Method of producing cycloalkylamines

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

 

The invention relates to the chemistry of amines and their derivatives, namely a new modification reaction gidroaminirovaniya (Lacarte-Vallaha), as a way to obtain cycloalkylation General formula

Where

,,,

,,

,,

which may be of interest as intermediates in the synthesis of some biologically active substances. In particular, some of them are structural analogues of known drug bromantan" (4-bromo-phenylamino-2-adamantane hydrochloride), used in sports medicine [Ishmuratov, Whitecrow, Chassereau. Pharmacology of adamantanes. - Volgograd: Volgograd medical Academy, 2001, - 320 C.]. In addition, 1-aminoadamantana and its derivatives are used as an antiviral and antiparkinsonian funds. Derived cyclohexylamine is applied for drug Bromhexine" [Mashkovsky PPM Medicines. 2 so, T.1. - Ed. 13-e, new. - Kharkov, Torching, 1998. - 560 C.].

The known method is n conjunction obtain the N-methylcyclohexylamine and dicyclohexylamine from cyclohexylamine by catalytic alkylation of cyclohexylamine methanol in the gas phase in a stream of hydrogen on the copper-zinc-chromium-aluminum catalyst [IPC SS 209/24, SS 211/35. RF patent №2344120 C1. Posted: 20.01.2009].

The disadvantages of this method are the use of rather complicated process conditions, is not applicable in laboratory conditions, as well as the fact that he is unfit to obtain other compounds of the claimed structural formulas.

A method of obtaining tertiary amines by the reaction of ketones with secondary amines, where the reductant is used triacetoxyborohydride sodium and the process is carried out in dichloromethane or tetrahydrofuran in the presence of acetic acid at room temperature for 0.5-75 hours [A.F.Abdel-Magid, K.G.Carson, .D.Harris, ..Maryanoff, R.D.Shah. The Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Animation Procedures. // J. Org. Chem., 1996, 61, 3849-3862; Ahmed F.Abdel-Magid, Steven J. Mehrman. A Review on the Use of Sodium Triacetoxyborohydride in the Reductive Amination of Ketones and Aldehydes. // Organic Process Research &Development 2006, 10, 971-1031].

The disadvantages of this method are the use of quite expensive and not readily available reductant, long synthesis time for some compounds. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining secondary and tertiary amines by the reaction of aldehydes or ketones with amines, where the reductant is used decaborane and the process is carried out in methanol at the room for the Noah temperature for 0.5-12 hours [J.W.Bae, S.H.Lee, Y.J.Cho, Smoop. A reductive animation of carbonyls with amines using decaborane in methanol. // J. Chem. Soc., Perkin Trans. 1, 2000, 145-146].

The disadvantages of this method are the use of quite expensive and not readily available reductant, it was a fire hazard. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining derivatives of arylalkylamines by the reaction of aldehydes or ketones with aniline derivatives, where the reductant is used triacetoxyborohydride sodium and the process is carried out in isopropanol in the presence of 2 equivalents triperoxonane acid at room temperature for 10 minutes [.McLaughlin, M.Palucki, I.W.Davies. Efficient Access to Azaindoles and Indoles. // Org. Lett., 2006, 8, - pp.3307-3310].

The disadvantage of this method is quite expensive and not readily available reductant. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining aminoalcohols by the reaction of aldehydes with secondary amines, where the reductant is used triethyl-gedrosian and the process proceeds in 1,4-dioxane at 75°C for 8 hours in the presence of a metal complex catalyst containing iridium [T.Mizuta, S.Sakaguchi, Y.Ishii. Catalytic Reductive Alkylation of the Secondary Amine with Aldehyde and Silane by an Indium Compound. // J. Org. Chem., 2005, 70, 2195-2199].

The disadvantage of this is about the method is the use of expensive and not readily available catalyst. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining tertiary amines by the reaction of β-hydroxyketones with amines, and as a reducing agent is used polymethylhydrosiloxane and the process proceeds in the presence of tetraisopropoxide at 25-60°C, up to 48 hours [Dirk Menche, Fatih Arikan, Jun Li, Sven Rudolph. Directed Reductive Animation of β-Hydroxy-ketones: Convergent Assembly of the Ritonavir/Lopinavir Core. // Org. Lett., Vol.9, No.2, 2007. - p.267-270].

The disadvantage of this method is the use of expensive and not readily available reductant and catalyst. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining tertiary amines by the reaction of aliphatic and aromatic ketones with derivatives of aniline, and as reductant used derivatives of ether Ganch and the process proceeds in the presence of complex chiral catalysts and molecular sieves at 40°C for 72 hours [R.Ian Storer, Diane E.Carrera, Yike Ni, and David W.C.MacMillan. Enantioselective Organocatalytic Reductive Animation. // J. Am. Chem. Soc., Vol.128, No.1, 2006. - p.84-86].

The disadvantages of this method are the use of expensive and not readily available reductant and catalyst, the high duration of the process. In addition, this method was not synthesized compounds claimed in the structural forms of the crystals.

A method of obtaining secondary amines by the reaction of aromatic and aliphatic ketones with aromatic amines, and as a reducing agent used is a mixture of a derivative of dihydropyridines and thiourea, the process proceeds in the presence of molecular sieve 5 Å, the duration of 24-48 hours [Dirk Menche, Jorma Hassfeld, Jun Li, Gerd Menche, Antje Ritter, Sven Rudolph. Hydrogen Bond Catalyzed Direct Reductive Amination of Ketones. // Org. Lett., Vol.8, No.4, 2006. - p.741-744]. The yields of products 36-94%.

The disadvantages of this method are the use of inaccessible ether Ganch, the long duration of the process. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining tertiary amines by the reaction of aliphatic and aromatic ketones with ammonium formate at a temperature of 70°C in an environment of methanol during the 2-31 hours, and the catalyst used metal complex compounds of platinum group metals, mainly rhodium [Masato Kitamura, Donghyun Lee, Shinnosuke Hayashi, Shinji Tanaka, Masahiro Yoshimura. Catalytic Leuckart-Wallach-Type Reductive Amination of Ketones. // J. Org. Chem. 2002, 67, pp.8685-8687]. Outputs the resulting amines are 3-99%.

The disadvantage of this method is the use of inaccessible and expensive catalyst. In addition, this method was not synthesized compounds claimed structural formulas.

A method of obtaining compounds and the illogical structure by the reaction of Lacerta-Vallaha, flowing within 8-24 hours with significant (up to 20-fold molar) excess of formamide or its derivative, in the presence of formic acid (an excess of up to 10-fold molar). Process temperature (with the exception of aldehydes and lower ketones) is not lower than 160°C., more 180-200°C [Organikum: 2 so Vol.2: TRANS. with it. - M.: Mir, 1992. - 474 S., ill.]. The yields range from 40 to 80%.

The disadvantage of this method is that there is a significant resinification of the reaction mixture due to prolonged heating, using a considerable consumption of formamide and formic acid, a long synthesis time (12-18 hours), high requirements to dehydration of the initial reagents. In addition, upon termination of the reaction are formed not target amines and the corresponding amides of formic acid, often requiring prolonged hydrolysis and subsequent selection of products. This method was not synthesized compounds claimed structural formulas.

A method of obtaining derivatives of 2-aminoadamantana hydroamination 2-adamantanone to 2-aminoadamantana hydrogen under pressure over platinum catalyst, followed by alkylation of 2-aminoadamantana or by acylation with further recovery [2-Adamantanamines. U.S. patent No. 3532748, publ. 1970. C07C 87/40, 91/14, 93/12; Pharmaceutical compositions and methods utilizing 2-aminoadamantane and its derivatives is atent U.S. No. 3328251, publ. 1967].

The disadvantages of this method are its multi-stage, using in some cases the fire lithium aluminum hydride. In addition, this method received only one connection of the claimed General formula.

A method of obtaining derivatives of 2-aminoadamantana hydroamination 2-adamantanone to 2-aminoadamantana hydrogen under pressure over platinum catalyst, further alkylation of 2-aminoadamantana or by acylation followed by reduction [2-Adamantanone and derivatives. U.S. patent No. 3257456, publ. 1966; Adamantane derivatives. Pat. UK No. 1157143, publ. 1969. C07C 87/40, 19/12].

The disadvantages of this method are its multi-stage, using hydrogen and expensive catalyst, in some cases also the fire of lithium aluminum hydride. In addition, this method received only one connection of the claimed General formula.

A method of obtaining derivatives of 2-aminoadamantana condensation of adamantanone-2 with the appropriate amine and subsequent restoration intermediate Iminov hydrogen under pressure over platinum or Nickel catalyst within 48-72 hours [U.S. Patent No. 5380947, publ. 1995. C07C 211/62, C07C 211/63].

The disadvantages of this method are its multi-stage, using hydrogen and expensive catalyst, in addition, this method is not with what was nasioulas of the claimed compounds of structural formulas.

The known method for preparation of aromatic derivatives of 2-aminoadamantana by the reaction of Lacerta-Vallaha between adamantanone-2 and derivatives of aniline at 160°C for 10 hours [N-ADAMANTYL DERIVATIVES OF AROMATIC AMINES. PART I. SYNTHESIS AND NEU-ROTROPIC ACTIVITY OF N-(ADAMANT-2-YL)ANILINES. / I.S.Morozov, N.V.Klimova, L.N.Lavrova, N.I.Avdyunina, B.M.Pyatin, V.S.Troitskaya, N.P.Bykov. // Pharmaceutical Chemistry Journal, Vol.32. No.1, 1998. - pp.1-4].

The disadvantages of this method are fairly rigid conditions the reaction, this method is not the compounds of the claimed General formula.

The closest to the proposed invention is a method of obtaining derivatives of 2-aminoadamantana by the reaction of 2-adamantanone or 2,6-aminoadamantane with amines of the number of 4-bromaniline, pyrrolidine, piperazine, 4-aminomaslana acid, etc. in the presence of formic acid at a temperature of 140-160°C for 4-10 hours [Antistaticity activity of heterocyclic derivatives of 2-aminoadamantana. Morozov I., Waldman EA, Voronina T.A., Neronova L.N., Klimova N.V., Ivanov L.N., Avdonina NI, Pyatin BM // Chem. Pharm. Journal WIP, No. 4, 2000. - p.27-30; ANTICATALEPTIC ACTIVITY OF HETEROCYCLIC 2-AMINOADAMANTANE DERIVATIVES. / I.S.Morozov, E.A.Val'dman, T.A.Voromna, L.N.Nerobkova, N.V.Klunova, L.N.Lavrova, N.I.Avdyunina, B.M.Pyatin. // Pharmaceutical Chemistry Journal, Vol.34, No.4, 2000. pp 189-192]. The yields of products are 40-75%.

The disadvantages of this method are low in most cases, the yields of target products when DOS is hard enough reaction conditions. In addition, this method could only make one connection of the claimed General formula.

The technical result is to develop a technologically advanced method of obtaining compounds of the claimed structural formulas.

The task of the invention is to develop technological molestating synthesis method cycloalkylation proceeding with a high output source ketones under relatively mild conditions.

The technical result is achieved in a new way to get cycloalkylation General formula

Where

,,,

,,

,,

which consists in the interaction of cyclic ketone with an amine derivative and formic acid, at the same time as cyclic ketones using Cyclopentanone, cyclohexanone or 2-adamantanone, and as amine derivative use formamid, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-Ethylenediamine, and the reaction proceeds when the molar ratio is aniah cyclic ketone:derived amine:HCOOH, equal to 1:3-4:5-10, at a temperature of 100°C for 3-9 hours in the presence of catalytic amounts of copper nanoparticles. When this copper nanoparticles get in the reaction mixture in situ recovery of copper chloride (II iron under stirring, or get them pre-restoration chloride copper (II iron with stirring in the solvent system of formamide-water mass ratio of CuCl2*2H2O:formamide:water = 1:4:1.5.

The essence of the method is the synthesis of cycloalkylation reaction gidroaminirovaniya cyclic ketones of the series: Cyclopentanone, cyclohexanone, 2-adamantanone in their interaction with formamide or formate amine or its derivative from a number of cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-Ethylenediamine and formic acid in the presence of catalytic amounts of copper nanoparticles.

Where

,,,

,,

,,

The reaction is based on a previously unknown property of copper nanoparticles to catalyze PR is the process gidroaminirovaniya cyclic ketones. The developed method allows one to obtain a wide range of cycloalkylation. The method is as follows.

In a flat-bottomed flask, equipped with magnetic stirrer with iron (steel) magnetic element without shell, thermometer and reflux condenser, download formamide or formate corresponding amine (obtained from the amine and formic acid), a catalytic amount of concentrated aqueous solution of CuCl2*2H2O and heated to 100°C. with vigorous stirring until the formation of colloidal copper. After the formation of reddish clear solution add cycloalkylation and formic acid. The reaction mass is stirred at 100°C 3-9 hours, thus there is a complete homogenization of the reaction mixture. When using formamide add the required amount of water and hydrochloric acid and hydrolyzing formyl amine derivative at boiling 1-1,5 hours, after which the amine is precipitated from the hydrochloric acid salt with an aqueous solution of alkali. When using amine formate stage hydrolysis and exclude Amin exhale, precipitating the free base corresponding muraveinikakh salt aqueous solution of alkali. After addition of NaOH to slightly alkaline environment the mixture is filtered to remove mechanical impurities on a Buechner funnel. Free base twice extragere is a small amount of diethyl ether, the ether is distilled off, the product is distilled. The yields of products of the inventive structural formulas are 68-91%.

Perhaps the use of catalytic amounts previously prepared colloidal copper. The preparation is carried out in flat-bottomed flask on the magnetic stirrer with the use of iron (steel) magnetic element without the shell. In the flask is charged with formamide and an aqueous solution of CuCl2*2H2O observing the mass ratio of CuCl2*2H2O:formamide:water = 1:4:1.5, and the reaction mixture is heated to 80-100°C with stirring for 2-3 hours before the termination of the formation of finely dispersed precipitate of copper. The mass of reactive iron (steel) magnetic element should be sufficient to complete the reaction of the exchange. Upon termination of the reaction mixture is optionally diluted with a small amount of water and filtered on a Buechner funnel with a paper filter, ensuring the transparency of the filtrate. The precipitate red or blond washed with water to remove formamide, sucked off, to remove excess moisture. The obtained colloidal copper is used for the reaction immediately or can be stored for quite a long time in a closed container.

Found that the reaction gidroaminirovaniya in these conditions do not depend strongly on bezbednosti initial substances and proceeds with the guarantee of the ow velocity in the presence of up to 10 wt.% water. It is shown that an excess of formamide, lower 3-fold, leads to the formation along with formilmetioninom formyl derivative dicyclohexylamine. At equimolar ratio of cyclohexanone and formamide these compounds are formed in near equal proportions. The optimal ratio of ketone: formamide: HCOOH is 1:3:5, and the minimum consumption of reagents, the conversion of cyclohexanone for 4-5 hours at 100°C, the output cyclohexylamine after hydrolysis of the formyl derivative reaches 70%.

Found that 2-adamantanone markedly inferior in reactivity of cyclohexanone at 100°C, including because of its partial sublimation under the reaction conditions. The increased duration of the reaction 2-adamantanone with wavelengths up to 6-7 hours and apply a small amount of inert solvent (2-3 ml benzene), which returns adamantane-2 in the reaction allowed to obtain the target product with a yield of 82% after separation. Discovered that the reaction of 2-adamantanone with piperidine under these conditions for 3 hours leads to the conversion of the ketone only 55%, increase in time up to 6 hours increases conversion up to 90%, and only 9 hours of reaction, there was complete disappearance of adamantanone-2.

When the interaction of 2-adamantanone with compounds containing two amino groups (piperazine, Ethylenediamine), you must use the th greater the excess of formic acid, spent on the education of deformation data amines. Found that the optimal molar ratio of cyclic ketone: derived amine: HCOOH in these cases is 1:3-4:9-10.

Determined that lowering the reaction temperature to 90°C dramatically reduces the yield of the target products due to the low conversion of the starting reagents. Temperature rise up to 130-160°C leads to acceleration of the reaction, however, the addition of formate amines or their derivatives are formed corresponding derivatives of formamide, requiring additional hydrolysis step, and therefore the specified temperature increase is unreasonable.

The structure of the synthesized cycloalkylation confirmed by NMR1N-spectroscopy, properties of known compounds correspond to the literature data.

The invention is illustrated by the following examples:

Example 1

Cyclohexylamin

In a flat-bottomed flask, equipped with magnetic stirrer, thermometer and reflux condenser, download 22.5 g (0.5 mol) of formamide, 2 g (0,0116 mol) CuCl2*2H2O and 4 ml of water and heated with stirring to 80 to 100°C. before the formation of a red solution of colloidal copper, added 16.3 g (0.167 mol) of cyclohexanone and 38.4 g (0.84 mol) of formic acid (molar ratio 1:3:5 respectively). The reaction mass was stirred at 100°C. 3 the Asa, thus there is a complete homogenization of the reaction mass and the disappearance of the smell of cyclohexanone. Add 100 ml of water, 50 ml of 33% hydrochloric acid and hydrolyzing formyl derivative cyclohexylamine at boiling 1-1,5 hours. The mixture is cooled, crystals fall of hydrochloric acid cyclohexylamine. Added with shaking NaOH to slightly alkaline environment, filter from mechanical impurities on a Buechner funnel. The free base is extracted twice with 20 ml diethyl ether, the ether is distilled off, the product is distilled, receiving 11.4 g (0.117 mol, 70%) cyclohexylamine, BP. 132-134°C, nD201.4314 (lit. BP. 134°C, nD201.4318 [Alfa Aesar. Research Chemicals, Metals and Materials. 2006-2007. - 2766 p.]).

Example 2

Dicyclohexylamine

In a flat-bottomed flask, equipped with magnetic stirrer, thermometer and reflux condenser, download 9.9 g (0.1 mol) of cyclohexylamine and portions are added 4.6 g (0.1 mol) of formic acid. To melt the salts was added 1 g (0,0058 mol) CuCl2*2H2O and 2 ml of water and heated with stirring to 80 to 100°C. before the formation of a red solution of colloidal copper, then added 3.3 g (0.033 mol) of cyclohexanone, and then 3 g (0.065 mol) of formic acid (molar ratio 1:3:5 respectively). The reaction mass was stirred at 100°C. for 4 hours, cool, add 100 ml of water and pribam Aut when shaken NaOH to slightly alkaline environment, filtered solids on a Buechner funnel. The free base is extracted twice with 20 ml diethyl ether, the ether is distilled off, the product is distilled, obtaining 4.1 g (0.022 mol, 68%) dicyclohexylamine, BP. 269-270°C, nD201.4839 (lit. BP. 270°C, nD201.4842 [Alfa Aesar. Research Chemicals, Metals and Materials. 2006-2007. - 2766 p.]).

Example 3

2-Formelementname

A mixture of 4 g (0.0233 mol) CuCl2*2H2O, 16 g (0.355 mol) of formamide and 6 ml of 0.333 mol) water (mass ratio of reactants is 1:4:1.5) is placed in a flat-bottomed flask, equipped with magnetic steel element (shaft) weight 2.5 g, and heated under vigorous stirring to 100°C for 2-3 hours. Observed color change from blue to brown and then red, and then from the supersaturated colloidal solution begins to fall fine orange-red precipitate of copper. Upon completion of the reaction the reaction mass is then cooled and filtered on a Buechner funnel through a paper filter, wash the precipitate with a small amount of water.

In a flat-bottomed flask, equipped with magnetic stirrer, thermometer and reflux condenser, download 4.5 g (0.1 mol) of formamide and 0.3 g of pre-prepared colloidal copper and heated to 100°C. After dissolution of copper and the formation of a reddish clear solution is added 5 g (0.033 mol) of 2-adamantane is on, 3 ml of benzene and 9.1 g (0.2 mol) of formic acid (molar ratio 1:3:6, respectively). The reaction mass was stirred at 100°C. for 8 hours, with a couple of benzene wash sublimating 2-adamantanone, returning it to the reaction mixture. Upon completion of the reaction the solvent is distilled off, the reaction mass must not remain insoluble unreacted 2-adamantanone. Add 100 ml of water, filter the precipitated white precipitate, washed with water and dried. Get 5 g (0.03 mol, 91%) 2 formylamino-Montana. An NMR spectrum1N, δ, ppm: 1.57-2.03 m (14N, 2-substituted), 4.00 (1H, CH-N, 2-substituted), 6.44 ush. (1H, NHCO), 1.97 (2H, CH2CO), 7.99 (1H, Cho).

Example 4

N-2-Adamantylidene

Similarly, from 5 g (0.033 mol) of 2-adamantanone, 10 g (0.12 mol) of piperidine, 8.8 g (0.19 mol) of formic acid (molar ratio 1:3.6:5.6, respectively) and 0.25 g of colloidal copper, previously obtained according to example 3, at 100°C for a reaction time of 7.5 hours of excretion receive 5.55 g (0.025 mol, 76%) of N-2-adamantylidene, BP. 166-168°C./10 mm Hg nD201.5051. Range. NMR1N, δ, ppm: 1.27-1.76 m (10H, 2-substituted, 6N, (CH2)3), 1.92 (1H, CH-N, 2-substituted), 2.00 (4H, substituted), 2.28 ush. (4H, N(CH2)2).

Example 5

N-2-Adamantylidene

In a flat-bottomed flask on a magnetic mesalc is, supplied with steel magnetic element without shell, a thermometer and a reflux condenser, a load of 10 g (0.12 mol) of the research, 5.5 g (0.12 mol) of formic acid. To melt the salts at 100°C add 1.71 g (0.01 mol) CuCl2*2H2O and 2.5 ml of water and heated with stirring until the formation of a red solution of colloidal copper, then add 5 g (0.033 mol) of 2-adamantanone, and then 2.3 g (0.05 mol) of formic acid (molar ratio 1:3.6:5.2, respectively). The reaction mass was stirred at 100°C. for 6 hours, cool, add 100 ml of water and added with shaking NaOH to slightly alkaline environment, filter from mechanical impurities on a Buechner funnel. The free base is extracted twice with 20 ml diethyl ether, the ether is distilled off, the product is distilled in a vacuum. Obtain 5.2 g (0.024 mol, 70%) N-2-adamantylamine, BP. 225-227°C/20 mm Hg, TPL 44-45°C. an NMR Spectrum1N, δ, ppm: 1.25-1.78 m (10H, 2-substituted), 1.92 (4H, substituted), 1.99 (1H, CH-N, 2-substituted), 2.26 ush. (4H, N(CH2)2), 3.51 t (4H, O(CH2)2).

Example 6

N-2-Adamantylidene

Similarly, for 9 hours at 100°C. of 5 g (0.033 mol) of 2-adamantanone, 11 g (0.13 mol) of piperazine, 15.2 g (0.33 mol) of formic acid (molar ratio 1:4:10, respectively) and 0.3 g of colloidal copper, previously obtained according to example 3, get the 5.4 g (0.025 mol, 74%) of N-2-adamantylamine, BP. 235-237°C/20 mm Hg NMR Spectrum1N, δ, ppm: 0.82 ush. s (1H, NH), 1.33-2.02 m (14N, 2-substituted), 1.99 (1H, CH-N, 2-substituted), 2.36 m (4H, N(CH2)2), 2.75 (1H, CH-N, 2-substituted), 3.36 D. T. (4H, N(CH2)2.

Example 7

N-2-Adamantylamine

Similarly, for 6.5 hours at 100°C. of 3 g (0.02 mol) 2-adamantanone, 6 g (0.06 mol) of cyclohexylamine, 4.6 g (0.1 mol) of formic acid (molar ratio 1:3:5 respectively) and 0.25 g of colloidal copper, previously obtained according to example 3, to obtain 3.3 g (0.014 mol, 71%) of N-2-adamantylamine, BP. 205-207°C./18 mm Hg NMR Spectrum1N, δ, ppm: 0.60 ush. s (1H, NH), 0.94-1.99 m (14N, 2-substituted, (CH2)5, cyclohexyl), 2.38 m (1H, CH-N, cyclohexyl), 2.74 (1H, CH-N, 2-substituted).

Example 8

2-Adamantanemethanol

Similarly, for 6 hours at 100°C. of 5 g (0.033 mol) of 2-adamantanone, 6.1 g (0.1 mol) of 2-aminoethanol, 8.8 g (0.19 mol) of formic acid (molar ratio 1:3:5.75, respectively) and 0.25 g of colloidal copper, previously obtained according to example 3, to obtain 5.1 g (0.26 mol, 78%) of 2-adamantanemethanol, TPL 118-120°C. an NMR Spectrum1H, δ, ppm: 0.82 ush. s (1H, NH), 1.43-2.01 m (10H, 2-substituted), 1.92 (4H, substituted), 2.63 (1H, CH-N, 2-substituted), 2.75 t (2H, NCH2), 2.87 ush. s (1H, OH), 3.61 t (2H, och2).

Example 9

2-(2-Substituted)amine the ylamine

Similarly, for 8.5 hours at 100°C. of 5 g (0.033 mol) of 2-adamantanone, 6.1 g (0.1 mol) of Ethylenediamine, 14.4 g (0.313 mol) of formic acid (molar ratio 1:3:9.5, respectively) and 0.3 g of colloidal copper, previously obtained according to example 3, to obtain 5.3 g (0.27 mol, 83%) of 2-(2-substituted)aminoethylamino, BP. 182-185°C/20 mm Hg NMR Spectrum1N, δ, ppm: 0.80 ush. s (1H, NH), 1.32-2.00 m (14N, 2-substituted), 2.87 (1H, CH-N, 2-substituted), 2.99 t (2H, NCH2), 3.57 t (2H, NCH2), 2.56 ush. (2H, NH2).

Example 10

N-Cyclopentenopyridine

Similarly, for 5 hours at 100°C. of 11 g (0.13 mol) of Cyclopentanone, 33.4 g (0.4 mol) of piperidine and 30 g (0.65 mol) of formic acid (molar ratio 1:3:5 respectively) and 0.75 g of colloidal copper, previously obtained according to example 3, to obtain 16.5 g (0.108 mol, 83%) of N-cyclopentenopyridine, BP. 230-231°C, nD201.4840. Lit. BP. 230°C [Preparation and Reactions of Sulfbnic Esters. V. Synthesis of Cyclic Tertiary Amines. / D.D.Reynolds, W.O.Kenyon. // J. Am. Chem. Soc., 1950, Vol.72. - p.1597-1598].

Example 11

N-Cyclohexylpiperidine

In a flat-bottomed flask on a magnetic stirrer supplied with steel magnetic element without shell, thermometer and reflux condenser, load 26 g (0.3 mol) of piperidine and 13.8 g (0.3 mol) of formic acid. To melt the salts at 100°C add 3.42 g (0.02 mol) CuCl2*2H2O the 4 ml of water and heated with stirring until the formation of a red solution of colloidal copper, then added 9.8 g (0.1 mol) of cyclohexanone, and then 9.2 g (0.2 mol) of formic acid (molar ratio 1:3.6:5.2, respectively). The reaction mass is heated at 100°C under vigorous stirring for 4 hours, after highlighting, similar to example 1, to obtain 12.7 g (0.076 mol, 76%) of N-cyclohexylpiperidine, BP. 232-234°C, nD201.4842. Lit. BP. 234°C [Preparation and Reactions of Sulfonic Esters. V. Synthesis of Cyclic Tertiary Amines. / D.D.Reynolds, W.O.Kenyon. // J. Am. Chem. Soc., 1950, Vol.72. - p.1597-1598].

Thus, the above data confirm that the implementation of the use of the claimed invention the following cumulative conditions:

the tool embodying the claimed invention in its implementation, is intended for use in various industries;

for the claimed invention in the form as it is described in the independent clause following claims, confirmed the possibility of its implementation using the above described in the application or known before the priority date tools and methods;

the tool embodying the claimed invention, it is able to achieve a technical result.

Therefore, the claimed invention meets the requirement of "industrial applicability".

Conclusions

Developed new technological melastatin method of synthesis pileal is ylamino, proceeding with a high output source ketones under relatively mild conditions. The structure of the obtained compounds was confirmed mass, NMR1N-spectroscopy and elemental analysis.

1. The method of producing cycloalkylation General formula Alk-R
where

,,,
,,,,
,,
which consists in the interaction of cyclic ketone with an amine derivative and formic acid, characterized in that as cyclic ketones using Cyclopentanone, cyclohexanone or 2-adamantanone, and as amine derivative use formamid, cyclohexylamine, piperidine, morpholine, piperazine, 2-aminoethanol, 1,2-Ethylenediamine, and the reaction proceeds at a molar ratio of cyclic ketone: derived amine: HCOOH 1:3-4:5-10, at a temperature of 100°C for 3-9 h in the presence of catalytic amounts of copper nanoparticles.

2. The method according to claim 1, characterized in that the copper nanoparticles get in the reaction mixture in situ recovery of copper chloride (II iron with stirring.

3. The way is about to claim 1, characterized in that the copper nanoparticles get pre-restoration chloride copper (II iron with stirring in the solvent system of formamide-water mass ratio of CuCl2·2H2O:formamide:water = 1:4:1,5.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 1-aminomethyl-2-phenylacetylenes of formula (1), where is characterised by that, phenylacetylene (Ph-C≡CH) is reacted with gem-diamines R2NCH2NR2, where R2N is as defined above, in the presence of a Sm(NO3)2*6H2O catalyst in molar ratio phenylacetylene: gem-diamine: Sm(NO3)2*6H2O=10:(8-12):(0.2-0.6) at 80°C and atmospheric pressure for 3-5 hours.

EFFECT: new method is designed for synthesis of 1-aminomethyl-2-phenylacetylenes, which can be used in fine organic synthesis, particularly for synthesis of scarce polycyclic compounds.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining substituted aminobenzhydrols, which can be used as semi-products in synthesis of medications of general formula , where: R1=R3=H, R2=NH2, R4=Cl (1); R1=R3=H, R2=NH2, R4=Br (2); R1=R3=H, R2=NH2, R4=OCH3 (3); R1=R4=H, R2=NH2, R3=Cl (4); R1=H, R2=NH2, R3=Cl, R4=Cl (5); R1=NH2, R2=Cl, R3=R4=H (6); R1=NH2, , R3=R4=H (7); R1=NH2, R2=Cl, R3=H, R4=Cl (8); R1=NH2, , R3=H, R4=Cl (9); R1=NH2, R3=Cl, R2=R4=H (10); R1=NH2, , R2=R4=H (11); R1=NH2, R2=H, R3=Cl, R4=Cl (12); R1=NH2, R2=H, , R4=Cl (13), whish lies in simultaneous reduction of nitro- and carbonyl groups of respective nitrobenzphenones of general formula , where: R1=R3=H, R2=NO2, R4=Cl; R1=R3=H, R2=NO2, R4=Br; R1=R3=H, R2=NO2, R4=OCH3; R1=R4=H, R2=NO2, R3=Cl; R1=H, R2=NO2, R3=Cl, R4=Cl; R,=NO2, R2=Cl, R3=R4=H; R1=NO2, , R3=R4=H; R1=NO2, R2=Cl, R3=H, R4=Cl; R1=NO2, , R3=H, R4=Cl; R1=NO2, R3=Cl, R2=R4=H; R1=NO2, , R2=R4=H; R1=NO2, R2=H, R3=Cl, R4=Cl; R1=NO2, R2=H, , R4=Cl, reducing system Zn-NaBH4 in alcohol with molar ratio of substratum : zinc: sodium tetrahydroborate equal 1 : 3.5 : 0.25.

EFFECT: reduction of synthesis cost, reduction of time and temperature for process carrying out, increase of target products output.

1 cl, 2 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of compounds of general formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2СН2NH2.

, , .

Claimed method includes interaction of 2-hydroxy-2-cyanoadamantane with ammonia or derivatives thereof such as piperidine, piperazine, 1,2-diaminoethane, etc, in ethanol medium, at 20-80°C for 8-72 h.

EFFECT: enhanced assortment of adamantine derivatives useful as synthetic intermediates for bioactive compounds, method of increased yield.

1 cl, 10 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.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) and its pharmaceutically acceptable salts. In general formula (I) , Y represents group -CONH(Q)- or -NHCONH(Q)-; Q represents 6-member aromatic ring or 5-10-member heteroaromatic ring, containing one or two N heteroatoms or two O heteroatoms; R represents hydrogen, halogen, linear or branched (C1-C6)alkyl; (C1-C6)alkoxy; di-(C1-C6)alkylamino, 5-member heteroaromatic ring, containing one O or S heteroatom; 6- or 9-member heteroaromatic ring, containing one or two N heteroatoms; phenyl, mono- or disubstituted with halogen, (C1-C6)alkyl, halogeno(C1-C6)alkyl, (C1-C6)alkoxy, acyl; hydroxy; piano; di-(C1-C6)alkylamino, acylamino' carbamoyl; X represents group : where Z represents CH2, N or O; m represents integer number from 1 to 3; p is equal 0, 1; R" is selected from group, consisting of di-( C1-C6)alkylaminocarbonyl, (C1-C6)alkyl, acyl. Invention also relates to pharmaceutical composition, containing as active ingredient, invention compound, to application of invention compound for manufacturing pharmaceutical composition, to method of inhibition of nicotinic acetylcholine receptor α7.

EFFECT: obtaining compound, which possesses agonistic activity with respect to nicotinic acetylcholine receptor (nAChR) α7.

7 cl, 2 tbl, 4 dwg, 270 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of General formula

where X1-X5denote SN2or one of them denotes NH, and the other X1-X5are CH2; k is 0 or 1, R1is1-8the alkyl, C1-8hydroxyalkoxy; t is 0, 1 or 2; And represents phenyl or pyridinyl; R2is H, hydroxyl, halogen or1-6the alkyl, C1-6alkoxygroup; n is 0, 1-4; p is 0 or an integer from 1 to 5, Y is-C(O)-; Z is CH2or their pharmaceutically acceptable salts

The invention relates to compounds of formula (I), their stereochemical isomeric forms, their salts obtained by the joining of acid or base, their N-oxides or Quaternary ammonium derivative, where the dotted line represents an optional bond; X is absent when the dotted line represents a bond, or X is a hydrogen or a hydroxy-group, when the dotted line is not a bond, R1, R2, R5and R6each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, SO3N and the like; R3and R4each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, nitro, amino, ceanography, trifloromethyl or cryptometer;represents a radical of the formula (a-1), (a-2), (a-3), (a-4), (a-5), (6), (7), (8), (9), (10), where a1represents a direct bond or C1-6alcander; AND2represents a C2-6alcander; R7- R11represents hydrogen, C1-6alkyl, amino1-6alkyl and the like, provided that when L is Soboh the

The invention relates to a new specified in the title of a chemical compound, which are presented below, and to methods for the treatment of painful conditions, modulating allergic, inflammatory or cholinergic activity in mammals, using the new mentioned above in the title of chemicals

FIELD: industrial organic synthesis.

SUBSTANCE: process involves formic acid-methylamine reaction via intermediate methylammonium formate salt, which is dehydrated in presence of molybdenum trioxide catalyst dissolved in aqueous methylamine and added to formic acid in amount 2.0-4.0 wt % based on the latter. Reaction is carried out for 1-2 h in reactor filled with inert packing material having developed surface without cooling of reaction mixture, whereupon volatile products are distilled away at bottom temperature up to 190°C for 60-90 min. Bottom residue containing catalyst, after isolation of desired product, is returned to reactor.

EFFECT: reduced reaction time, reduced power consumption, improved quality of product obtained at increased yield, and diminished production waste.

5 cl, 8 ex

The invention relates to methods for metachlorophenylpiperazine, which can be used as an intermediate product in the preparation of biologically active compounds, particularly in the industrial development of the production of original domestic anticonvulsant galadima (meta-chlorobenzhydryl)
Up!