Method for preparing 3,5-dimethyladamantyl-1-amine or its salts

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 3,5-dimethyladamantyl-1-amine or its salts. Method involves the bromination step of 1,3-dimethyladamantane with liquid bromine at boiling. The bromination reaction is carried out in the mole ratio 1,3-dimethyladamantane to bromine = 1:(2-8) but preferably in the ratio = 1:(3-6), and separation of bromine is carried out by distillation. Then the excessive amount of formamide is added to a synthesized residue and kept the mixture at temperature 120-180°C but preferably at 150-160°C. The end product is isolated in free form or as a salt. Proposed method allows simplifying the process based on decreasing non-utilizable waste and possibility for carrying out the process in a single apparatus to yield the end product of high quality and purity.

EFFECT: improved method of synthesis.

3 cl, 11 ex

 

The present invention relates to the field of organic chemistry, specifically to an improved method for producing a 3,5-dimethyladamantane-1-amine or its salts, which can find application in pharmaceutical industry.

Hydrochloride 3,5-dimethyladamantane-1-amine is used in medical practice under the international nonproprietary name memantine for the treatment of dementia of different origin, Parkinson's disease, Alzheimer's disease and other

A method of obtaining a 3.5-dimethyladamantane-1-amine, namely, that 1,3-dimethyladamantane liquid bromine and get 1-bromo-3,5-dimethyladamantane with the release of 77.5%. 1-Bromo-3,5-dimethyladamantane interaction with acetonitrile in an environment of concentrated sulfuric acid is transformed into 1-acetamido-3,5-dimethyladamantane raw with the release of 96%. 1-Acetamido-3,5-dimethyladamantane hydrolized by boiling with alkali in diethylene glycol and allocate hydrochloride 3,5-dimethyladamantane-1-amine with a yield of 87%. Total yield per 1,3-dimethyladamantane is 63% [K.Gerson, E.V.Krumkalns, R.L.Brindle, F.J.Marshall, M.A.Root. J.Med.Chem., v.6. N11, p.760-763, 1963. The Adamantyl Group in Medicinal Agents. I.]. The disadvantages of this method of obtaining the target product are strict conditions for hydrolysis step and a large number of acidic and alkaline waste.

Another way to obtain 3,5-dimethyladamantane the-1-amine is the reaction of 1-bromo-3,5-dimethyladamantane with urea, which is carried out by heating the reaction mixture in an open flame until the beginning of the exothermic reaction, then boil the reaction mass after long-term treatment get the target product with a yield of 70% [J.Burkhard, S.Landa, Proceedings Institute of Chemical technology in Prague. Technology fuels .29D, p.91-96, 1973. On adamantane and its derivatives. XXX.]. The disadvantage of this method is the difficulty of scaling process, its fire.

Closest to the proposed method (prototype) is a method of obtaining a 3.5-dimethyladamantane-1-amine or its hydrochloride, which consists in the fact that 1,3-dimethyladamantane boil with liquid bromine and acetonitrile in a molar ratio of 1:10:4, the reaction mass is then cooled to room temperature and poured into cooled to 5°With methanol, then, continuing the cooling with ice water, add sodium metabisulfite until the colour disappears bromine, to the resulting suspension add water, an acidic solution is alkalinized sodium carbonate to pH 8-9 and incubated at 30°5 hours, followed by additional alkalizing sodium hydroxide is extracted with ether, the solvent is distilled off, the residue sublimate in a vacuum. The target product is obtained with a yield of 88% of theoretical, TPL hydrochloride 290-292° [Angeliki, Vframes, Vphr. ZHUR.ORG.CHEM. 32 VIP, str-1024, 1996. The interaction of adamantane, the carb is new acid adamantanol and bicyclo[3,3,1]nonanalog series with acetonitrile in the environment of liquid bromine]. The disadvantage of this method is the large excess of liquid bromine, which cannot easily be recycled. In addition, the selection of the target product leads to large amounts of reaction mass and it is difficult recycled waste.

The aim of the invention is to simplify the process and create a more environmentally friendly method for the synthesis of the target product.

This goal is achieved by the proposed method to obtain 3,5-dimethyladamantane-1-amine or its salts, which consists in the fact that 1,3-dimethyladamantane subjected to interaction with liquid bromine (molar ratio from 1:2 to 1:8, mainly 1:3-6) when boiling the reaction mixture, after completion of the reaction (termination selection HBR) excess traces of bromine and hydrogen bromide is distilled off, to the residue add formamide. taken in excess, the reaction mass is stirred at a temperature of 120-180°C, preferably at a temperature of 150-160°conduct acidic hydrolysis, for example, halomonadaceae acid and produce the target product in the form of a base or salt. The yield of the target product is the proposed method of 63-75%.

Advantages of the proposed method are odnogolosoe (one-pot) process, a small amount of unusable waste, high yield of the target product. The person is but it should be emphasized, the excess amount of distilled bromine can be used in the process without additional processing, absorbed hydrogen bromide can be used at the stage of hydrolysis of the acyl derivative, the use of formamide allows you to hydrolysis under more mild conditions than in the hydrolysis of N-acetyl derivative. In addition, when implementing the method according to this invention reduces the amount of equipment required and organic solvents or organic solvents are not used at all.

Distinctive features of the proposed method is distillation of excess bromine and the use of formamide in the synthesis of acyl derived.

The structure of the obtained products is confirmed by the methods of physicochemical analysis and comparison of the notorious examples of 3,5-dimethyladamantane-1-amine and its hydrochloride.

The following examples illustrate but do not limit the claims of the applicant.

EXPERIMENTAL EXAMPLES

Example 1.

A mixture of 16.4 g (0.1 M, 18.7 ml) of 1,3-dimethyladamantane and 80 g (0.5 M, with 25.5 ml) of bromine is boiled in a flask equipped with a stirrer, a refrigerator and a tube for drainage of eye-catching HBR, which absorb the chilled water in the bubbler, boil until the termination of allocation of HBR (approximately 5 hours). Redundant if estvo bromine is distilled off (the volume of distillate 19 ml), the remains of the bromine is removed in vacuum. To the residue is a light beige color was added 13.5 g (0.3 M, 12.0 ml) of formamide and incubated at a temperature of 120°to the lack of bromo derivatives in the reaction mixture is cooled to 90°and adds 20% Hydrobromic acid, taken in excessive quantities. Acyl derived hydrolyzing boiling of the reaction mixture. The mixture is cooled, the precipitate is filtered off and get to 13.6 g bromhidrosis 3,5-dimethyladamantane-1-amine, yield 63%, TPL 303-304° (of water).

Example 2.

A mixture of 3.28 g (0.02 M, and 3.72 ml) of 1,3-dimethyladamantane and 16 g (0.1 M, 5,1 ml) of bromine is boiled in a flask equipped with a stirrer, a refrigerator and a tube for drainage of eye-catching methyl hydrogen for 6 hours. Excess bromine is distilled off, the remains of hydrogen bromide is removed in vacuum. To the reaction mass is added 4.5 g (0.1 M, 4 ml) of formamide and at a temperature of 120-130°stirred for 4 hours, add 14 ml of 18% hydrochloric acid and boil the reaction mass 1.5 hours. After cooling and aging in the fridge over night sucked precipitated hydrochloride 3,5-dimethyladamantane-1-amine. Yield 3 g (69,8%), TPL 293-294°With (30% isopropanol), the basic substance content of 99.4%.

Example 3.

Analogously to example 1, but the ratio of 1,3-dimethyladamantane : bromine 1:2, synthesized 6 hours. The yield of the desired product in 58%.

P the emer 4.

Analogously to example 1, but the ratio of 1,3-dimethyladamantane : bromine 1: 7. The yield of the target product to 63%.

Example 5.

Analogously to example 2, but the ratio of 1,3-dimethyladamantane : formamid 1:20, the distillation of formamide. The yield of the target product 75%.

Example 6.

Analogously to example 2, but the ratio of 1,3-dimethyladamantane : formamid 1:6. The yield of the target product is 60%.

Example 7.

Analogously to example 4, but after carrying out hydrolysis of the reaction mass is evaporated in vacuum to dryness. The solid residue is crystallized from 30% aqueous isopropanol. The yield of the target product is 60%.

Example 9.

Analogously to example 2, but the hydrolysis with 10% hydrochloric acid. The yield of the target product 64%.

Example 10.

Analogously to example 2, but after acidic hydrolysis of the reaction mass is alkalinized with sodium hydroxide solution and extracted with a target product. Obtain 11.3 g of the base. Exit 63% of theoretical.

Example 11.

To the ethereal solution of 3,5-dimethyladamantane-1-amine was added an ethereal solution of hydrogen chloride deposited precipitate is filtered off, washed with ether and receive hydrochloride 3,5-dimethyladamantane-1-amine with almost quantitative yield, so pl. 293-294°C.

Similarly receive other salts of 3,5-dimethyladamantane-1-amine:

oxalate, TPL 214-215°C (With decomp.),

adipate, TPL 202-204°C.

1. The way to obtain 3,5-di is millamant-1-amine or its salts, including the state of the synthesized 1,3-dimethyladamantane liquid bromine at boiling, separating excess bromine, and the stage of hydrolysis and separation of the target product in free form or in salt form, wherein the bromination is carried out at a molar ratio of 1,3-dimethyladamantane : bromine is 1 : 2-8, Department of bromine is carried out by distillation, adding to the obtained residue, excess of formamide and aged at a temperature of 120-180°With subsequent acid hydrolysis of the resulting formyl derivative.

2. The method according to claim 1, characterized in that the molar ratio of 1,3-dimethyladamantane : bromine is 1 : 3-6.

3. The method according to any one of claims 1 and 2, characterized in that the reaction with formamide is carried out at a temperature of 150-160°C.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing 1-amino-3,5-dimethyladamantane hydrochloride (the preparation memantin or acatinol) used in medicinal practice as agent for treatment of such diseases as Parkinson's disease, neurodegenerative disorders, glaucoma. Method for preparing 1-amino-3,5-dimethyladamantane hydrochloride involves addition of nitric acid to preliminary prepared 1,3-dimethyladamantane emulsion in acetic acid at 10-30oC followed by addition of 30-55% urea solution in water in the mole ratio 1,3-dimethyladamantane : acetic acid : nitric acid : urea = (1:3)-(4:9)-(12:2.5)-5.0, respectively followed by neutralization of obtained reaction mass with alkali an aqueous solution, extraction and the following isolation of product as hydrochloride and its crystallization from water. Method provides preparing product of the high quality that satisfies requirements of Pharmacopoeia.

EFFECT: improved preparing method, enhanced quality of product.

5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

< / BR>
< / BR>
< / BR>
which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

FIELD: chemistry of metalloorganic compounds.

SUBSTANCE: invention relates to the improved method for preparing imino salt of the formula Mx+[-N(CF3)2]x that is a source of anions N(CH3)2 and the following replacing halide or other groups in organic molecules with the group N(CH3)2. Method involves interaction of metal fluoride of the general formula MFx wherein M is Na, K, Rb, Cs, Ag, Cu, Hg; x = 1 or 2 under condition that x = 1 if M means Na, K, Rb, Cs or Ag, and x = 2 if M represents Cu or Hg with sulfonamide of the general formula: RfSO2N(CF3)2 wherein Rf means F or CnF2n+1; n = 1-4, or with sulfonamide of the general formula (CF3)2N(SO2CF2)mSO2N(CF3)2 wherein m = 0, 1 or with N,N-bis-(trifluoromethyl)perfluoroacylamide of the general formula: RfCON(CF3)2 in polar organic solvent medium to obtain the corresponding solutions containing imino salts of the general formula Mx+[-N(CF3)2]x and, respectively, sulfonylfluorides of the general formula RfSO2F, and sulfonyldifluorides of the general formula: F(SO2CF2)mSO2F of salt of the general formula: RfCF2O-M+. Also, invention relates to applying imino salts of the general formula Mx+[-N(CF3)2]x and [bis-(trifluoromethyl)imido]rubidium as a reagent for replacing halogen or other groups in organic molecules with the group N(CF3)2.

EFFECT: improved preparing method.

10 cl, 9 ex

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FIELD: chemistry of metalloorganic compounds.

SUBSTANCE: invention relates to the improved method for preparing imino salt of the formula Mx+[-N(CF3)2]x that is a source of anions N(CH3)2 and the following replacing halide or other groups in organic molecules with the group N(CH3)2. Method involves interaction of metal fluoride of the general formula MFx wherein M is Na, K, Rb, Cs, Ag, Cu, Hg; x = 1 or 2 under condition that x = 1 if M means Na, K, Rb, Cs or Ag, and x = 2 if M represents Cu or Hg with sulfonamide of the general formula: RfSO2N(CF3)2 wherein Rf means F or CnF2n+1; n = 1-4, or with sulfonamide of the general formula (CF3)2N(SO2CF2)mSO2N(CF3)2 wherein m = 0, 1 or with N,N-bis-(trifluoromethyl)perfluoroacylamide of the general formula: RfCON(CF3)2 in polar organic solvent medium to obtain the corresponding solutions containing imino salts of the general formula Mx+[-N(CF3)2]x and, respectively, sulfonylfluorides of the general formula RfSO2F, and sulfonyldifluorides of the general formula: F(SO2CF2)mSO2F of salt of the general formula: RfCF2O-M+. Also, invention relates to applying imino salts of the general formula Mx+[-N(CF3)2]x and [bis-(trifluoromethyl)imido]rubidium as a reagent for replacing halogen or other groups in organic molecules with the group N(CF3)2.

EFFECT: improved preparing method.

10 cl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 3,5-dimethyladamantyl-1-amine or its salts. Method involves the bromination step of 1,3-dimethyladamantane with liquid bromine at boiling. The bromination reaction is carried out in the mole ratio 1,3-dimethyladamantane to bromine = 1:(2-8) but preferably in the ratio = 1:(3-6), and separation of bromine is carried out by distillation. Then the excessive amount of formamide is added to a synthesized residue and kept the mixture at temperature 120-180°C but preferably at 150-160°C. The end product is isolated in free form or as a salt. Proposed method allows simplifying the process based on decreasing non-utilizable waste and possibility for carrying out the process in a single apparatus to yield the end product of high quality and purity.

EFFECT: improved method of synthesis.

3 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel improved method of obtaining benzylamine derivative of general formula (3)

and method of obtaining from the latter of carbamate derivative of general formula (6) where X1 represents halogen atom and R1 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, R3 represents alkyl group. Methods include interaction of benzyl derivative of general formula (1)

with halogen compound of general formula (2): where X2 represents halogen atom, and R2 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, in presence of Lewis acid. From obtained compound of general formula (3) carbamate derivative of general formula (6) is obtained. For this purpose compound of general formula (3) is subjected to hydrolysis obtaining aminoderivative of general formula (4)

which is further subjected to interaction with ester of halogen-formic acid of general formula (5) where X1 and R2 are determined above, X3 represents halogen atom, and R3 represents alkyl group, in presence of base. Invention also relates to novel acylbenzylamine derivatives of general formula (7):

where X1 represents halogen atom, each of R2 and R4 independently represents C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and R can additionally represent hydrogen atom. Benzylamine derivatives of formula (3) and formula (7) can be used as intermediate products for obtaining agricultural or garden bactericide based on formula (6) carbamate.

EFFECT: elaboration of improved method of obtaining benzylamine derivative.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: method of producing partially fluorinated aromatic amines which contain at least one hydrogen atom in the ortho-position of the amino group, having general formula 1, , X = F (1a) or H (1b), is distinguished by that pentafluoroaniline is functionalised on the amino group through treatment with a derivative of aliphatic or aromatic mono- or dicarboxylic acid to obtain the corresponding derivative of pentafluoroaniline as a substrate which undergoes hydrodefluorination under the effect of a reducing metal in the presence of a proton source and in the presence of a catalyst - complex compound of nickel and/or cobalt with ligands selected from heterocyclic nitrogen-containing compounds or phosphorus-containing compounds in a medium of an aprotic dipolar solvent with subsequent alkaline or acid hydrolysis of the reaction mixture to form the corresponding amine.

EFFECT: improved method.

7 cl, 1 dwg, 6 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing compounds of formula

, where the fluoro group is possibly [18F]fluoro; ring A is substituted with benzothiazol-2-yl, which is substituted with hydroxy, C1-6alkyl, C1-6alkoxy, halogen, OCH2OR11, where R11 is C1-6alkyl; R1 is C1-6alkyl. The method involves reaction of the corresponding compound of formula , where ring A is substituted as defined for the compound of formula (I); R2 is selected from hydrogen, C1-10alkyl, C1-10halogenalkyl, -(CH2CH2O)q-CH3, where q is an integer from 1 to 10; R1 is as defined for the compound of formula (I); R3 is a leaving group such as nitro, with an alkali metal fluoride or tetra-alkylammonium, possibly with [18F]fluoride, to obtain a compound of formula , where R1 and R2 are as defined for compounds of formulae (I) and (II), the fluoro group is possibly [18F]fluoro and ring A is substituted as defined for the compound of formula (I); with subsequent conversion of the -C(O)R2 group to hydrogen through hydrolysis and possible removal of any extra protective groups. The invention also relates to novel compounds of formulae

, where R1-R3, R9, defined above, are precursors of compounds of formula (I), as well as to a radiopharmaceutical set and a cartridge for use in positron emission tomography, which contain said precursors.

EFFECT: method enables to obtain compounds of formula (I) using a simpler and more efficient method.

11 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing partially fluorinated aromatic amines, particularly 3,4,5-trifluoroaniline of formula: , which can be used in synthesis of biologically active compounds. The disclosed three-step process involves acylation of pentafluoroaniline on the amine group with a derivative of mono- or di- lower aliphatic or benzene carboxylic acid, reductive hydrodefluorination of the obtained acylpentafluoroaniline in the presence of a catalyst - a complex compound of nickel and/or cobalt with heterocyclic nitrogen-containing compounds or phosphorus-containing ligands, such as 2,2'-bipyridyl, 1,10- phenanthroline, alkyl- or arylphosphines, using ionic liquids as solvents, selected from a 1,3-dialkylimidazolinium salt of general formula: where: R1 and R2 are C1-C10 alkyl groups which can contain different substitutes, X is an inorganic or organic anion such as Cl-, Br-, BF4-, OAc- at temperature 20-150°C under the effect of a metal reducing agent, for example zinc or magnesium, in the presence of proton sources such as water, in a solvent medium while heating, with subsequent alkaline or acid hydrolysis of the reaction mixture. The ionic liquid used as the solvent can be recycled.

EFFECT: method shortens reaction time by increasing catalytic activity of the used catalyst while maintaining high output and quality of the obtained product.

5 cl, 5 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing methylenediamine dinitrate, which can be used in synthesis of powerful explosives. The disclosed method includes hydrolysis of methylene bisformamide with nitric acid in a medium of 65-75% nitric acid at 15-25°C for 15-20 hours in ratio of 2.0-3.0 weight parts of nitric acid per 1 part methylene bisformamide. The obtained suspension is then cooled to temperature of 0 to -10°C. Methylenediamine dinitrate is then filtered out and washed with ethanol.

EFFECT: method enables to obtain methylenediamine dinitrate with a good output while avoiding the development of uncontrolled decomposition processes.

1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel trihydrochlorides of (R)- and (S)-isomers of 1,8-diamino-3-methyl-4-azaoctane (3-methylspermidine), corresponding to structural formulae given below and to a method for production thereof. Said compounds can be used in vitro and in vivo to investigate individual cell functions of easily interconvertible and partially interchangeable spermine and spermidine, which are vital for tumour cells and pathogenic trypanosomatids. The (R)-isomer of 3-methylspermidine trihydrochloride is the first metabolically stable functionally active spermidine mimetic.

. A method of producing said isomers includes alkylating salts of (R)- and (S)-isomers of N1-protected 1,3-diaminobutane sulphamide with N-protected 1-amino-4-butylhalides, followed by successive removal of protective groups and treatment of the obtained residue with hydrochloric acid solution. The alkylating agent used can be N-(phthaloyl)-1-amino-4-butylhalides in aprotic polar solvents or N-(4-iodobutyl)phthalimide in dimethyl formamide in the presence of calcium carbonate. Removal of the phthalyl protection is normally carried out with hydrazine hydrate in alcohol. Removal of benzyloxycarbonyl groups is normally carried out by catalytic hydrogenation over Pd-black at atmospheric pressure in a mixture of methanol and acetic acid.

EFFECT: converting the obtained triacetates of R)- and (S)-isomers of 1,8-diamino-3-methyl-4-azaoctane into tetrahydrochlorides is carried out with aqueous hydrochloric acid solution.

7 cl, 5 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2-(N, N-dialkylaminomethyl) styrenes of general formula: where R1= R2= Et; R1=R2=Me; R1=Me, R2=Et; R1=Me, R2=Bn; R1=Me, R2=n-Bu; R1=Me, R2=i-Pr; R1=Et, R2=i-Pr; R1=Et, R2=Bn or R1=Et, R2=n-Bu. Method consists in fact that isoquinoline is subjected to react with alkyl halide or dialkyl sulphate to produce respective isoquinoline salt. Latter should be reduced in presence of formic acid and triethylamine to obtain N-alkyl-1, 2, 3, 4-tetrahydroisoquinoline which again reacted with alkyl halide or dialkyl sulphate to produce the respective tetrahydroisoquinoline salt. Latter is split by Hofmann reaction under action of alkali. Alkyl halide preferably selected from benzyl chloride, 1-bromo butane or 2-iodide propane and dialkyl sulphate is from ethyl sulphate or dimethyl sulphate. Invention allows improve effectiveness of the process of producing 2-(N, N-dialkylaminomethyl) styrenes and takes place in mild conditions, which do not require complex equipment, inert atmosphere, expensive and toxic reagents.

EFFECT: method increases output of target products to 75-88 % with respect to the initial isoquinoline.

3 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention refers to versions of a method for production of 2-fluorine-3-methylbut-2-enyl amine (I) or its hydrochloride (II). These compounds area key structural fragments of some biologically active substances. For example, hydrochloride (II) may be used for production of agricultural chemicals. These compounds may be used also for production of medicines for treatment of ophthalmological diseases, anti-inflammatory or antiviral agents. This method consists in the fact that 2-fluorine-2-chlorine-1,1-dimethyl cyclopropane is heated in presence of catalytic quantities of the CuCl and LiCl mixture in acetonitrile medium at a temperature of 80-90°C with subsequent treatment of the obtained reaction mixture with potassium phthalimide in dimethyl formamide medium at a temperature of 100-120°C and formed intermediate N-(2-fluorine-3-methylbut-2-enyl)phthalimide is treated with hydrasine hydrate in methanol medium; or 2-fluorine-2-chlorine-1.1-dimethyl cyclopropane is subject to interaction with urotropine with boiling in methylene chloride medium, and formed intermediate N-(2-fluorine-3-methylbut-2-enyl) urotropinium chloride is treated with hydrochloric acid solution in ethyl alcohol. The target product is isolated in the form of base (I) or its hydrochloride (II). Initial 2-fluorie-2-chlorine-1,1-dimethyl cyclopropane may be produced of widely available isobutylene.

EFFECT: method allows to increase target product output (32-36% instead of 11%), reduce stage number and exclude expensive reagents.

2 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing 1-amino-3,5-dimethyladamantane hydrochloride (the preparation memantin or acatinol) used in medicinal practice as agent for treatment of such diseases as Parkinson's disease, neurodegenerative disorders, glaucoma. Method for preparing 1-amino-3,5-dimethyladamantane hydrochloride involves addition of nitric acid to preliminary prepared 1,3-dimethyladamantane emulsion in acetic acid at 10-30oC followed by addition of 30-55% urea solution in water in the mole ratio 1,3-dimethyladamantane : acetic acid : nitric acid : urea = (1:3)-(4:9)-(12:2.5)-5.0, respectively followed by neutralization of obtained reaction mass with alkali an aqueous solution, extraction and the following isolation of product as hydrochloride and its crystallization from water. Method provides preparing product of the high quality that satisfies requirements of Pharmacopoeia.

EFFECT: improved preparing method, enhanced quality of product.

5 ex

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