RU2547141C1 - Method of obtaining n-(4-bromophenyl)-n-(2-adamantyl)amine (bromantane) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method is realised according to the following scheme:

A mixture of adamantanone, bromaniline and carbon monoxide is subjected to interaction under the conditions, catalysed by salts or metal carbonyls, selected from the group, which include rhodium, ruthenium, iridium, cobalt, iron. The interaction is carried out under increased pressure and with heating in the presence of a drier in a polar protic or aprotic solvent, selected from the group: tetrahydrofuran, acetonitrile, ethylacetate. The molar ratio of adamantanone, para-bromaniline and catalyst constitutes 1.0-1.1:1.0:0.01-0.05. The method is preferably realised under CO pressure of 5-100 atm and temperature of 25-200°C. It is desirable to apply RuCl₃·3H₂O, dimer of rhodium diacetate, cobalt carbonyl, iridium (III) chloride, iron carbonyl as the catalyst.

EFFECT: method makes it possible to simplify the process due to its realisation in one stage with the high output of the target product, eliminates the necessity of removing a large quantity of reagents that did not react.

8 cl, 1 tbl, 10 ex

Description

The invention relates to organic chemistry, in particular to amino derivatives of adamantane, in particular to the production of N- (4-bromophenyl) -N- (2-adamantyl) amine (bromantane), a compound having a psychostimulating and immunoprotective effect. N- (4-bromophenyl) -N- (2-adamantyl) amine is the active substance of such well-known pharmaceuticals as bromantanum and ladasten (Ladasten®).

These drugs have a wide range of biological effects, in particular stimulating and anxiolytic properties, the main pharmacological effect is a stimulating effect on the central nervous system, which is manifested in increasing physical and mental performance, slowing the development of fatigue and accelerating recovery after intense physical and mental stress. A certain role in the implementation of the pharmacological action of bromantanum is played by its antiradical and membrane-protective properties [Research Methods and Pharmacological Correction of Human Physical Performance. / Ed. I.B. Ushakova, M., Medicine, 2007; Morozov I.S., Petrov V.I., Sergeeva S.A. Pharmacology of adamantanes. - Volgograd: VMA, 2001; RF patent No. 2175229, A61K 31/35; A61P 25/22 (1999); B.I. No. 30; Syunyakov S.A., Grishin S.A., Teleshova E.S., Neznamov G.G., Seredenin S.B. The results of a pilot clinical study of Ladasten, Experimental and Clinical Pharmacology, 2006, 69 (4), pp. 10-15)].

A known method of producing N- (4-bromophenyl) -N- (2-adamantyl) amine, which consists in the amination of para-dibromobenzene with adamantane-2-amine in the presence of palladium catalysts and phosphorus-containing cocatalysts [Averin AD, Ulanovskaya MA , Kovalev V.V., Buryak A.K., Orlinson B.S., Novakov I.A., Beletskaya I.P. Palladium-catalyzed amination of adamantane-1- and -2-amines of isomeric dihalogenobenzenes. ZhORKh, 46 (1), 2010, pp. 64-72].

The method has several disadvantages: the yield of the target product does not exceed 57%, it is necessary to use a large amount of palladium catalyst (4 mol.%) And expensive cocatalyst.

Known methods for producing N- (4-bromophenyl) -N- (2-adamantyl) amine (bromantane) based on reductive amination of adamantanone by the Leukart-Wallach reaction, where the starting adamantanone is reacted with para-bromaniline in formic acid [SU Aut. testimonial. USSR No. 860446, C07C 211/00, A61K 31/136, A61P 25/26, (1993), publ. 11/30/1993; RU Patent of the Russian Federation No. 1601978, 1995; I.S. Morozov, N.V. Klimova, L.N. Lavrova, N.I. Avdyunina, B.M. Pyatin, B.C. Troitskaya, N.P. Bulls. N-adamantyl derivatives of aromatic amines. Communication I. Synthesis and neurotropic activity of N-adamant-2-yl) anilines. Chem.-farm. J., 1998, 32 (1), 3)].

One of the above methods for producing N- (4-bromophenyl) -N- (2-adamantyl) amine involves the interaction of adamantanone with 99% formic acid and para-bromaniline and subsequent processing of the resulting formyl derivative with 15% hydrochloric acid [SU Aut. testimonial. USSR No. 860446, C07C 211/00, A61K 31/136, A61P 25/26, (1993), publ. November 30, 1993]. The molar ratio of reactants: para-bromaniline: formic acid: adamantanone is 2: 2: 1. The yield of the target product is 80%. Mp 100-102 ° C (absolute ethanol). The disadvantage of this method is the use of a 2-fold excess of toxic bromaniline and formic acid, which requires careful and time-consuming purification of the target product.

A known method of obtaining a number of N- (adamant-2-yl) anilines, including N- (4-bromophenyl) -N- (2-adamantyl) amine [I. S. Morozov, N.V. Klimova, L.N. Lavrova, N.I. Avdyunina, B.M. Pyatin, B.C. Troitskaya, N.P. Bulls. N-adamantyl derivatives of aromatic amines. Communication I. Synthesis and neurotropic activity of N-adamant-2-yl) anilines. Chem.-farm. G., 1998, 32 (1), p.3], the reductive amination of adamantanone is carried out by boiling adamantanone with the corresponding aniline in formic acid at a molar ratio of these substances of 1: 2: 4, respectively (Scheme 2).

The method consists of 3 stages: at the stage (1), a formyl derivative is formed, which is hydrolyzed with hydrochloric acid at the stage (2) and at the stage (3) the formed hydrochloride of the target product is converted to the base. In the case of producing bromantane (R = R ′ = H, R ″ = Br), the technical hydrochloride formed after hydrolysis in step (2) is separated by filtration, suspended in a sodium hydroxide solution and the target product is obtained in the form of a base, which is purified by crystallization from ethanol. Mp 107-109 ° C. The base yield is not indicated; the hydrochloride yield is 95.8%.

The disadvantages of the method is its multi-stage and the need to use a large excess of reagents.

Another of the above methods for producing N- (4-bromophenyl) -N- (2-adamantyl) amine by reductive amination of adamantanone is carried out by boiling a mixture of adamantanone, para-bromaniline and formic acid at a molar ratio of reactants 1: 2-3: 3-4, respectively [RU Patent of the Russian Federation No. 1601978, C07C 211/49, A61K 31/135, (1995), publ. 10/27/1995].

The method consists of the 3 above stages (Scheme 2). As a reagent, 80-85% formic acid is used, after boiling a mixture of adamantanone, para-bromaniline and formic acid for several hours, the excess formic acid is distilled off, the temperature of the reaction mixture is raised to 110-130 ° C and the reaction is continued until the content of adamantanone 1-2 %, then the resulting formamide is hydrolyzed in the presence of hydrochloric acid at the boiling point of the reaction mixture, the obtained hydrochloride of the target product is converted to the base by treatment with an aqueous solution of sodium hydroxide, and the base is purified recrystallization from isopropanol and additional reprecipitation with water from isopropanol. The yield of the target product is 97.3-97.8%. Mp 108-109 ° C.

This method seems to be the most effective and, according to some essential features, is closest to the claimed method, so it was chosen as a prototype.

The disadvantages of the prototype method are the presence of several stages, the need to use a 2-4-fold excess of reagents (amine and formic acid, respectively), which requires additional labor-intensive operations to purify the target product and remove unreacted substances, while a large amount of acids and bases are used, which also need to be regenerated or disposed of as waste.

Thus, there is a need for a technologically simple and economical method for producing bromantane, applicable in industry for the production of this drug.

An object of the present invention is to provide a simple one-step process for the preparation of N- (4-bromophenyl) -N- (2-adamantyl) amine from available raw materials suitable for industrial use.

The problem is solved by the claimed method of obtaining N- (4-bromophenyl) -N- (2-adamantyl) amine from adamantanone and para-bromaniline, which consists in the fact that a mixture of adamantanone, para-bromaniline and carbon monoxide is subjected to an interaction catalyzed by salts or carbonyls of a metal selected from the group comprising rhodium, ruthenium, iridium, cobalt and iron, moreover, the interaction is carried out at elevated pressure and when heated in the presence of a desiccant in a polar protic or aprotic solvent selected from the group: tetrahydride ofuran, acetonitrile, ethyl acetate, and the molar ratio of adamantanone, para-bromoaniline and the catalyst is 1.0-1.1: 1.0: 0.01-0.05 (Scheme 3). The method is carried out at a pressure of CO 5-100 atm and a temperature of 25-200 ° C, molecular sieves are used as a desiccant.

The inventive method is carried out in one stage: a mixture of adamantanone, para-bromoaniline, a solution of catalyst, carbon monoxide and a desiccant is maintained at elevated pressure and when heated for 11-24 hours. Gaseous products are easily removed from the reaction mixture by known methods and are subjected to regeneration, purification or disposal. After removal of the gaseous substances, the desired crude product is obtained with a yield of 79-95%, recrystallization of which from acetonitrile or isopropanol gives purified bromantane, so pl. 108-109 ° C. The method includes a minimum number of operations: loading reagents into the reactor, heating, extracting the target product and its purification.

Thus, the inventive method allows to obtain the target product in one stage with a high yield. The use of almost equimolar amounts of the starting adamantanone and para-bromoaniline makes the purification of the target product less difficult, eliminates the need to remove large amounts of unreacted reagents, and minimizes the amount of waste. The CO removed from the reaction mixture can be converted to CO ₂ by a known technique (on a palladium catalyst). Thus, the claimed method is very promising from an environmental point of view. The method includes a minimum number of operations: loading reagents into the reactor, heating, extracting the target product and its purification.

The method is based on the reductive amination reaction of adamantanone, the reducing agent in this case being carbon monoxide. It is known that carbon monoxide is a potential reducing agent, but the scope of this reducing agent has so far been limited mainly to inorganic chemistry, in particular metallurgy, where it is used to reduce metal oxides. In organic chemistry, it is known to use carbon monoxide as a reducing agent only for the reduction of aromatic nitro groups. Other examples of the use of CO as a reducing agent in organic synthesis have not yet been known. It was unexpectedly found that CO is an effective reducing agent in the reductive amination reaction of adamantanone, which made it possible to obtain the target bromantane in one step with a high yield (see examples 1-10 and the table).

The starting materials, solvents and reagents necessary for the implementation of the proposed method are manufactured by industry and are commercially available.

The invention is illustrated by specific examples of its implementation, below.

¹ H NMR spectra were recorded on BrukerAvance 300 and BrukerAvance 400 NMR spectrometers. Chemical shifts are given in ppm. relative to tetramethylsilane, calibrated to the appropriate peak solvent.

Example 1

0.52 g (3 mmol) of para-bromoaniline, 3.2 ml of a solution of ruthenium chloride in acetonitrile containing 16 mg RuCl ₃ · 3H ₂ O (0.06 mmol), 292 mg molecular sieves (MS 4Å) are placed in the bottle 0.5 g (3.3 mmol) of adamantanone. The bucks are placed in a 100 ml Parr autoclave, the autoclave is closed and 10 atmospheres of carbon monoxide are collected three times, followed by depressurization. After which 30 atmospheres of CO are collected and the autoclave is kept in an oven at a temperature of 140 ° C for 11 hours. Then the autoclave is cooled, the pressure is released and the bottle containing the raw product in the form of a white crystalline substance (0.88 g, yield> 95%) is located, it is recrystallized from acetonitrile, filtered off and an additional amount of pure product is isolated from the mother liquor on a chromatographic column with silica gel. The yield of purified product is 82%. Mp 108-109 ° C.

¹ N NMR (300 MHz, CDCl ₃ ) δ 7.23 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 8.6 Hz, 2H), 4.06 (s, J = 98.0 Hz, 1H), 3.49 (s , 1H), 1.80 (m, 15H).

Examples 2-10 are carried out by a method similar to that described in example 1. The results are presented in the table below.

The inventive method has the following advantages compared with known analogues: (i) the target product is obtained in one stage; (ii) excess CO is readily removed by standard techniques; and, if necessary, CO is converted to CO ₂ by a known technology; (iii) the use of almost equimolar amounts of the starting adamantanone and para-bromoaniline and small amounts of catalyst, which simplifies the purification of the target product, eliminates the need to remove large amounts of unreacted reagents and minimizes the amount of waste, therefore, the method is promising from the point of view of environmental protection.

The technical result of the invention is a new low-waste method for producing bromantane, which allows to obtain the target product in one stage with a high yield.

Claims (8)

1. The method of obtaining N- (4-bromophenyl) -N- (2-adamantyl) amine from adamantanone and para-bromaniline, characterized in that the mixture of adamantanone, para-bromaniline and carbon monoxide is subjected to interaction catalyzed by metal salts or carbonyls selected from the group comprising rhodium, ruthenium, iridium, cobalt, iron, moreover, the interaction is carried out under elevated pressure and when heated in the presence of a desiccant in a polar protic or aprotic solvent selected from the group tetrahydrofuran, acetonitrile, ethyl acetate, while e ratio adamantanone, p-bromoaniline, and the catalyst is 1.0-1.1: 1.0: 0.01-0.05. 2. The method according to claim 1, characterized in that it is carried out at a pressure of CO 5-100 atm. 3. The method according to claim 1, characterized in that it is carried out at a temperature of 25-200 ° C. 4. The method according to claim 1, characterized in that the catalyst used is RuCl ₃ · 3H ₂ O. 5. The method according to claim 1, characterized in that the catalyst used is a rhodium diacetate dimer. 6. The method according to claim 1, characterized in that the catalyst used is cobalt carbonyl. 7. The method according to claim 1, characterized in that the catalyst used is iridium (III) chloride. 8. The method according to claim 1, characterized in that the carbonyl iron is used as a catalyst.