Method for preparing 1-aryl-4-oxoadamantanes

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to chemistry of adamantanes, namely to a method for synthesis of 1-aryl-4-oxoadamantanes of the general formula: wherein R means -CH3, -OH, -N(CH3)2, -OCH3. Method involves interaction of 1-bromo-4-oxoadamantane with benzene derivative chosen from the following order: toluene, phenol, dimethylaniline or anisole in the mole ratio of reagents = 1:(506), at temperature 100-180°C in the presence Lewis acids AlCl3, FeBr3, ZnCl2 for 5-8 h. Method provides synthesis of novel compounds that are semifinished substances in synthesis of biologically active compounds.

EFFECT: improved method of synthesis.

4 ex

 

The invention relates to the chemistry of adamantane derivatives, and in particular to a new process for the preparation of 1-aryl-4-oxoacetate General formula

where R=CH3HE, N(CH3)2The co3,

which are important intermediates in the synthesis of probable biologically active substances. For example, a known drug bromantan" (4 brompheniramine-2-adamantane), used in sports medicine. Provides information on medicinal drug "Kelantan", about the testing of other compounds of similar structure as medicines [Ishmuratov, Whitecrow, Chassereau. Pharmacology of adamantanes. - Volgograd: Volgograd medical Academy, 2001, - 320 C.].

Thus, the introduction of functional groups into the molecule of adamantanone-2 leads to various kinds of biological activity, or enhances existing ones.

At the same time, in the literature there is no description of how to obtain a 1-of aryl-substituted adamantanes containing a keto group in position 4. A method of obtaining 1-hydroxy-4-accoutumance (preparation "Kelantan") of adamantanone-2 by oxidation with a mixture of nitric and sulphuric acids for 72 h, and the selection of the target product requires neutralization of the total amount of sulfuric-nitric acid medium with alkali (NaOH), which leads the big expenditure ratios as acids and alkalis, and extractants. [RF patent №974757, MKI 6 07 With 49/24, C 07 C 45/00, publ. 27.09.1995].

The disadvantage of this method is that it allows you to get only one derivative, namely the drug Kelantan"and great reaction time and the consumption of raw materials. In addition, this method does not lead to obtaining substances claimed structural formulas.

A method of obtaining 1-chloro-4-accoutumance, consisting in the interaction of 1-hydroxy-4-accoutumance with thionyl chloride [J.Josef, .Jiri, V.Ludek. Collekt. Czechosl. Chem. Commun. 1987, 52, 8, 2028-2034] or adamantanone-2 use of carbon tetrachloride and salts of manganese [RF Patent №2197468, MKI 7 07 With 49/483, C 07 C 45/63, publ. 2003].

This method also does not receive the substance of the claimed structural formulas.

Also known is a method of obtaining 1-carboxy-4-accoutumance, consisting in the interaction of 1-hydroxy-4-accoutumance in strongly acidic media (a mixture of concentrated sulfuric and nitric acids or 60% oleum) with formic acid, followed by pouring the reaction mass into crushed ice and filtering sediment [Synthesis of 4-keto-1-adamantanecarbonyl acid and its derivatives / Laptev VI // Zhur.org.chem., t, 7, - 1975, - S-1568].

This method also does not receive the substance of the claimed structural formulas. In addition, among the disadvantages of this method is the use of much of the considerable quantities of acids and therefore, acidic waste.

Closest to the proposed invention is the synthesis of p-adamantylamine, consisting in the catalytic interaction of 1-bromoguanine with toluene, leading to the desired product with a yield up to 95% [of novaki I.A. abstract. Diss. Kida. Sciences., Moscow, 1975].

This method does not lead to obtaining substances claimed structural formulas, as in position 4 missing keto-group. In addition, this method cannot obtain the claimed compounds of structural formula as the well-known reaction of adamantane-2 with aromatic substances under conditions of acid catalysis. In particular, the known reaction of adamantane-2 with two equivalents of aniline or its homologues in the presence of hydrochloric acid with the formation of 2,2-bis-(4-AMINOPHENYL)adamantane or its homologues [U.S. Patent No. 5420351, MKI 07 With 211/54, publ. 1995], this reaction leads to the formation of substances claimed structural formulas. Oxidation of 1-arredamento to 1-aryl-4-oxoacetate in strongly acidic environments is impossible due to the large number of side reactions (sulfonation of the aromatic nucleus, oxidation of functional groups, aryl radical, and others).

The task of the invention is to develop technological molestating method of synthesis of 1-aryl-4-oxoacetate.

The technical result of the t is aetsa synthesis of new derivatives of adamantane.

The technical result is achieved in the method of obtaining unknown 1-aryl-4-oxoacetate General formula

R=CH3HE, N(CH3)2The co3,

which consists in the interaction of 1-bromo-4-accoutumance derivative of benzene from a number of: toluene, phenol, dimethylaniline and anisole at a molar ratio of reactants is 1:5-6, at a temperature of 100-180°With, in the presence of Lewis acids AlCl3, FeBr3, ZnCl2within 5-8 hours.

The essence of the method is the reaction of a 1-aryl-4-oxoacetate by the reaction of 1-bromo-4-accoutumance derivative of benzene:

R=CH3HE, N(CH3)2The co3

The method is as follows.

A mixture of 1-bromo-4-accoutumance and a derivative of benzene from a number of: toluene, phenol, dimethylaniline and anisole (molar ratio of 1-bromo-4-accoutumance: a derivative of benzene =1:5-6) and catalyst from the series: the Lewis acids: ZnCl2, FeBr3, AlCl3(5-10% wt. taken from 1-bromo-4-accoutumance) is heated at a temperature of 100-180°C for 5-8 hours. Upon completion of the reaction and cooling to room temperature the reaction mass is washed from the catalyst with a weak solution of hydrochloric acid, then with soda solution until neutral, the organic layer alisado dried, distilled in vacuum excess derivative of benzene, the residue sublimate in a vacuum. The outputs of the claimed compounds of structural formula reaches 56%.

As studies have shown, the optimal technological and condition of the reaction is its implementation in an environment of excess benzene derivatives at a molar ratio of 1-bromo-4-accoutumance: derived benzene 1:5÷6. Less excess leads to a reduction in the yield of the target products by polyallylamine derivative of benzene. A further increase of the excess benzene derivatives does not affect the yield of the target products is inappropriate. The optimal reaction temperature is the temperature of the beginning of intensive selection HBR and for each derivative of benzene depends on the applied catalyst. Discovered that the excessive temperature rise, along with the acceleration of the reaction, leads to the resinification of the reaction mixture and the occurrence of adverse reactions sequential alkylation. The dependence of the reaction rate from the electron-donating effect of the substituent in the original derivative of benzene. So, the higher the donor effect of the substituent, those with more mild conditions reaction takes place and the higher its speed ceteris paribus. We studied the effect of catalyst on the reaction. Found ujena, the stronger donor effect of the substituent in the derivative of benzene, the less strong the catalyst. Selection of catalyst from a number of: zinc chloride, aluminium chloride, iron bromide for each example of the synthesis were selected individually. The NMR spectra of1N in some cases showed the presence in the reaction mixture 3-4% impurities ortho-isomers of the substances claimed structural formulas.

Determined that this reaction under the conditions shown in the prototype, does not leak; all of the examples require more stringent conditions of synthesis, which is explained by the lower reactivity of 1-bromo-4-accoutumance compared to 1-bromoguanine.

The structure of the synthesized compounds was confirmed by NMR1H-spectroscopy and elemental analysis.

The invention is illustrated by the following examples:

Example 1. 1-n-Hydroxyphenyl-4-accoutumance

A mixture of 2.2 g (0,0096 mol) 1-bromo-4-accoutumance and 4.52 g of phenol (0,048 mole) (molar ratio 1:5) and catalytic amounts of FeBr3heated air refrigerator at a temperature of 180°C for 6 hours. Upon completion of the reaction, to the reaction mass is added 15 ml of 20% alkali to remove the original phenol. When this salt is 1-n-hydroxyphenyl-4-accoutumance insoluble in water and filtered. Unreacted bromoguanine washed on the filter with methylene chloride. After about what ivania a weak solution of hydrochloric acid until the acid reaction of the precipitate washed with distilled water. After drying and sublimation get 1,32 g (0,0054 mol) of 1-n-hydroxyphenyl-4-accoutumance, white crystalline substance. MP.=184-185°C. a Yield of 56%. An NMR spectrum1N, δ, ppm: 1.69, 1.806, 1.87, 1.91, 2.02, 2.44 6s (13H, Ad); 5.21 sh (1H, HE); 6.58-7.04 2D (2+2N,1,4-C6H4). Found, %: C 79.35, N S16H18O2. Calculated, %: C 79.43, N 7.35.

Example 2. 1-n-Tolyl-4-accoutumance.

A mixture of 4.8 g (0,021 mol) 1-bromo-4-accoutumance and 11.6 g (0,126 mol) toluene (molar ratio 1:6) is heated in the presence of 0.5 g (0,004 mol) of catalyst is AlCl3at a temperature of 100°C for 7 hours. Upon completion of the reaction, the catalyst was washed with water, the toluene is removed by straight distillation. After sublimirovanny get to 2.57 g (to 0.011 mol) of 1-n-tolyl-4-accoutumance, white crystalline substance. MP.=106-108°C. Yield =51%. The NMR spectra of1N, δ, ppm: 1.5-2.64 5C (13H, Ad); 2.21 (3H, CH3); 6.98, 7.03 2D (2+2N,1,4-C6H4). Found, %: C 85.01, N, 8.33. With17H20O. Calculated, %: C 85.21, H 8.12.

Example 3. 1-(n-N,N-Dimethylamino)phenyl-4-accoutumance.

A mixture of 4.8 g (0,021 mol) 1-bromo-4-accoutumance and 12.7 g (0.11 mol) of dimethylaniline (molar ratio 1:5.2) is heated in the presence of 0.6 g (0,0048 mol) of catalyst ZnCl2at a temperature of 120°C for 8 hours. Upon completion of the reaction, the catalyst was washed with water, the excess of dimethylaniline remove peregonka is in a water-jet vacuum pump. After sublimirovanny residue receive 2,89 g (0,0113 mol) 1-(n-N,N-dimethylamino)phenyl-4-accoutumance, slightly colored crystalline substance. MP.=81-83°C. Yield =54%. The NMR spectra of1N, δ, ppm: 1.7, 2.32, 2.58, 3.25 4C (13H, Ad); 2.82 (6N, N(CH3)2); 6.68, 6.83 2D (2+2N,1,4-C6H4). Found, %: C 80.41, N 8.43, N 5.18. C18H23ON. Calculated, %: C 80.29, H 8.55, N 5.20.

Example 4. 1-(n-Methoxy)phenyl-4-accoutumance.

A mixture of 4.5 g (0.019 mol) of 1-bromo-4-accoutumance and 10.8 g (0.1 mol) of anisole (molar ratio of 1:5.3) is heated in the presence of 0.6 g (0,0048 mol) of catalyst ZnCl2at a temperature of 120°C for 5 hours. Upon completion of the reaction, the catalyst was washed with water, anisole are removed by distillation in a water jet vacuum pump. After sublimirovanny gain of 2.23 g (0,0093 mol) 1-(n-methoxy)phenyl-4-accoutumance, white crystalline substance. MP.=68-70°C. Yield =49%. The NMR spectra of1H δ, ppm: 1.75-2.74 5C (13H, Ad); 3.81 (3H, och3); 7.10, 7.42 2D (2+2N,1,4-C6H4). Found, %: C 79.72, N, 7.83. C17H20O2. Calculated, %: C 79.69, H 7.81.

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 of the branches of industry;

for the claimed invention in the form as it is described in the independent claim, 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 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 for the synthesis of 1-aryl-4-oxoacetate, enabling a wide range of the claimed compounds of structural formulas. The structure of the obtained compounds was confirmed by NMR1H-spectroscopy and elemental analysis.

A method of obtaining a 1-aryl-4-oxoacetate General formula

where R is CH3HE, N(CH3)2The co3,

which consists in the interaction of 1-bromo-4-accoutumance with a derivative of benzene from a number of toluene, phenol, dimethylaniline and anisole at a molar ratio of reagents 1:5-6, at a temperature of 100-180°in the presence of Lewis acids AlCl3, FeBr3, ZnCl2within 5-8 hours



 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: method involves the alkylation reaction of adamantine or mixture of alkyladamantanes with the general number of carbon atoms 11-20 in methylene chloride solution medium at temperature 15-25°C in the presence of catalytic system representing an equimolar mixture of aluminum halide and halide-containing promoter of the general formula: AlX3 x CpHrXz wherein X means Cl, Br; p = 0; r = 0; z = 2, or P = 1; z = 4, either p = 1; r = 2; z = 2. The conversion of adamantine is 78-94%. Invention provides the development of the improved technological procedure for preparing the end substances with the enhanced importance.

EFFECT: improved preparing method.

7 tbl, 16 ex

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: method involves the alkylation reaction of adamantine or mixture of alkyladamantanes with the general number of carbon atoms 11-20 in methylene chloride solution medium at temperature 15-25°C in the presence of catalytic system representing an equimolar mixture of aluminum halide and halide-containing promoter of the general formula: AlX3 x CpHrXz wherein X means Cl, Br; p = 0; r = 0; z = 2, or P = 1; z = 4, either p = 1; r = 2; z = 2. The conversion of adamantine is 78-94%. Invention provides the development of the improved technological procedure for preparing the end substances with the enhanced importance.

EFFECT: improved preparing method.

7 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to chemistry of adamantanes, namely to a method for synthesis of 1-aryl-4-oxoadamantanes of the general formula: wherein R means -CH3, -OH, -N(CH3)2, -OCH3. Method involves interaction of 1-bromo-4-oxoadamantane with benzene derivative chosen from the following order: toluene, phenol, dimethylaniline or anisole in the mole ratio of reagents = 1:(506), at temperature 100-180°C in the presence Lewis acids AlCl3, FeBr3, ZnCl2 for 5-8 h. Method provides synthesis of novel compounds that are semifinished substances in synthesis of biologically active compounds.

EFFECT: improved method of synthesis.

4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to chemistry of adamantine derivatives, namely to a method for synthesis of 1-dialkylamino-4-oxoadamantanes of the general formula: wherein R means Method involves substitution of bromine atom in 1-bromo-4-oxoadamantane for dialkylamino-group in interaction with dialkylamine chosen from the following order: piperidine, morpholine or piperazine in the mole ratio of reagents = 1:((3-4), at temperature 190-220°C for 7-8 h. Invention provides synthesis of semifinished products used in synthesis of biologically active substances.

EFFECT: improved method of synthesis.

3 ex

FIELD: organic synthesis.

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

EFFECT: expanded synthetic possibilities.

6 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to chemistry of adamantine derivatives, namely, to a novel method for synthesis of (adamant-1-ylmethylene)-containing aromatic compounds of the general formula (I): , wherein R1 = R2 = R3 = R4 means hydrogen atom (H) (1); R1 means -CH3; R2 = R3 = R4 means H (2); R1 = R3 = R4 means H; R2 means -CH3 (3); R1 = R2 = R4 means H; R3 means -CH3 (4); R1 = R2 means H; R2 = R4 means -CH3 (5); R1 = R3 = R4 means -CH3; R2 means H (6); Ad means 1-adamantyl that are intermediate products for synthesis of biologically active substances. Method involves adding aromatic compounds to adamantine derivative wherein 1,3-dehydroadamantane is used as a adamantine derivative, and the following compounds are used as aromatic compounds: toluene, o-, m-, p-xylene, mesitylene, durene in the mole ratio of reagent = 1:(2-4) in the parent aromatic compound medium, at their boiling point (110-197°C) for 60 min. Invention provides simplifying method for synthesis of abovementioned compounds and their synthesis with higher yields.

EFFECT: improved methods of synthesis.

6 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of adamantyl-containing aromatic compounds of the general formula: , wherein R1 = R2 = R3 = R4 means hydrogen atom (H); R5 means Ad (1); R1 means -CH3; R2 = R3 = R5 means H; R4 means Ad (2); R1 means -C2H5; R2 = R3 = R5 means H; R4 means Ad (3); R1 means i-C3H7; R2 = R3 = R5 means H; R4 means Ad (4); R1 = R2 means -CH3; R3 = R5 means H; R4 means Ad (5); R1 = R3 means -CH3; R2 = R5 means H; R4 means Ad (6); R1 = R4 means -CH3; R2 = R3 means H; R5 means Ad (7) that are intermediate products for synthesis of biologically active substances. Method involves adding aromatic compounds to a adamantine derivative wherein 1,3-dehydroadamantane is used as a adamantine derivative, and compounds chosen from the following order: benzene, toluene, ethylbenzene, isopropylbenzene (cumene), o-, m-, p-xylene are used as aromatic compounds in the mole ratio of reagents = 1:(2-4) in diethyl ether medium, at temperature 30-35°C, or in the parent aromatic compound medium at their boiling point (80-110°C) for 30 min, in the presence of catalytic amounts of sulfuric acid. Method provides preparing the claimed compounds with the high yield.

EFFECT: improved method of synthesis.

7 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining adamantyl containing phenol derivatives with general formula , where R1=R2=R4=H, R3=Ad (I); R1=CH3, R2=R4=H, R3=Ad (II); R1=Ad, R2=R3=H, R4=CH3(III); R1=Ad, R2=R4=H, R3=CH3(IV); R1=OH, R2=R4=H, R3=Ad (V); R1=Ad, R2=R3=H, R4=OH(VI); R1=Ad, R2=R4=H, R3=OH (VII), which are intermediate products during synthesis of biologically active substances. The method lies in that, the adamantane derivative is subjected to interaction with aromatic compounds at reagent molar ratios of 1:(1.5-2) in medium of diethyl ether at its boiling temperature for a period of 20-30 min. in the presence of catalyst quantities of sulphuric acid. The adamantane derivative used is 1,3-dehydroadamantane. The aromatic compound used is chosen from: phenol, o- , m-, p-cresol, pyrocatechol, resorcin, and hydroquinone.

EFFECT: invention enables design of a less-staged method, which allows to obtain a wide range of chemical compounds with high output.

7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

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