-C1-C4alkyl, O-benzyl, CF3, Cl or F, wherein the compound of formula I in which one of the radicals R4, R5or R6means O-CH3and both of the other radicals are H, is subjected to the interaction with the hydride diisobutylaluminum or a compound of the formula I in which one of the radicals R4, R5or R6mean O-benzyl, and the other two radicals are H, subjected to recovery dibenzylamine.

The interaction of dimethyl(3-arival-3-enyl)amino compounds surahs in the range 60oC to 130oC (see Synthesis 1975. 617; DE 2409990, DE 2409991; Chem. Abstr. 84, 59862 1974)).

Restorative dibenzylamine the compounds of formula I according to the invention, in which one of the radicals R4, R5or R6means O-benzyl, can be carried out in the presence of platinum or palladium on a carrier, such as charcoal, in the presence of hydrogen in a solvent, such as acetic acid or C1-C4Akilova alcohol, at a pressure of from 1 to 100 bar and in the temperature range of 20oC to 100oC.

Dimethyl(3-arival-3-enyl)amino compounds of General formula I, in which one or more of the aromatic substituents 4, R5and R6mean OR8and OR8represents a phosphate, carbonate, urethane, carboxylate or aryloxy any heteroepitaxy can be obtained by interaction of the corresponding dimethyl[3-(hydroxyphenyl)but-3 - enyl]the amino compounds of the formula I, in which R4, R5and/or R6mean IT-group, in the form of a salt of an alkali metal with dialkylphosphate, alkylchlorosilanes, aryl - or heteroarylboronic, the acid chloride of carboxylic acid or aryl - or heteroarylboronic. These reactions the ri temperatures in the range -15oC to +110oC (see Drugs of the Future 16, 443 (1991); Journ. Med. Chem. 30, 2008 (1989) and 32, 2503 (1989); Journ. Org. Chem. 43, 4797 (1978); Tetrahedron Lett. 1977. 1571; Journ. Pharm. Sci. 57, 774 (1968)). Interaction with the aryl-, respectively heteroarylboronic carried out with the addition of copper powder and/or copper halide (1) acting as a catalyst.

Dimethyl(3-arival-3-enyl)amino compounds of the formula I, in which OR8represents-aminocarboxylate group, can be obtained by interaction of the corresponding dimethyl [3-(hydroxyphenyl)but-3-enyl]the amino compounds of the formula I, in which R4, R5and/or R6means OH-group, with the corresponding 2-tert-butoxycarbonylamino acid using triethylamine and reagent combinations, such as hexaphosphate benzotriazol-1-electroparadise, in a solvent, such as dichloromethane.

Proposed according to the invention the compounds of formula I with physiologically acceptable acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric ciearly salt formation carried out preferably in a solvent, for example in diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone. To obtain hydrochloride can be used, in addition, trimethylchlorosilane in aqueous solution.

Proposed according to the invention compounds have a pronounced analgesic effect and toxicologically safe. You can apply them so as pharmaceutical active substances. The subject of the invention in accordance with this is the use of dimethyl(3-arival-3-enyl)amino compounds of the formula I as active substances in medicinal products, preferably as such in the analgesics.

Along with at least one of dimethyl(3-arival-3 - enyl)aminoguanidinium formula I drug according to the invention also contain carriers, fillers, solvents, diluents, dyes and/or binders. The choice of these auxiliary substances as well as the used amount depend on the route of administration of the medicinal product, i.e., designate whether its for oral, intravenous, intraperitoneal, intradermal, intramuscular, vnutripuzarnogo, buccal or topical administration, for example, when bleak, pills, capsules, granules, drops, medicines and syrups; for parenteral, local, and inhalation can be applied solutions, suspensions, easily reconstructed dry compositions, as well as aerosols. As examples preparative forms designed for percutaneous introduction, you can call connection according to the invention in a depot in a soluble form or in a plaster, optionally with the addition of tools to facilitate skin penetration. From the insertion oral route or through the skin preparative form release compounds according to the invention may be gradual.

Assigned to the patient an amount of active ingredients vary depending on the weight of the patient, method of administration, the indication and the severity of the disease. Usually prescribed dosage from 10 to 500 mg of at least one of dimethyl(3-arival-3-enyl)amino compounds of formula I.

Examples

Obtaining the compounds according to the invention

The term "simple ether" means diethyl ether.

As stationary phase in chromatography columns used silica gel 60 (0,040-0,063 mm) of the firm E. Merck, Darmstadt.

Chromatographic analyses were performed by means of plates for which were carried out on a column Chiracel OD company Daicel Chemical Industries, LTD.

Ratio in mixtures of eluents for all chromatographic studies indicated in volume (volume/volume).

Example 1

(Z)-(RS)-[3-(methoxyphenyl)-2-methylpent-3-enyl] dimethylamine, hydrochloride (1)

Stage 1

(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, hydrochloride (2)

of 27.0 g (1,11 mol) of magnesium shavings were mixed in 150 ml of tetrahydrofuran and was added dropwise 207,6 g (1,11 mole) 1-bromo-3-methoxybenzene dissolved in 400 ml of tetrahydrofuran. It was further heated for one hour under reflux and then cooled to a temperature of 5-10oC. At this temperature, was added dropwise 128,30 g (0,89 mol) of (RS)-1 - dimethylamino-2-methylpentan-3-one, dissolved in 400 ml of tetrahydrofuran. The reaction mixture was left to stand, then re-cooled to a temperature of 5-10oC. After adding 300 ml of 20 wt.%-aqueous ammonium chloride solution was diluted with 400 ml of a simple ester. After separation of the phases were extracted twice by a simple ether, dried over sodium sulfate and the solvent was removed by distillation. The obtained residue was dissolved in 3.2 liters of 2-butanone and mixed with 120,60 g (1,11 mole) of trimethylchlorosilane and 20 ml of water. In this way got to 121.5 g of the hydrochloride (2) (38% of theory is methylamine, hydrochloride (1)

200 g (0,69 mole) of the hydrochloride (2) was dissolved in one liter of concentrated hydrochloric acid and left to stand at room temperature. Hydrochloric acid was removed by distillation under vacuum. The residue was dissolved in 1 l of ice water and 10-molar sodium hydroxide was set to pH 13. After simple extraction with ether, drying of the organic extract and removal by distillation of solvent received 162 g of crude product, which was purified by recrystallization. The result was 79 g (42% of theory) of hydrochloride (1) with a melting point 169-170oC.

Example 2

(Z)-(RS)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (3)

1.6 l of 20 wt.%-aqueous solution of hydride diisobutylaluminum in toluene at room temperature was added dropwise 182 g (Z)-(RS)-[3-(3-methoxyphenyl)-2-methylpent-3-enyl] dimethylamine dissolved in 360 ml of toluene. Then for 11 h was heated under reflux. After cooling to 0oC was added dropwise while cooling to 450 ml of ethanol. Next was stirred for 15 min and diluted with 1 l of toluene. Then, when the cooling was added dropwise to 450 ml of a mixture of ethanol-water (1:1). After stirring for one hour at room temperature, dropped the houtem received 167 g (97.6% of theory) of the crude base, which was dissolved in 1,67 l of acetone and mixed with 65 ml of concentrated hydrochloric acid. In this way, in the form of crystals were 152 g (76% of theory) of hydrochloride (3) with a melting point 161-162oC.

Example 3

The enantiomers of the compound (3):

(+)-(Z)-(S)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (+3) and

(-)-(Z)-(R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (-3)

From the obtained analogously to example 2 hydrochloride (3) using dichlormethane solution of sodium bicarbonate was released basis. After drying the dichloromethane solution kept under vacuum. Then the racemate was separated by chiral ghud-hand column. From the resulting enantiomers interaction with concentrated hydrochloric acid in acetone was allocated hydrochloride with a melting point 166-167oC.

(+3): Yield: 42% of theory

[]KDT= +3.6Vo(C=1,04; methanol)

(-3): Yield: 44% of theory

[]KDT= -3,6o(C=1,04; methanol).

Example 4

3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenyl ester (Z)-(RS)-2-acetoxybenzoic acid, hydrochloride (4)

From the obtained analogously to example 2 hydrochloride (3) using dichloromethane-water mind. of 0.67 g (3.0 mmole) obtained was dissolved in 7 ml of dry dichloromethane and at room temperature was mixed with 0.6 g (3,24 mmole) of 2-acetylbenzoate dissolved in 3 ml of dry dichloromethane. After 20 hours stirring at room temperature the reaction mixture was mixed with 20 ml of a solution of sodium bicarbonate and the aqueous phase was extracted twice with 10 ml dichloromethane. The organic phases were combined and dried over sodium sulfate. After removal by distillation of the solvent was obtained 1.1 g of a crude mixture, which was applied on a column Packed with silica gel. After elution of simple ether got to 0.68 g of base, from which with the help of water trimethylchlorosilane in a simple broadcast received of 0.68 g (54% of theory) of hydrochloride (4) with a melting point 86-88oC.

Example 5

(E)-(RS)-[3-(3-methoxyphenyl)-2-methylpent-3-enyl] dimethylamine, hydrochloride (5)

75 g (of 0.26 mole) of (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl) -2-methylpentan-3-ol, hydrochloride (1) of example 1 (stage 1), was dissolved in one liter of concentrated formic acid and heated for 2 h under reflux. Then formic acid kept in a water-jet vacuum, the residue was dissolved in ice water and mixed with caustic natro the crude base ((Z)-isomer (2): (E)-isomer (5) = 6:4). The crude base was applied on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol = 7:1 received 20 g of base, from which with the help of water trimethylchlorosilane in 2-butanone got to 18.4 g (26% of theory) of hydrochloride (5) with a melting point 139-140oC.

Example 6

(E)-(RS)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (6)

From the compound (5) obtained analogously to example 5, using dichloromethane-caustic soda released the substrate and after drying a solution of dichloromethane was removed by distillation. From the obtained base conditions described in example 2, received hydrochloride (6) yield 73% of theory and the melting point 80oC.

Example 7

The enantiomers of the compound (6):

(+)-(E)-(R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (+6) and

(-)-(E)-(S)-3-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (-6)

From the obtained analogously to example 6 hydrochloride (6) using dichloromethane-aqueous solution of sodium bicarbonate was released basis. After drying the dichloromethane solution kept under vacuum. Then the racemate was separated by chiral ghud-hand column. From the resulting enantiomers interaction with con ptx2">

(+6): Yield: 42% of theory

[]KDT= +36,3o(C=0,96; methanol)

(-6): Yield: 44% of theory

[]KDT= -33,7 (=1,07; methanol).

Example 8

(Z)-(RS)-4-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (7)

Stage 1

(Z)-(RS)-[3-(4-methoxyphenyl)-2-methylpent-3-enyl]dimethylamine (8)

On the basis of (RS)-1-dimethylamino-2-methylpentan-3-one and 1-bromo-4 - methoxybenzene, under the conditions described in example 1 (stage 1), obtained (2RS,3RS)-1-dimethylamino-3-(4-methoxyphenyl)-2 - methylpentan-3-ol, hydrochloride, with a yield of 44% and a melting point of 188-189oC, which under the conditions described in example 1 (stage 2), using concentrated hydrochloric acid was transferred into the (Z)-(RS)-[3-(4-methoxyphenyl)-2-methylpent-3-enyl] dimethylamine (8). Compound (8) was obtained as a pale yellow oil with a yield of 46%.

Stage 2

(Z)-(RS)-4-[1-(2-dimethylamino-1-methylethyl)propenyl] phenol hydrochloride (7)

From the obtained in stage 1 of the base conditions described in example 2, received hydrochloride (7) yield 79% of theory and the melting point 203oC.

Example 9

(Z)-(RS)-dimethyl(2-methyl-3-m-tailment-3 - enyl)amine, hydrochloride (9)

On the basis of (RS)-1-dimethylamino-2-methylpentan-3-one and 3-bromo rochloride, with the release of 24% and a melting point 154-155oC, which under the conditions described in example 1 (stage 2), using concentrated hydrochloric acid was transferred into the (Z)-(RS)-dimethyl(2-methyl-3-m-tailment-3-enyl)amine, hydrochloride (9). Compound (9) was obtained with the yield of 36% (in terms of used alcohol) and a melting point of 172oC.

Example 10

(E)-(RS)-dimethyl(2-methyl-3-m-tailment-3-enyl)amine, hydrochloride (10)

On the basis of (2RS, 3RS)-1-dimethylamino-2-methyl-3-(m-tolyl)pentane-3-ol, hydrochloride is obtained analogously to example 9, in the conditions described in example 5, the obtained hydrochloride (10) with the release of 36% and a melting point 153oC.

Example 11

(Z)-(RS)-[3-(3-deformational)-2-methylpent-3-enyl] dimethylamine, hydrochloride (11)

Stage 1

(2RS, 3RS)-3-(3-deformational)-1-dimethylamino-2-methylpentan - 3-ol, hydrochloride (12)

7.0 g (34 mmole) 1-bromo-Z-deformational obtained from Z-bromo-benzaldehyde and diethylaminosulfur according to Org. React. 35. 513 (1988), was dissolved in 110 ml of dry tetrahydrofuran and cooled to -75oC. After adding 34 mmol of a 1.6 molar solution of n-utility in hexane was stirred for one hour at -75oC. Then was added dropwise 4.8 g (34 mmole) of (2RS)-ect was heated to room temperature.

For further processing while cooling with ice bath, was added dropwise 65 ml of 5% hydrochloric acid so that the internal temperature did not exceed 15oC. After separation of the phases the organic phase was extracted with 40 ml of 5% hydrochloric acid. The combined aqueous phase was twice washed with 50 ml of a simple ester. To free base was mixed with concentrated sodium hydroxide and was extracted with dichloromethane. In this way received 7.8 g of crude product, which was applied on a column Packed with silica gel. After elution in the system ethyl ester acetic acid-methanol = 1:1 received 4,89 g base, from which with the help of water trimethylchlorosilane in 2-butanone was obtained 4.6 g (44% of theory) of hydrochloride (12) with a melting point 194 - 195oC.

Stage 2

(Z)-(RS)-[3-(3-deformational)-2-methylpent-3-enyl] dimethylamine, hydrochloride (11)

10 g (32 mmole) of (2RS,3RS)-3-(3-deformational)-1-dimethylamino-2-methylpentan-3-ol, hydrochloride (12) from stage 1, was dissolved in 150 ml of concentrated formic acid for 2 h was heated under reflux. Then formic acid kept in a water-jet vacuum, the residue was dissolved in ice water and mixed with caustic soda - PR is th reason, which was applied on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol=7:1 was obtained 3.0 g of base, from which with the help of water trimethylchlorosilane in 2-butanone was obtained 2.3 g (24% of theory) of hydrochloride (11)with a melting point 160-161oC.

Example 12

(Z)-(RS)-6-[1-(2-dimethylamino-1-methylethyl)propenyl] naphthas-2-ol, hydrochloride (13)

From (1RS, 2RS)-6-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) naphthas-2-ol, hydrochloride obtained according to Chirality 6, 389 (1994), under the conditions described in example 1 (stage 2), received hydrochloride (13) 39% yield and melting point 207-208oC.

Example 13

(E)-(RS)-[3-(3-methoxyphenyl) -2-metrex-3 - enyl] dimethylamine, hydrochloride (14) and

(Z)-(RS)-[3-(3-methoxyphenyl)-2-metrex-3-enyl] dimethylamine, hydrochloride (15)

On the basis of (2RS)-3-dimethylamino-1-(3-methoxyphenyl)-2-methylpropan-1-it 1-bromopropane, under the conditions described in example 1 (stage 1), using a simple ether as solvent obtained (2RS,3SR)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylhexan-3-ol, hydrochloride (16), with a yield of 81% and a melting point 131-132oC.

30 g (0.1 mol) of the compound (16) analogously to example 5 were subjected to interaction with 450 m)-isomers, served on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol = 7:1 received 7 g of the base (E)-compounds (14) and 17 g of the base (Z) connection (15). Both the base with water trimethylchlorosilane in 2-butanone were translated into hydrochloride.

(14): Yield: 5.9 g (21% of theory), tPL: 154oC

(15): Output: 15,8 g (56% of theory), tPL: 110-112oC.

Example 14

(E)-(RS)-3-[1-(2-dimethylamino-1-methylethyl)buta-1-enyl] phenol hydrochloride (17)

From the compound (14) obtained analogously to example 13, using dichloromethane-caustic soda released the substrate and after drying a solution of dichloromethane was removed by distillation. From the thus obtained base under the conditions described in example 2, received hydrochloride (17) yield 86% of theory and the melting point of 214oC.

Example 15

(Z)-(RS)-3-[1-(2-dimethylamino-1-methylethyl)buta-1-enyl] phenol hydrochloride (18)

From the compound (15) obtained analogously to example 13, using dichloromethane-caustic soda released the substrate and after drying a solution of dichloromethane was removed by distillation. From the thus obtained base under the conditions described in example 2, received hydrochloride (18)yield 86% of theory and t is min, hydrochloride (19)

On the basis of (RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl) pentane-1-it and under the conditions, in the conditions described in example 1 (stage 1), using a simple ether as solvent obtained (2RS,3SR)-3-dimethylamino-methyl-2- (3-methoxyphenyl)hexane-2-ol, hydrochloride (20), with a yield of 76% and a melting point of 137-138oC.

30 g (0.1 mol) of the compound (20) analogously to example 5 were subjected to interaction with 300 ml of concentrated formic acid. The resulting crude base was applied on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol = 7:1 received 24 g of base, from which with the help of water trimethylchlorosilane in 2-butanone received 23.1 g (74% of theory) of hydrochloride (19) with a melting point of 120-121oC.

Example 17

(RS)-3-[1-(2-dimethylamino-1-methylethyl)vinyl]phenol hydrochloride (21)

Stage 1

(1RS,2SR)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol hydrochloride (22)

On the basis of (RS)-3-dimethylamino-1-(3-methoxyphenyl) -2-methylpropan-1-it and under the conditions, in the conditions described in example 1 (stage 1), using a simple ether as solvent obtained (2RS,3SR)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutane - 2-ol, was hydrochloridetramadol basis. After drying the dichloromethane solution kept under vacuum. of 23.7 g (0.1 mole) of the base as in example 2 was subjected to interaction with hydride diisobutylaluminum. In this way got to 18.5 g (71% of theory) of hydrochloride (22) with a melting point 183-184oC.

Stage 2

(RS)-3-[1-(2-dimethylamino-1-methylethyl)vinyl] phenol hydrochloride (21)

10 g (37 mmol) of hydrochloride (22) from stage 1 was dissolved in 150 ml of concentrated formic acid for 2 h was heated under reflux. Then formic acid kept in a water-jet vacuum, the residue was dissolved in ice water and mixed with caustic soda - simple ether. After drying the organic phase and removal by distillation of the solvent, got 9.1 g of crude base from which with the help of concentrated hydrochloric acid in acetone received 7.5 g (83% of theory) of hydrochloride (21) with a melting point 228 - 230oC.

Example 18

(RS)-3-[1-(2-dimethylamino-1-methylethyl)-2-methylpropenyl] phenol hydrochloride (24)

Stage 1

(RS)-[3-(3-methoxyphenyl)-2,4-dimethylpent-3-enyl]dimethylamine (25)

On the basis of (RS)-1-dimethylamino-2,4-dimethylpentan-3-one and 1-bromo-3-methoxybenzoyl, under the conditions described in example 1 (stage 1), obtained (2RS, 3RS)-1-dimetilan the tx2">

30 g (0.1 mol) of the compound (26) analogously to example 5 were subjected to interaction with 450 ml of concentrated formic acid. The resulting crude base was applied on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol = 7:1 received 19 g of the base (77% of theory) as a light yellow viscous oil.

Stage 2

(RS)-3-[1-(2-dimethylamino-1-methylethyl)-2-methylpropenyl] phenol hydrochloride (24)

From the obtained in stage 1 of the base conditions described in example 2, received hydrochloride (24) to yield 84% of theory and the melting point of 176-177oC.

Example 19

(RS)-dimethyl[2-(4-triptoreline)cyclopent - 2-animetal]amine, hydrochloride (27)

Under the conditions described in example 1 (stage 1) were subjected to interaction (RS)-2-dimethylaminomethylphenol and 1-bromo-4-cryptomaterial. 30 g of the obtained crude product was applied on a column Packed with silica gel. After elution in the system ethyl ester acetic acid-methanol=5:1 was obtained 11.6 g of the base, which with the help of water trimethylchlorosilane in 2-butanone were transferred to 12.0 g (21% of theory) of (1RS,2RS)-2-dimethylaminomethyl-1-(4-triptoreline)Cyclopentanol, hydrochloride (28), with the temperature of prawle the ml of concentrated formic acid. The resulting crude base was applied on a column Packed with silica gel. After elution in the system diisopropyl ether-methanol = 7:1 received 9.6 g of a Foundation that using water trimethylchlorosilane in 2-butanone translated 8.9 g (29% of theory) of hydrochloride (27) with a melting point 219-220oC.

Example 20

The enantiomers of the compound (27):

(+)-(S)-dimethyl [2-(4-triptoreline)cyclopent-2 - animetal] amine, hydrochloride (+27) and

(-)-(R)-dimethyl [2-(4-triptoreline)cyclopent-2 - animetal] amine, hydrochloride (-27)

From the compound (27) using dichloromethane-caustic soda released basis. After drying the dichloromethane solution kept under vacuum. The racemate was then separated on chiral ghud-hand column. From the resulting enantiomers interaction with concentrated hydrochloric acid in acetone received hydrochloride with a melting point 244-246oC.

(+27): Yield: 42% of theory

[]KDT= +33,8o(C=1.00; methanol)

(-27): Yield: 44% of theory

[]KDT= -34,3o(C=1,06; methanol).

Example 21

(RS)-2-(6-dimethylaminomethylene-1-enyl)phenol hydrochloride (29)

On the basis of (RS)-2-dimethylaminomethylene and 1-postvaricella obtained (1RS,2RS)-2-dimethylaminomethyl-1-(2-methoxyphenyl)cyclohexanol, hydrochloride (30), with a yield of 47%.

From the compound (30) using dichloromethane-caustic soda released basis. After drying the dichloromethane solution kept under vacuum. 30,0 g (0.1 mole) of the base as in example 2 was subjected to interaction with hydride diisobutylaluminum. In this way received an increase of 22.7 g (78% of theory) of (1RS,2RS)-2-(2-dimethylaminomethyl-1 - hydroxycyclohexyl)phenol, hydrochloride (31), with a melting point 168-170oC.

of 28.6 g (0.1 mol) of the compound (31) analogously to example 5 were subjected to interaction with 450 ml of concentrated formic acid. The resulting crude base was applied on a column Packed with silica gel, and was suirable in the system diisopropyl ether-methanol = 7:1. The result was 21 g of base, from which with the help of concentrated hydrochloric acid in acetone received 18.6 g (69% of theory) of hydrochloride (29) with a melting point of 168oC.

Example 22

The enantiomers of compound (29):

(-)-(R)-2-(6-dimethylaminomethylene-1-enyl)phenol hydrochloride (-29) and

(+)-(S)-2-(6-dimethylaminomethylene-1-enyl)phenol hydrochloride (+29)

From the compound (29) using dichloromethane-aqueous solution of sodium bicarbonate was released basis. After drying rastvorov interaction with concentrated hydrochloric acid in acetone was allocated hydrochloride with a melting point 271-272oC.

(+29): Yield: 43% of theory

[]KDT= +24,1o(C=0,96; methanol)

(-29): Yield: 44% of theory

[]KDT= -23,5o(C=0,94; methanol).

Example 23

(RS)-dimethyl[2-(4-triptoreline)cyclohex-2-animetal] amine, hydrochloride (32)

(RS)-2-dimethylaminomethylene and 1-bromo-4-cryptomaterial were subjected to interaction under the conditions described in example 1 (stage 1). 30 g of the obtained crude product was applied on a column Packed with silica gel. After elution in the system ethyl ester acetic acid-methanol = 5:1 got to 18.9 g of the base, which with the help of water trimethylchlorosilane in 2 - butanone translated in 16.4 g (37% of theory) of (1RS,2RS)-2-dimethylaminomethyl-1-(4-triptoreline) cyclohexanol, hydrochloride (33), with a melting point 234oC.

33,7 g (0.1 mol) of hydrochloride (33) analogously to example 5 were subjected to interaction with 450 ml of concentrated formic acid. The resulting crude base was applied on a column Packed with silica gel, and was suirable in the system diisopropyl ether-methanol = 7:1. Thus obtained 12.3 g of a Foundation that using water trimethylchlorosilane in 2-butanone were transferred to 10.4 g (32.5% of theory]thiophene-4-yl)cyclohex-2 - animetal]amine, hydrochloride (34)

(RS)-2-dimethylaminomethylene and 4-bromo-2-methylbenzo [b] thiophene was subjected to interaction under the conditions described in example 1 (stage 1), using a simple ether as solvent and 1,2-dibromethane as conductor of the reaction. 25 g of the obtained crude product was applied on a column Packed with silica gel. After elution in the system ethyl ester acetic acid-methanol = 1:1 received of 12.6 g of a Foundation that using water trimethylchlorosilane in 2 - butanone were transferred to 10.4 g (29% of theory) of (1RS,2RS)-2 - dimethylaminomethyl-1-(2-methylbenzo[b]thiophene-4-yl)cyclohexanol, hydrochloride (35), with a melting point of 204oC.

34,0 g (0.1 mol) of hydrochloride (35) analogously to example 5 were subjected to interaction with 450 ml of concentrated formic acid. Thus obtained crude base (28.4 g) was applied on a column Packed with silica gel. After elution of simple ether obtained 17.5 G. of the base, which with the help of water trimethylchlorosilane in 2-butanone were transferred to 15.2 g (54.8% of theory) of hydrochloride (34) with a melting point 179-182oC.

Example 25

(-)-(3S,6R)-3-(6-dimethylaminomethyl-3-methylcyclohex-1 - enyl)phenol hydrochloride (-36) and

(+)-(3R, 6S)-3-(6-diml-1-(3 - methoxyphenyl)-5-methylcyclohexanol, hydrochloride (37)

95 ml (750 mmol) of 1-bromo-3-methoxybenzene was dissolved in 425 ml of dry tetrahydrofuran and cooled to -75oC. After adding 750 mmol of a 1.6 molar solution of n-utility in hexane was stirred for one hour at -75oC. Then was added dropwise 82 g (484 mmole) of (2RS,5SR)-2-dimethylaminomethyl-5-methylcyclohexanone series obtained from 3-methylcyclohexanone series, dimethylaminohydrolase and para-formaldehyde in glacial vinegar dissolved in 120 ml of dry tetrahydrofuran. For 2.5 h, the reaction mixture was heated to room temperature.

For further processing was added dropwise while cooling with ice bath 200 ml of water so that the internal temperature did not exceed 15oC. After separation of the phases the aqueous phase was extracted three times with 50 ml ethyl ester of acetic acid. The combined organic phases were dried over sodium sulfate. After removal by distillation of the solvent the residue was dissolved in 700 ml of acetone and mixed with water trimethylchlorosilane. At 4-5oC in the form of crystals fell 67 g (48% of theory) of hydrochloride (37) with a melting point 173-175oC.

Stage 2

The enantiomers of compound (37):

(+)-(1R, 2R,5S)-2-dimethylaminomethyl-1-(3-what titikaveka, hydrochloride (-37)

From the compound (37) using dichloromethane-caustic soda released basis. After drying the dichloromethane solution kept under vacuum. Then the racemate was separated by chiral ghud-hand column. From the resulting enantiomers interaction with water trimethylchlorosilane in 2 - butanone were isolated hydrochloride with a melting point of 151-153oC.

(+ 37): Yield 43% of theory

[]KDT= +36,4o(C=1,01; methanol).

(-37): Yield: 44% of theory

[]KDT= -37,7o(C= 1,01; methanol).

Stage 3

(-)-(1R, 4S)-[2-(3-methoxyphenyl)-4-methylcyclohex-2-animetal] dimethylamine, hydrochloride (-38) and

(+)-(1S, 4R)-[2-(3-methoxyphenyl)-4-methylcyclohex-2-animetal] dimethylamine, hydrochloride, (+38)

Methoxyamine (-37) and (+37) from stage 2 under the conditions described in example 5 were transferred to hydrochloride (+38) and (-38) to yield 87% of theory and the melting point of 122-123oC.

Stage 4

(-)-(3S,6R)-3-(6-dimethylaminomethyl-3-methylcyclohex-1 - enyl)phenol hydrochloride (-36) and

(+)-(3R,6S)-3-(6-dimethylaminomethyl-3-methylcyclohex-1-enyl) phenol, hydrochloride, (+36)

From the obtained in stage 3 of the grounds under the conditions described in example 2, the interaction with the hydride Hai is received hydrochloride (-36) and (36) yield 79% of theory and the melting point 131-133oC.

(-36): []KTD/= -75,5o(C=0,96; methanol)

(+36): []KDT= +77,7o(C=1,08; methanol).

Example 26

(-)-(R)-3-(6-dimethylaminomethylene-1-enyl)phenol hydrochloride (-39)

of 28.8 g (0.1 mole) of (+)-(1R,2R)-3-(2 - dimethylaminomethyl-1-hydroxycyclohexyl) phenol, hydrochloride, was dissolved in 450 ml of concentrated formic acid for 2 h was heated under reflux. Then formic acid kept in a water-jet vacuum and the residue using dichloromethane-aqueous solution of sodium carbonate was released base from which with the help of concentrated hydrochloric acid in acetone received 21.8 g (81,4% of theory) of hydrochloride (-39) with a melting point 216-217oC.

(-39): []KDT= -96,6o(C=1,04; methanol).

Example 27

(+)-(S)-3-(6-dimethylaminomethylene-1-enyl)phenol, hydrochloride, (+39)

Under the conditions described in example 26, of 28.8 g (0.1 mole) of (-)-(1S,2S)-3-(2-dimethylaminomethyl-1-hydroxycyclohexyl) phenol, hydrochloride, got 21.8 g (81,4% of theory) of hydrochloride (+39) with a melting point 216-217oC.

(+39): []KDT= +89,0 (=0,99; methanol).

Pharmacological issledovannosti were performed on mice in the test for pain, induced familienaam (modified method I. C. Hendershot and J. Forsaith, Journ. Pharmacol. Exp. Ther. 125, 237-240 (1959)). For these purposes, used of male NMRI mice weighing 25-30 g Groups of 10 animals each, designed to test a single dose of a substance, after 10 min after intravenous injection of the compounds according to the invention in a dosage of 0.3 ml/mouse were injected intraperitoneally with 0.02% aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; preparation of the solution with the addition of 5% ethanol and the extract in a water bath at 45oC). Experimental animals were placed singly in a special cell to monitor and using a push-button counter in intervals from 5 to 20 min after injection of finishinga counted the number of induced pain extensor movements (the so-called reaction to pain, i.e., the bowing of the body with stretching of the hind limbs). On the basis of dose-dependent decrease in the number of responses to pain compared with those of the tested simultaneously control groups, which did not enter the compounds according to the invention, by means of regression analysis (processing program Martens EDV Service, Eckental) was calculated values of the ED50reactions Bo is a pronounced analgesic effect, significantly superior in their effectiveness tramadol.

The results presented in the table.

1. Dimethyl(3-arival-3-enyl)amino compounds of the formula I

< / BR>
in which R1is1-C5-alkyl, and R2means N or1-C5-alkyl, or R1and R2both together represent -(CH2)2-4-, -(CH2)2-R7or-CH2-R7-CH2-;

R3means N or1-C5-alkyl;

R4means H, HE, C1-C4-alkyl, O-C1-C4-alkyl, CF3or OR8;

R5represents H, HE, C1-C4-alkyl, O-C1-C4-alkyl, CHF2, CF3On or OR8;

R6means H, HE, C1-C4-alkyl, O-C1-C4-alkyl, CF3or OR8provided that two of the radicals R4, R5or R6are H, or R4and R5both together means-CH=C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(or SIG10)=CH-, provided that R4is N;

R7means1-C8-alkyl;

R8means CO6N>1
mean OS(O)1-C3the alkyl in anthopology,

in the form of their bases and/or salts of physiologically acceptable acids, in the form of enantiomers or racemates, provided that the exception is the racemate of compounds of formula I in which R1and R2both together represent -(CH2)3-, R3, R4and R6mean N and R5is the co3.

2. Dimethyl(3-arival-3-enyl)amino compounds on p. 1, wherein R1is1-C3-alkyl, and R2means N or1-C3-alkyl, or R1and R2both together represent -(CH2)2-4- or -(CH2)2-R7, R3means N or1-C3-alkyl, R4means H, HE, CF3or OR8, R5represents H, HE, C1-C4-alkyl, O-C1-C4-alkyl, F2, CF3or OR8and R6means H, HE, O-C1-C4-alkyl, CF3or OR8provided that two of the radicals R4, R5or R6are H, or R4and R5both together means-CH=C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OR101is CH3or3H7and R2represents N, CH3or CH2CH3or R1and R2both together means -(CH2)2-3- or -(CH2)2-R7, R3means H, CH3or CH2CH3, R4means H or HE, R5means H, HE, co3, CHF2or OR8and R6means N, HE or CF3provided that two of the radicals R4, R5or R6are H, or R4and R5both together represent-CH= C(CH3)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OH)=CH-, provided that R4is N, and R8is a CO6H4-R11where R11mean OS(O)1-C3the alkyl in anthopology.

4. Dimethyl(3-arival-3-enyl)the amino compounds, one or more paragraphs. 1-3, wherein R1is CH3and R2means N or CH3or R1and R2both together represent -(CH2)2-3- or -(CH2)2-CH(CH3)-, R3means N or CH3, R4means N, R5means HE libcam OS(O)-CH3in anthopology.

5. The way to obtain dimethyl(3-arival-3-enyl)amino compounds of the formula I

< / BR>
where R1is1-C5-alkyl, and R2means N or1-C5-alkyl, or R1and R2both together represent -(CH2)2-4-, -(CH2)2-R7or-CH2-R7-CH2-;

R3means N or1-C5-alkyl;

R4means H, C1-C4-alkyl, O-C1-C4-alkyl or CF3;

R5is the failure of H, C1-C4-alkyl, O-C1-C4-alkyl, CHF2either CF3and R6means H, C1-C4-alkyl, O-C1-C4-alkyl or CF3provided that two of the radicals R4, R5or R6are H, or R4and R5both together means-CH= C(R9)-S-, provided that R6is H, or R5and R6both together means-CH=CH-C(OR10)=CH-, provided that R4is N;

R7means1-C8-alkyl;

R9means N or1-C4-alkyl;

R10means N,

the exception is the compound of formula I, in which R1and R2about the CH3, characterized in that dimetilaminometil formula II

< / BR>
interaction with the ORGANOMETALLIC compound of formula III

< / BR>
in which Z denotes MgCl, MgBr, MgI or Li,

transform into a tertiary alcohol of the formula IV

< / BR>
then dehydration with the obtained compounds of formula I.

6. The way to obtain dimethyl(3-arival-3-enyl)amino compounds of the formula I

< / BR>
in which R1is1-C5-alkyl, and R2means N or1-C5-alkyl, or R1and R2both together means -(CH2)2-4-, -(CH2)2-CHR7or-CH2-CHR7-CH2-;

R3means N or1-C5-alkyl;

one of the radicals R4, R5or R6IT means, while the two other radicals are H;

R7means1-C8-alkyl,

characterized in that the compound of the formula I in which one of the radicals R4, R5or R6means O-CH3and both of the other radicals are H, is subjected to the interaction with the hydride diisobutylaluminum.

 

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FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: organic chemistry and synthesis, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of benzidine derivatives. Invention proposes a single-step method for synthesis of derivatives of benzidine. Method involves oxidation of corresponding aromatic amines with hydrogen peroxide in organic solvent medium in the presence of catalytic amounts of substituted iron or cobalt phthalocyanines. The proposed method provides preparing different derivatives of benzidine with good yield and high content of the main substance. Method can be used for the development in aims of industrial technology. Derivatives of benzidine are used widely as redox-indicators for determination of some metal ions, in immunoenzyme analysis and for preparing electroluminescent materials also.

EFFECT: improved preparing method.

14 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to improved method of preparing title compounds depicted by general formula: , wherein R1 = R2 = H : R = N(CH3)2, OCH3, C(CH3)3; R1 = H, R2 = CH3 : R = N(CH3)2, C(CH3)3; R1 = R2 = CH3 : R = N(CH3)2, which are intermediates in synthesis of biologically active products, via reaction of 1,3-dehydroadamantane or homologues thereof with benzene derivatives selected from series: N,N-dimethylaniline, anisole, and tert-butylbenzene at molar ratio of reactants1:(5-6), respectively, in a benzene derivative at 120-130°C for 5-6 h.

EFFECT: expanded synthetic possibilities.

6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improvement of the method of alkylating diphenylamine, involving addition of isobutylene oligomers to diphenylamine in the presence of acid clay catalyst with formation of a mixture, and carrying out the reaction at temperature sufficiently low for preventing significant reduction of catalyst activity until completion of the said addition. Temperature is then increased, obtaining a mixture of alkylated diphenylamines, containing: 0.1 to 1% diphenylamine, less than 10% (tert-butyl)diphenylamine, less than 10% monooctyldiphenylamine, more than 20% dodecyldiphenylamine, more than 15% hexadecyldiphenylamine, less than 10% eicosenyldiphenylamine, less than 7% tetracosenyldiphenylamine, less than 4% octacosenyldiphenylamine and less than 2% polyisobutyldiphenylamine. The said diphenylamine is added to a mixture of olefins, containing fractions which are characterised by high reaction capacity, as well as fractions, which exhibit relatively lower reaction capacity, at temperature sufficiently low for preventing significant reduction of catalyst activity until the said addition is complete, and then latter at high temperature, obtaining a mixture of alkylated diphenylamines, where the given mixture contains not more than 27% products of alkylation with C8 chains or shorter, and more than 15% products of alkylation with C24 chains or longer, so as to increase rate of alkylation with participation of less reactive fractions. The invention also relates to the obtained mixture of alkylated diphenylamines, with antioxidant properties, and to a composition with antioxidant properties, containing A) an organic product, chosen from a group consisting of lubricant materials, hydraulic liquids, process oils, fuel and polymers, in amount of 90 to 99.5 wt %; and B) stabilising quantity of a mixture of alkylated diphenylamines from 0.05 to 10 wt %.

EFFECT: new compounds have useful biological properties.

13 cl, 3 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for alkylating a phenyl ring of diphenylamine. The method involves reaction of diphenylamine with an alkylating agent selected from straight of branched olefin in an inert atmosphere in the presence of an ionic liquid which contains a Lewis acid, selected from a metal halide, a quaternary cation selected from a quaternary ammonium cation, an alkylimidazolium cation, an alkyltriazolium cation and an alkylpyridinium cation, to obtain an alkylated derivative of diphenylamine.

EFFECT: method simplifies extraction of the end product from the reaction mass.

11 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a single-step alkylation into a ring of at least one N-alkyl-N'-phenyl-phenylene diamine with at least one olefin selected from a group comprising hydrocarbon acyclic mono-olefins containing 2 to approximately 50 carbon atoms, cyclic olefins containing 5 to 10 carbon atoms, and aryl-substituted mono-olefins containing 8 to 20 carbon atoms. The method involves one step for heating the mixture of N-alkyl-N'-phenyl-phenylene diamine(s) and olefin(s) in the presence of a catalytic amount of at least one halide of alkylaluminium at temperature from approximately 50 to approximately 350C in an air-tight vessel for approximately 1 hour to approximately 30 hours.

EFFECT: method simplifies the process by carrying out the process in a single step while maintaining high output of end products.

13 cl, 5 tbl, 22 ex

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