Method for preparing 1-amino-3,5-dimethyladamantane hydrochloride

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

 

The invention relates to a process for the preparation of the hydrochloride of 1-amino-3,5-dimethyladamantane (drug memantine or akatinol)used in clinical practice as a treatment for Parkinson's disease, neurodegenerative diseases, glaucoma, etc.

There are a number of methods of synthesis of this compound:

the reaction of the alkaline hydrolysis of 1-acetylamino-3,5-dimethyladamantane (J. Med. Chem., 1963, R-763, 1982, 51-56);

the interaction of 1,3-dimethyladamantane or perhydroanthracene with nitrogen trichloride in the presence of aluminium chloride in dichloromethane (Tetrahedron Lett., 1968, R-5835, J. Amer. Chem. Soc., 1969, p.6457-6460);

the reaction of 1-chloro - or 1-bromo-3,5-dimethyladamantane with urea at elevated temperature (U.S. Pat. Czechoslovakia, No. 146405).

However, the above methods require hard-to-reach parent compounds, highly toxic and expensive reagents, solvents and catalysts, which limits the scope and reduces the economic efficiency of these methods.

The closest in technical essence to the claimed method is a method of obtaining a hydrochloride of 1-amino-3,5-dimethyladamantane the interaction of 1-chloro-3,5-dimethyladamantane and urea at a temperature of 200° (US patent No. 4122193 published 24.10.78).

This method has a number of disadvantages: the potential of the Naya explosive, low technology, and the danger to personnel and the fire method, the method does not ensure the achievement of quality indicators of the hydrochloride of 1-amino-3,5-dimethyladamantane, meet the requirements for medical preparations, method for isolation of the target product is characterized by low technology and does not allow you to use the method on an industrial scale.

The technical result - the ensuring explosion of production, simplify the process, improve the quality of the target product to a level consistent with the requirements of the monograph.

The technical result is achieved in that in the method of obtaining the hydrochloride of 1-amino-3,5-dimethyladamantane using urea to a pre-obtained emulsion 1,3-dimethyladamantane in acetic acid is added nitric acid with 10-30°With, then add 30-55%solution of urea in water at a molar ratio of 1,3-dimethyladamantane acetic acid nitric acid - urea 1:3-4:9-12:2,5-5,0 respectively, followed by neutralization of the resulting reaction mass with an aqueous solution of alkali, extraction and subsequent isolation of the product as hydrochloride and crystallization from water.

Distinctive features

1. Adding nitric acid to the emulsion 1,3-dimethyladamantane in the criminal code is usnei acid.

2. Adding urea in aqueous solution.

3. Reduced the number of acetic acid and nitric acid.

4. Neutralizing the reaction mass with an aqueous solution of alkali and subsequent extraction.

The invention has the following advantages.

Provided the explosion process by adding nitric acid to a pre-obtained emulsion 1,3-dimethyladamantane in acetic acid. In this case, the oxidizing agent, i.e. nitric acid, is always in disadvantage in relation to fuel. Moreover, required for susceptibility to the originating impulse balance fuel - oxidizer is not achieved because of the notorious presence in the reaction mixture an additional quantity of fuel in the form of acetic acid.

Simplified process through better manageability heat fluxes, the exclusion of fire-hazardous and environmentally harmful operations. This is achieved primarily by the dosage of urea in the reaction mixture in aqueous solution, as well as through the use of caustic soda solution by neutralizing and toluene for extraction.

The cheapening of production and reducing the volume of wastewater by reducing the quantities of acetic acid and nitric acid.

Necessary for pharmaceutical level of quality for the public performance of the hydrochloride of 1-amino-3,5-dimethyladamantane. This is due to the exclusion of a large excess of oxidant and local overheating by adding nitric acid to the emulsion of hydrocarbon in acetic acid and dosage of urea in aqueous solution. Moreover, the presence of water in the reaction mixture reduces the acidity of the environment, suppresses the reaction of thermal decomposition of nitric acid at the last stage of the process and, therefore, eliminates the possibility of formation of impurities further oxidation products on the nodal positions adamantanol frame. Extraction with toluene as a non-polar solvent additionally gives the opportunity to avoid even trace amounts of more polar impurities in the final product.

The proposed method is tested on an industrial scale, and the quality of the resulting pharmaceutical product fully complies with the requirements of the Pharmacopoeia.

Examples of the complete method.

Analysis was performed by gas chromatography-mass spectrometer HP GC/MS A at an energy of ionizing electrons 70 eV using a quartz capillary column with a length of 50 m with immobilizovannoi phase SE-30.

Example 1.

In a flask with a capacity of 1000 ml load 68 ml (60,5 g) 1,3-dimethyladamantane, 62 ml of acetic acid and at a temperature of 25-30°add 142 ml of fuming nitric acid, can withstand the reaction mass 3 h at 20-25°With doba is given in 100 g of a 55%aqueous solution of urea, incubated 2 h at 25°C, for 1 h, heated to 125°C and kept at this temperature for 3 h Then the reaction mass is then cooled, add 320 ml of 30%aqueous caustic soda at 50°C, extracted with 500 ml of toluene, the toluene layer is separated, add 30 ml of hydrochloric acid, dried and recrystallized from water. Get 64 g (82%) of the hydrochloride of 1-amino-3,5-dimethyladamantane, TPL 324-328°C. IR spectrum, cm-1: 2080, 1600, 1498, 1315, 967. Mass spectrum m/z(%): 179(16), 122(93), 108(100). The quality meets the requirements of formstate.

Example 2.

In a flask with a capacity of 1000 ml load 68 ml (60,5 g) 1,3-dimethyladamantane, 82 ml of acetic acid and at a temperature of 10-15°add 190 ml of fuming nitric acid, can withstand the reaction mass of 1 h and at 20°add 365 g of a 30%aqueous urea solution, allowed to stand for 1 h at 20°C, for 3 h and heated to 90°C and kept at this temperature for 1 h Then the reaction mass is then cooled, add 400 ml of 45%-aqueous sodium hydroxide at 85°C, extracted with 800 ml of toluene, the toluene layer is separated, add 35 ml of hydrochloric acid, dried and recrystallized from water. Get 68 g (87%) of the hydrochloride of 1-amino-3,5-dimethyladamantane, TPL 324-328°C. IR spectrum, cm-1: 2080, 1600, 1498, 1315, 967. Mass spectrum m/z(%): 179(16), 122(93), 108(100). The quality meets the requirements pharmacopeial article.

Example 3.

In a flask with a capacity of 1000 ml is Agregat 68 ml (60,5 g) 1,3-dimethyladamantane, 70 ml of acetic acid and at a temperature of 15-20°add 180 ml of fuming nitric acid, can withstand the reaction mass of 2 h at 20-25°add 140 g of a 50%aqueous urea solution, allowed to stand for 1 h at 25°C, for 2 h, heated to 110°C and maintained at this temperature for 2 hours Then the reaction mass is then cooled, add 400 ml of 30%sodium hydroxide at 70°C, extracted with 700 ml of toluene, toluene layer is separated, add 30 ml of hydrochloric acid, dried and recrystallized from water. Get 72 g (92%) of the hydrochloride of 1-amino-3,5-dimethyladamantane, TPL 324-328°C. IR spectrum, cm-1: 2080, 1600, 1498, 1315, 967. Mass spectrum m/z(%): 179(16), 122(93), 108(100). The quality meets the requirements pharmacopeial article.

Example 4 (comparative).

In a flask with a capacity of 1000 ml load 250 ml of 98-100%nitric acid and 15-20°add 50 ml of 1,3-dimethyladamantane, maintain the reaction mass 3 h at 20°add 100 ml of acetic acid and 50 g of urea, heated 4 h at 80°C. Then the reaction mass is then cooled, add solid sodium hydroxide to pH>10, extracted with 2000 ml of diethyl ether. The ether extracts are dried with sodium hydroxide and saturated with gaseous hydrogen chloride. The precipitation is filtered off and dried to constant weight. Get 72 g (92%) of the hydrochloride of 1-amino-3,5-dimethyladamantane, TPL >300°C. IR spectrum, cm-1: 2080 1600, 1498, 1315, 967. Mass spectrum m/z(%): 179(16), 122(93), 108(100). According to gas chromatography-mass spectrometry basic substance content of 97.6%. In the sample there are more than a heavy admixture with the characteristics of a mass spectrum, m/z(%): 195 (18), 180 (7), 124 (100). After elution of the product on a column of silica gel (benzene - 2-propanol 25%ammonia = 10:10:1) selected impurity, which is the hydrochloride of 3-amino-5,7-dimethyl-1-adamantanol, TPL >340°C (2-propanol), the spectrum of IR, cm-1: 3305, 2630, 2060, 1620, 1510, 1335, 1195; an NMR spectrum1N δ, ppm: 0.98 (6N, CH3), 1.15-2.15 m (13H, Ad+OH), 8.64 (3H, NH

+
3
); found, %: C 62.84, N 10.01, 5.98 N, C12H21NO×HCl, calculated, %: C 62.75, N 9.58, N 6.10.

Example 5.

In a flask with a capacity of 1000 ml load 68 ml (60,5 g) 1,3-dimethyladamantane, 70 ml of acetic acid and at a temperature of 15-20°add 180 ml of fuming nitric acid, can withstand the reaction mass of 2 h at 20-25°add 140 g of a 50%aqueous urea solution, allowed to stand for 1 h at 25°C, for 2 h, heated to 110°C and maintained at this temperature for 2 hours Then the reaction mass is then cooled, add 560 ml of 30%-aqueous sodium hydroxide at 70°C, extracted with 700 ml of toluene, the toluene layer is separated, add 30 ml of hydrochloric acid, dried and recrystallized from water. Get the 65 g (82%) of the hydrochloride of 1-amino-3,5-dimethyladamantane, TPL 324-328°C. IR spectrum, cm-1: 2080, 1600, 1498, 1315, 967. Mass spectrum m/z(%): 179(16), 122(93), 108(100). The quality meets the requirements of the monograph.

The way to obtain hydrochloride of 1-amino-3,5-dimethyladamantane using urea, wherein the pre-obtained emulsion 1,3-dimethyladamantane in acetic acid is added nitric acid at 10-30aboutWith, then add 30-55%solution of urea in water at a molar ratio of 1,3-dimethyladamantane - acetic acid - nitric acid - urea 1:3-4:9-12:2,5-5,0 respectively, followed by neutralization of the resulting reaction mass with an aqueous solution of alkali, extraction and subsequent isolation of the product as hydrochloride and crystallization from water.



 

Same patents:

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,

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

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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, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing N-alkyl-N'-phenyl-p-phenylenediamines. Method involves interaction of aminodiphenylamine with aliphatic alcohols at temperature 170-235°C in the presence of potassium hydroxide by azeotrope distillation off and the following condensation of formed water and alcohol vapors in heat exchanger device, separation of water from alcohol in water separator device and recovery settled alcohol to the parent reaction mass through tubular film vaporizer heated by a heat carrier with temperature 175°C, not below. Method provides diminishing the reaction time and losses of alcohol, and to reduce energy consumption in the process due to decreasing temperature.

EFFECT: improved preparing method.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining N-2-ethylhexyl-N'-phenyl-п-phenylenediamine, which is used as antioxidant for polymers by alkylation of n-aminodiphenylamine with aliphatic alcohols at temperature 170-235°C in presence of potassium hydroxide with distillation of alcohol azeotrope with water through refluxer, in which s temperature 90-110°C is supported, by return of condensed hot alcohol in reaction zone, by separating of target product from organic layer after water extraction of reaction mass.

EFFECT: increasing of product quality by reduction of alkylation time.

3 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-2-ethylhexyl-N'-phenyl n-phenylenediamine, which can be used as an antioxidant for polymers and separation of commercial 2-ethylhexanoic acid from wastes from production of N-2-ethylhexyl-N'-phenyl n-phenylenediamine, which is achieved through alkylation of n-aminodiphenylamine with 2-ethylhexanol at temperature ranging from 170 to 235°C with distillation of azeotropic alcohol with water, returning condensed hot alcohol to the reaction zone, separation of the desired product from the organic layer after aqueous extraction of the reaction mass. The alkylating agent used is an alcohol solution of potassium alcoholate, which is added continuously in uniform portions to molten n-aminodiphenylamine, preheated to temperature ranging from 210 to 230°C. Distillation of azeotropic alcohol with water is done using a fractional column in which temperature is kept between 90 and 110°C; the aqueous layer remaining after separation of the organic layer is treated with hydrochloric, sulphuric or phosphoric acid until pH between 2 and 4, the obtained mixture is divided into layers and 2-ethylhexanoic acid is extracted from the organic layer through vacuum distillation.

EFFECT: cutting on alkylation time, increased amine conversion, reduced specific consumption of alcohol, specific energy consumption, higher quality of desired product and obtaining end product from waste products.

5 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of N-(1-adamantylalkyl)cycloalkylamines of general formula:

,

1: X=- single bond, Z is cyclopentyl; 2: X=-CH2-, Z-cyclopentyl; 3: X=-CH-CH3, Z-cyclopentyl; 4: X=-CH-CH3, Z-cyclohexyl. Method involves reacting amino derivatives of adamantane with corresponding cyclic alcohols (cyclopentanol and cyclohexanol) in the presence of a Raney-Ni catalyst. The reaction is carried out in 8-16 hours with molar ratio of catalyst: adamantane-containing amine: alcohol equal to 0.21-0.6:1:6-14.8, which enables to obtain desired products in a single step with high selectivity and output of 53-91%.

EFFECT: improved method.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-2-ethylhexyl-N'-phenyl-n-phenylenediamine. The method is realised through alkylation of n-aminophenyl-amine with a potassium alcoholate solution in 2-ethylhexanol, added continuously in equal portions into molten n-aminophenyl-amine. Alcohol azeotrope is distilled with water through a fractionating column in which temperature is kept at 90-110°C by returning the condensed hot alcohol into the reaction zone. The end product is separated from the organic layer after aqueous extraction of the reaction mass. Temperature of the added potassium alcoholate solution is kept at 135-160°C. Before adding the potassium alcoholate solution, molten n-aminophenyl-amine is heated to 200-209°C, and addition is carried out until achieving 95% conversion of n-aminophenyl-amine, after which temperature in the reactor is raised to 231-237°C in order to complete alkylation.

EFFECT: short duration of the alkylation step, low power consumption during alkylation, low specific consumption of 2-ethylhexanol, high quality of the product.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing cycloalkylamines of general formula Alk-R, where

, , , , , , , , , . The method is realised by reacting a cyclic ketone with an amine derivative and formic acid in the presence of a catalyst. The cyclic ketones used include cyclopentanone, cyclohexanone and 2-adamantanone, and the amine derivative used is formamide, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-ethylenediamine, and the catalyst used is copper nanoparticles. The process is carried out in molar ratio ketone: amine derivative: HCOOH equal to 1:3-4:5-10, at temperature 100°C for 3-9 hours. The copper nanoparticles can be obtained in situ, as well as beforehand.

EFFECT: high output of cycloalkylamines under milder conditions for carrying out the process.

3 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing hydrochlorides of amine-derivatives of adamantane of general formula:

,

where R=H, CH3; n=0, 1. According to the disclosed method, biologically active compounds such as, for example, hydrochlorides of 1-aminoadamantane (R=H, n=0) (amantadine) and 1-amino-3,5-dimethyl-adamantane (R=CH3, n=0) (memantine) are obtained, which are used in the chemical and pharmaceutical industry to prepare medicinal agents for treating Parkinson's disease, Alzheimer's diseases, neurodegenerative diseases, glaucoma etc. The method involves reaction of adamantane carboxylic acid with thionyl chloride at its boiling point for 1.5 hours in molar ratio 1:1.1 respectively, to form an acyl chloride of adamantane carboxylic acid, which reacts with sodium azide in anhydrous toluene at its boiling point in molar ratio 1:1:15-20 respectively for 1.5-2 hours, followed by addition of concentrated hydrochloric acid and holding the reaction mass for 1 hour and extracting the end product.

EFFECT: method is more technologically effective and ecologically clean and enables to obtain a large number of homologues of hydrochlorides of amine-derivatives of adamantane with quantitative output of 92-95%.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-n-octyl-N'-phenyl-p-phenylenediamine and N-2-ethylhexyl-N'-phenyl-p-phenylenediamine. The method is realised through alkylation of p-aminodiphenylamine with potassium alcoholate solution in p-octyl (or 2-ethylhexyl) alcohol in uniform portions added to hot molten p-aminodiphenylamine. Alcohol azeotrope is then distilled with water. An organic layer is then separated after aqueous extraction of the reaction mass and N-n-octyl-N'-phenyl-p-phenylenediamine or N-2-ethylhexyl-N'-phenyl-p-phenylenediamine is then extracted therefrom. Alkylation is carried out with half of the prepared amount of potassium alcoholate solution by adding in a single step to the molten p-aminodiphenylamine which is heated to 140-150°C. Temperature in the reactor is then raised to 209°C and the remaining amount of the potassium alcoholate solution is fed. Feeding is carried out until 90% conversion of p-aminodiphenylamine, after which the reaction mass is heated to 232-235°C while blowing with a nitrogen current. The invention also relates to a method of producing N-2-ethylhexyl-N'-phenyl-p-phenylenediamine through vacuum distillation at cut vapour temperature of 240±5°C.

EFFECT: reduced increase in viscosity, acid number and formation of sludge of lubricating and/or motor fuel subjected to thermal oxidation.

2 cl, 6 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-2-ethylhexyl-N'-phenyl-p-phenylenediamine by reacting p-aminodiphenylamine with 2-ethylhexanol in the presence of potassium hydroxide, at temperature 170-235°C with simultaneous distillation of the alcohol azeotrope with water through a heated refluxer and returning the condensed hot alcohol into the reaction zone, separating the end product from the organic layer after aqueous extraction. The mixture of 2-ethylhexanol and potassium hydroxide is preheated to 90-140°C fed into the reaction mass in two steps, at the first step at temperature of the p-aminodiphenylamine not lower than 100°C, 50-90 wt % of the calculated amount of the mixture of 2-ethylhexanol and potassium hydroxide is fed, and the remaining amount is continuously fed until temperature of the reaction mass reaches 200-235°C.

EFFECT: method cuts the duration of the alkylation step and increases efficiency of the equipment.

1 tbl, 9 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

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.

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

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