Method for production of 2-amino-2-cyanoadamantane or derivatives thereof

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 2-amino-2-cyanoadamantane and its derivatives of General formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2CH2NH2.

,,.

which are intermediates in the synthesis of probable biologically active substances. In the literature information about the methods of preparing compounds of the claimed formula is missing.

Closest to the proposed invention is a method for iminodiethanol acid, where the initial connection is diethylketone, which enter into reaction with sodium cyanide in the presence of ammonium chloride with getting cyanhydrin ketone, which on reaction with concentrated ammonium hydroxide in an environment of methanol at 60°With or with methanolic ammonia solution and at a low pressure is transformed into a nitrile α-iminodiethylamine acid [Robert E. Steiger. Organic synthesis, V3, 66. Tiemann and Friedländer, Ber., 14, 1973 (1881)].

This method does not lead to obtaining substances claimed structural formulas. In addition, among the drawbacks of this method is about the mark using methanol and toxic sodium cyanide.

The task of the invention is to develop technological molestating method of synthesis of 2-amino-2-cyanoadamantane or of its derivatives of various structures, proceeding with a high output source 2-hydroxy-2-cyanoadamantane.

The technical result is the expansion of the range of adamantane derivatives, namely intermediates in the synthesis of probable biologically active compounds, to develop a method of synthesis of new derivatives of adamantane with high output.

The technical result is achieved in a new method of obtaining 2-amino-2-cyanoadamantane or its derivatives of General formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2CH2NH2.

,,.

by reacting 2-hydroxy-2-cyanoadamantane with ammonia or its derivatives from a number of: piperidine, morpholine, piperazine, 1,2-diaminoethane, monoethanolamine, benzylamine, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine in the environment of technical ethanol at a molar ratio of reactants is 1:2.35-4, respectively, at a temperature of 20-80°within 8-72 hours.

The essence of the method are the two who is the reaction of obtaining 2-amino-2-cyanoadamantane or its derivatives by the reaction of 2-hydroxy-2-cyanoadamantane with ammonia or its derivatives

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2CH2NH2.

,,.

The method is as follows.

A mixture of 2-hydroxy-2-cyanoadamantane and ammonia or its derivatives from a number of: piperidine, morpholine, piperazine, 1,2-diaminoethane, monoethanolamine, benzylamine, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine in the ratio of 1:2.35-4 in the technical environment of ethanol sealed in an ampoule or heated in a flask under reflux for 8 hours, or stand 24 to 72 hours at room temperature. Upon completion of the reaction, ethanol, water and unreacted ammonia or its derivative is removed in a water jet vacuum pump. After distillation in a vacuum or recrystallization from ethanol obtain the corresponding 2-amino-2-cyanoadamantane or its derivatives. The output of these products is 55-76%.

As studies have shown, the most convenient way of carrying out the reaction is its implementation in the environment of technical ethanol in the presence of 2.35-4-fold excess of ammonia or its derivative. Less excess has resulted in a slight decrease of the yield of the target product is due to the incomplete conversion of 2-hydroxy-2-cyanoadamantane, in the case of use as derivatives of ammonia are to the possible formation of by-products of tizamidine. A further increase in excess of ammonia or its derivative does not affect the yield of target products was inappropriate. It is possible to conduct the reaction as by boiling the reaction mixture at 78-80°C for 8 hours, and keeping the reaction mixture at room temperature (20° (C) within 8-72 hours.

Determined that the slightly basic ammonia derivatives, such as derivatives of aniline, 4-toluidine and N-ethylaniline, do not interact with 2-hydroxy-2-cyanoadamantane even after prolonged boiling, which imposes constraints on the choice of the initial reagents.

Discovered that ammonia derivatives such as tert.-butylamine, diethylamine, dibutylamine, also do not react with 2-hydroxy-2-cyanoadamantane or form products with a lower output, which may be due to steric hindrances created by the substituents at the amino group. On the other hand, piperidine, morpholine and piperazine, having the amino substituents bound in the cycle and not allowing free rotation of the alkyl groups at the nitrogen atom, to react with 2-hydroxy-2-cyanoadamantane, forming the target products.

The structure of the synthesized compounds was confirmed by NMR1H-SPECT is Ecopia and elemental analysis.

The invention is illustrated by the following examples:

Example 1

2-Amino-2-cyanoadamantane

2 g (samples of 0.0113 mol) of 2-hydroxy-2-cyanoadamantane, 4 ml (0.235 mol) of a 25% solution of aqueous ammonia (molar ratio 1:3), 20 ml of technical ethanol is heated in a sealed glass ampoule up to 40°C for 8 hours. Upon completion of the reaction, the ampoule is opened, the alcohol and the ammonia is removed in a water jet vacuum pump (partially crystallize the reaction product), the remainder of the sublimate in a vacuum. Obtain 1.17 g (0.0067 mol) of 2-amino-2-cyanoadamantane, TPL>200°C. the Yield 55%. An NMR spectrum1N, δ, ppm: 1.70, 1.83, 1.87, 1.96, 2.404 5C (14N,2,2-Ad, 2H, NH2). Found, %: C 74.91, N 9.17, N 15.92, C11H16N2. Calculated, %: C 74.96, H 9.15, N 15.89.

Example 2

2-N-Piperidino-2-cyanoadamantane

1.5 g (0.0085 mol) of 2-hydroxy-2-cyanoadamantane, 3 g (0.035 mol) of piperidine (molar ratio 1:4) in 10 ml of technical ethanol is heated in a flask under reflux at 78°C for 4 hours after which the reaction mixture was kept at room temperature for another 4 hours. Upon completion of the reaction the alcohol and piperidine distilled off, the product is distilled in a water jet vacuum pump. T Kip.=240-242°C/20 mm Hg Obtain 1.41 g (0.00578 mol) of 2-N-piperidino-2-cyanoadamantane, yield 68%. sub> PL=77-78°C. an NMR Spectrum1N, δ, ppm: 1.35-1.45 (6N, 3-CH2-); 1.65-2.34 (14N,2,2-Ad); 2.59 (4H, 2-CH2N-). Found, %: C 78.64, N 9.82, N 11.51. C16H24N2. Calculated, %: C 78.69, N 9.83, N, 11.48.

Example 3

2-N-piperazine derivatives-2-cyanoadamantane

1.8 g (0,0102 mol) of 2-hydroxy-2-cyanoadamantane, 3.5 g (0,0407 mol) piperazine (molar ratio 1:4) in 10 ml of technical ethanol is heated to 80°C for 4 hours after which the reaction mixture was kept at room temperature for another 4 hours (thus precipitate the reaction product and excess piperazine). Upon completion of the reaction the alcohol and piperazine is distilled off. The product is distilled in a water jet vacuum pump, TKip=259-262°C/ 20 mm Hg Obtain 1.55 g (0.0063 mol) of 2-N-piperazine derivatives-2-cyanoadamantane, yield 62%. TPL=117-118°C. an NMR Spectrum1H δ, ppm: 1.67-2.35 (14N,2,2-Ad, 1H, NH); 2.805 t (4N, (CH2)2N); 2.95 t (4N, (CH2)2N). Found, %: C 73.49, N 9.39, N, 11.12. With15H23N3. Calculated, %: C 73.47, N 9.39, N 17.14.

Example 4

2-N-Morpholino-2-cyanoadamantane

5 g (0,0282 mol) of 2-hydroxy-2-cyanoadamantane, 8 g (0,092 mol) drained research (molar ratio 1: 3.26) in 30 ml of technical ethanol is heated to 78-80°C for 4 hours. Then the reaction mixture was kept at room temperature is re 4 hours. Upon completion of the reaction the alcohol and morpholine distilled off, the product is distilled in a water jet vacuum pump. TKip=249-250°C/20 mm Hg Receive 5.27 g (0.0214 mol) of 2-N-morpholino-2-cyanoadamantane, yield 76%. An NMR spectrum1N, δ, ppm: 1.35-2.20 (14N,2,2-Ad); 2.58 t (4N, (CH2)2O); 3.72 t (4N, (CH2)2N). Found, %: C 73.20, N 8.92, N 11.42. C15H22N2O. Calculated, %: C 73.17; H 8.94, N 11.38.

Example 5

2-(β-Hydroxyethylamino)-2-cyanoadamantane

4.5 g (0,025 mol) of 2-hydroxy-2-cyanoadamantane, 6.1 g ( 0.1 mol) monoethanolamine (molar ratio 1:4) in 25 ml of technical ethanol is heated to 78-80°C for 4 hours after which the reaction mixture was kept at room temperature for another 4 hours. Upon completion of the reaction the alcohol and distilled morpholine. The product is distilled in a water jet vacuum pump. TKip=278-280°C/12 mm Hg Receive 3.854 g (0.0175 mol) of 2-(β-hydroxyethylamino)-2-cyanoadamantane, yield 70%. An NMR spectrum1N, δ, ppm: 1.21 (1H, NH); 1.45-2.25 (14N,2,2-Ad); 2.67 (1H, HE); 2.99 (2H, CH2N), 3.58 t (2H,CH2O). Found, %: C 70.89, H 9.08, N, 12.71. C13H20N2O. Calculated, %: C at 70.91, N 9.09, N 12.73.

Example 6

2 Benzylamino-2-cyanoadamantane

Mix at room temperature for 3 g (0.017 mol) of 2-hydroxy-2-cyanoadamantane, 4.5 g (0.042 mol) b is Salamina (molar ratio 1:2.5) and 25 ml of technical ethanol to dissolve and leave the reaction mixture for 24-48 h at room temperature (20° C). From the reaction mixture crystallizes the reaction product in the form of light yellow crystals, which are filtered off and recrystallized from aqueous ethanol. Obtain 3.46 g (0.013 mol) of 2-benzylamino-2-cyanoadamantane, yield 75%. TPL=104-105°C. an NMR Spectrum1N, δ, ppm: 1.11 (1H, NH); 1.43-2.29 (14N,2,2-Ad); 3.73 (2H, CH2); 7.11-7.28 m (5H, Ph). Found, %: C 81.23, N 10.41, N, 11.16. C18H22N2. Calculated, %: C 81.16, H 8.32, N 10.52.

Example 7

2 Hydrazino-2-cyanoadamantane

Mix 1.5 g (0.0085 mol) of 2-hydroxy-2-cyanoadamantane, 1.5 g (0.0255 mol) of hydrazine in the form of hydrazine hydrate is added (molar ratio 1:3) and 15 ml of technical ethanol to dissolve and leave the reaction mixture for 72 h at room temperature (20°). From the reaction mixture crystallizes the reaction product in the form of colourless crystals, which are filtered off and recrystallized from aqueous ethanol. Obtain 1.15 g (0.006 mol) of 2-hydrazino-2-cyanoadamantane, yield 70%. An NMR spectrum1N, δ, ppm: 1.44-2.50 (14N,2,2-Ad); 2.93 (1H, NH); 4.48 (2H, NH2). Found, %: C 69.30, N 9.03, N 22.08. With11H17N3. Calculated, %: C 69.07, H 8.96, N 21.97.

Example 8

2-(1-(2-Phenyl)hydrazino)-2-cyanoadamantane

Mix at room temperature, 1.5 g (0.0085 mol) of 2-hydroxy-2-cyanoadamantane, 2.16 g 0.02 mol) of fresh phenylhydrazine (molar ratio 1: 2.35) and 25 ml of technical ethanol and the reaction mixture is stored at 12-16 hours From the reaction mixture crystallizes the reaction product in the form of light yellow crystals, which are filtered off and recrystallized from aqueous ethanol. Obtain 1.68 g (0.0063 mol) of 2-(1-(2-phenyl)hydrazino)-2-cyanoadamantane, bestv. crystals, yield 74%. TPL=152-153°C. an NMR Spectrum1N, δ, ppm: 1.47-2.28 (14N,2,2-Ad); 3.48 (1H, NH); 5.17 (1H, NH); 6.41, 6.81, 7.04 3 m (1+2+2H, Ph). Found, %: C at 76.39, H 7.97, N 15.69. With17H21N3. Calculated, %: C 76.37, H 7.92, N 15.72.

Example 9

2-(β-amino-ethyl)amino-2-cyanoadamantane

4.5 g (0,025 mol) of 2-hydroxy-2-cyanoadamantane, 5.8 g (0.1 mol) of 1,2-diaminoethane (molar ratio 1:4) in 30 ml of technical ethanol is heated to 78-80°C for 4 hours after which the reaction mixture was kept at room temperature for another 4 hours. Upon completion of the reaction is distilled off approximately half of the solvent, the reaction mixture is cooled. The product precipitates, forming white crystals, which are filtered off, washed with a small amount of cold ethanol and receive 4.16 g (0.019 mol) of 2-(β-amino-ethyl)amino-2-cyanoadamantane, yield 76%. An NMR spectrum1H δ, ppm: 1. 25 Sh.S. (3H, NH, NH2); 1.45-2.12 (14H, 2,2-Ad); 2.16 (2H, CH2N); 2.82 (2H, CH2-N). Found, %: C at 71.25, N 9.56, N 19.21. C13H21N3. Calculated, %: C 71.23, N 9.59, N 19.18.

Example 10

2-(2-(2,4-Dinitrophenyl)hydrazino)-2-cyanoadamantane

Mix at room temperature, 1.5 g (0.0085 mol) of 2-hydroxy-2-cyanoadamantane, 3.68 g (0.02 mol) of 2,4-dinitrophenylhydrazine (molar ratio 1: 2.35) and 65 ml of technical ethanol to dissolve 2,4-dinitrophenylhydrazine) and the reaction mixture is boiled for 8 hours. After partial removal of the solvent and cooling crystallizes from the reaction mixture the reaction product as yellow-orange crystals, which are filtered off. Obtain 1.87 g (0.0054 mol) of 2-(2-(2,4-dinitrophenyl)hydrazino)-2-cyanoadamantane, TPL=183-185°exit 64%. An NMR spectrum1H δ, ppm: 1.8-2.25 (14N,2,2-Ad); 3.13 (1H, NH); 7.89, 8.19, 8.99 3 m (1+1+1H, C6H3); 11.1 (1H, NH). Found, %: C at 59.52, H 5.54, N 16.29. C17H19N4O4. Calculated, %: C at 59.48, H 5.54, N 16.33.

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 up to date with what's means and methods;

the tool embodying the claimed invention in its implementation, is able to achieve a technical result.

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

Conclusions

Developed technologically melastatin method of synthesis of 2-amino-2-cyanoadamantane or its derivatives, which allows to obtain a wide range of compounds with high yield. The structure of the synthesized compounds was confirmed by NMR1H-spectroscopy and elemental analysis.

The method of obtaining 2-amino-2-cyanoadamantane or its derivatives of General formula

R=-NH2, -NHCH2CH2OH, -NHCH2C6H5, -NHNHC6H3(NO2)2, -NHNH2, -NHNHC6H5, -NHCH2CH2NH2,

which consists in the interaction of 2-hydroxy-2-cyanoadamantane with ammonia or its derivatives from a number of: piperidine, morpholine, piperazine, 1,2-diaminoethane, monoethanolamine, benzylamine, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine in the environment of technical ethanol at a molar ratio of reagents, respectively 1:2.35-4, at a temperature of 20-80°within 8-72 hours



 

Same patents:

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"

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.

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11 cl, 37 ex, 5 dwg

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13 cl, 2 tbl, 20 ex

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,

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6 cl, 15 tbl, 130 ex

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8 ex

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5 cl, 5 tbl, 8 ex

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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

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2 cl, 100 ex

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1 cl, 2 tbl, 13 ex

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1 tbl, 1 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.

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3 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a heterocyclic compound, involving: reaction of a mixture of 1-methylpiperazine and 5-halogen-2-nitroaniline in a first solvent and at a first temperature ranging from approximately 90°C to approximately 110°C to obtain a compound of formula where the first solvent contains alcohol; cooling the mixture containing the compound of formula VIH to a second temperature ranging from approximately 85°C to approximately 95°C; adding a volume of a second solvent which is different from the first solvent to the mixture, where the second solvent contains water; and forming a suspension of the compound of formula VIH; where the second solvent is heated to the second temperature. The invention also relates to methods of producing a compound of formula VIH using other solvents such as heptane and HO-(CH2)q-OH or HO-CH2CH2OCH2CH2-OH, where q is selected from 2, 3 or 4.

EFFECT: novel method of producing a compound of formula VIH, which enables to obtain a highly pure product which does not require additional purification and is more suitable for use on a large scale owing to the solvents used.

74 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing cyclohexane and derivatives thereof of general formula R=H, . The method involves producing saturated hydrocarbons and derivatives thereof, which can be used as semi-products in organic synthesis. The method involves hydrogenation of cyclohexene or a derivative thereof, which is selected from 1-(N-piperidino)cyclohexene-1,1-(N-morpholino)cyclohexene-1 or 1,4-dicyclohex-1-enylpiperazine with hydrogen gas at atmospheric pressure of hydrogen in the presence of a nanocatalyst in tetrahydrofuran medium at temperature of 50-70°C for 5-6 hours, followed by extraction of the end product. The nanocatalyst used is nickel nanoparticles which are obtained by reducing nickel (II) chloride with lithium aluminium hydride in situ. The method can also be used to obtain a wider range of cyclohexane derivatives which contain heterocyclic groups.

EFFECT: method enables to conduct the process at atmospheric pressure using a catalyst obtained using a simpler technique, which simplifies the method overall.

4 ex

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