RU2440971C1 - Method of producing hydrochlorides of amine-derivatives of adamantane - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to a novel method of producing hydrochlorides of amine-derivatives of adamantane of general formula: ^ , ^ where R=H, CH3; n=0, 1. According to the disclosed method, biologically active compounds such as, for example, hydrochlorides of 1-aminoadamantane (R=H, n=0) (amantadine) and 1-amino-3,5-dimethyl-adamantane (R=CH3, n=0) (memantine) are obtained, which are used in the chemical and pharmaceutical industry to prepare medicinal agents for treating Parkinson's disease, Alzheimer's diseases, neurodegenerative diseases, glaucoma etc. The method involves reaction of adamantane carboxylic acid with thionyl chloride at its boiling point for 1.5 hours in molar ratio 1:1.1 respectively, to form an acyl chloride of adamantane carboxylic acid, which reacts with sodium azide in anhydrous toluene at its boiling point in molar ratio 1:1:15-20 respectively for 1.5-2 hours, followed by addition of concentrated hydrochloric acid and holding the reaction mass for 1 hour and extracting the end product. ^ EFFECT: method is more technologically effective and ecologically clean and enables to obtain a large number of homologues of hydrochlorides of amine-derivatives of adamantane with quantitative output of 92-95%. ^ 4 ex

Description

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method for the preparation of hydrochlorides of amino derivatives of adamantane of the general formula

where R = H, CH ₃ ; n = 0, 1,

which may find application in the pharmaceutical industry.

It is known that the compounds are biologically active substances, and the hydrochlorides of 1-aminoadamantane (R = H, n = 0) and 1-amino-3,5-dimethyladamantane (R = CH ₃ , n = 0) are used in medical practice under international non-proprietary names midantan and memantine, respectively, as agents for the treatment of Parkinson’s, Alzheimer's, neurodegenerative diseases, glaucoma, etc., respectively [Vidal Handbook, 2009. Medicines in Russia. Ed. 15th, revised, rev. and additional M: AstraFarmService, 2009. 1760 p.].

A number of known methods for producing hydrochlorides of amines of dimethyl-damantane, namely 1-amino-3,5-dimethyladamantane hydrochloride:

the interaction of 1,3-dimethyladamantane or perhydroacenaphthene with nitrogen trichloride in the presence of aluminum in dichloroethane [Tetrahedron Lett., 1968, p. 5833-5835];

the reaction of alkaline or acid hydrolysis of 1-acetamino-3,5-dimethyladamantane obtained by treating 1,3-dimethyladamantane with liquid bromine followed by the reaction of the resulting 1-bromo-3,5-dimethyladamantane with acetonitrile in concentrated sulfuric acid with a total yield calculated as 1,3-dimethyladamantane 63% [K. Gerson, E.V. Krumkalns, RLBrindle, FJMarrshall, M.A. Root. J. Med. Chem., V. 6. N 11, 1963, p. 760-763] or by boiling 1,3-dimethyladamantane with liquid bromine and acetonitrile [A.N. Khmelnitsky, V.F.Baklan, V.P. Kuhar. ZhORKH, v.32, issue 7, 1996, pp. 1022-1024. The interaction of adamantane, carboxylic acids of adamantane and bicyclo [3.3.1] nonane series with acetonitrile in liquid bromine];

by acid hydrolysis of the formyl derivative of 1-amino-3,5-dimethyladamantane obtained by treating 1,3-dimethyladamantane with liquid bromine followed by reaction of the resulting 1-bromo-3,5-dimethyladamantane with formamide at 150-160 ° C with a total yield calculated as 1,3-dimethyladamantane 63-75% [US Pat. RF 2309940, С07С 211/38, С07С 209/62, publ. November 10, 2007];

by acid hydrolysis of the formyl derivative of 1-amino-3,5-dimethyladamantane obtained by treating 1,3-dimethyladamantane with bromine water, followed by treatment of the hydroxyl derivative with hydrochloric acid, and the chlorine derivative obtained with formamide at 95-100 ° C with a total yield of 1, 3-dimethyladamantane 50-60% [J. M. Reddy, G. Prasad, V. Raju, M. Ravikumar, V. Himabindu, and G. M. Reddy Org. Proc. Res. & Dev., 11, 2007, p. 268-269].

However, the above methods require the use of hard-to-reach, highly toxic and expensive starting reagents, are multi-stage, give difficult-to-regenerate wastes, and the methods do not provide qualitative indicators of 1-amino-3,5-dimethyladamantane hydrochloride for medical preparations. In addition, the known methods do not allow to obtain hydrochlorides of amino derivatives of adamantane containing a methylene group between the amino group and the adamantyl radical.

A known method for producing adamantane-containing amines is that 1,3-dimethyladamantane is treated with sodium azide in 57% sulfuric acid to obtain azide, which is reduced with lithium aluminum hydride in absolute ether and converted to 1-amino-3,5-dimethyladamantane. The total yield of 1-amino-3,5-dimethyladamantane in terms of 1,3-dimethyladamantane is 50-60% [T. Sasaki, S. Eguchi, T. Katada, and O. Hiroaki. Ogr. Chem. Vol. 42, No. 23, 1977, p. 3741].

The disadvantages of this method are the relatively low yield of the final product, leading to the loss of expensive raw materials, and the multi-stage process.

The technical result of the invention is to simplify the process, to develop a more technologically advanced and environmentally friendly method for producing hydrochlorides of amino derivatives of adamantane, which proceeds with a high yield in the initial adamantanecarboxylic acid.

The technical result is achieved by the proposed method for the preparation of hydrochlorides of amino derivatives of adamantane, which consists in the interaction of adamantanecarboxylic acid of the general formula

where R = H, CH ₃ ; n = 0, 1,

with thionyl chloride at its boiling point for 1.5 hours at their molar ratio (1: 1.1-1.2), respectively, with the formation of adamantanecarboxylic acid chloride, which is subjected to interaction with sodium azide in anhydrous toluene at its boiling point at the molar ratio of 1: 1: 15-20, respectively, for 1.5-2 hours, followed by the addition of concentrated hydrochloric acid at a molar ratio of carboxylic acid: hydrochloric acid 1: 1.1, keeping the reaction mass for 1 hour and isolating the target THE PRODUCT.

The yield of the target product by the proposed method is 90-95%.

The advantages of the proposed method are the absence of difficultly regenerated waste, high yield, and the possibility of obtaining a large number of homologues of aminoadamantane.

Adamantanecarboxylic acid react with thionyl chloride within 1.5 hours. By reducing the reaction time, a high yield of the main product is not achieved. The increase in the duration of the reaction is impractical and economically disadvantageous.

It was found that the optimal condition for the reaction of the interaction of adamantanecarboxylic acid with thionyl chloride is its implementation at a molar ratio of carboxylic acid: thionyl chloride (1: 1.1-1.2). A smaller excess led to a slight decrease in the yield of the target products. A further increase in the content of thionyl chloride did not affect the yield of the target products and was impractical.

It was found that the optimal condition for the reaction of the interaction of adamantanecarboxylic acid with thionyl chloride is its implementation at the boiling point of the latter. Carrying out the reaction at a lower temperature led to a significant increase in the reaction time, and a further increase in temperature is associated with high energy costs and is impractical.

Adamantanecarboxylic acid chloride react with sodium azide within 1.5-2 hours. By reducing the reaction time, a high yield of the main product is not achieved. The increase in the duration of the reaction is impractical and economically disadvantageous.

It was found that the optimal condition for the reaction of the interaction of adamantanecarboxylic acid chloride with sodium azide in toluene is its implementation at a molar ratio of adamantanecarboxylic acid chloride: sodium azide: toluene 1: 1: 15-20. Excess sodium azide led to some decrease in the yield of the target products. A smaller excess of toluene led to a slight decrease in the yield of the target products. A further increase in the toluene excess did not affect the yield of the target products and was impractical.

It was found that the optimal condition for the reaction of the interaction of the adamantanecarboxylic acid chloride with sodium azide in toluene is its implementation at the boiling point of the latter. Carrying out the reaction at a lower temperature led to a significant increase in the reaction time, and a further increase in temperature is associated with high energy costs and is impractical.

The hydrolysis process using hydrochloric acid is carried out for 1 hour. By reducing the reaction time, a high yield of the main product is not achieved. The increase in the duration of the reaction is impractical and economically disadvantageous.

It was found that the optimal condition for hydrolysis is its implementation at a molar ratio of adamantanecarboxylic acid: HCl equal to 1: 1.1. A smaller excess led to a slight decrease in the yield of the target products. A further increase in the excess of HCl did not affect the yield of the target products and was impractical.

It was found that the optimal condition for hydrolysis is its implementation at room temperature. Carrying out the reaction at a lower temperature led to a significant increase in the reaction time, and also required energy consumption, a further increase in temperature did not lead to a significant decrease in the reaction time and is impractical.

The method is as follows: to the corresponding adamantanecarboxylic acid from the series: admanat-1-ylcarboxylic, adamant-1-yl-acetic, 3,5-dimethyladamant-1-yl-carboxylic, 3,5-dimethyladamant-1-yl-acetic, thionyl chloride is added in a ratio of 1 : 1.1 and boil for 1.5 hours. Then the excess thionyl chloride is distilled off in vacuo, and the remaining acid chloride of the corresponding adamantanecarboxylic acid is added dropwise within 30 minutes to a boiling suspension of sodium azide in toluene in a ratio of 1: 1: 15-20. The reaction mass is stirred for another 1 hour, cooled, filtered, concentrated hydrochloric acid is added to the filtrate with stirring, and after 1 hour the precipitate formed is filtered off, dried and recrystallized from water.

The invention is illustrated by the following examples.

Example 1

Obtaining 1-aminoadamantane hydrochloride

(drug substance midantan).

A mixture of 18.0 g (0.1 M) of 1-adamantanecarboxylic acid (R = H, n = 0) and 14.8 g (0.12 M, 9.0 ml) of thionyl chloride (molar ratio 1: 1.2 ) are boiled in a flask equipped with a reflux condenser and a tube for the removal of released hydrogen chloride, which is absorbed by chilled water in a bubbler, until gas evolution ceases (1.5 hours). An excess of thionyl chloride is distilled off first at atmospheric pressure (1 ml distillation volume) and then in vacuum. 10 ml of toluene is added to the residue and the resulting solution is added dropwise within 30 minutes to a boiling suspension of 6.8 g (0.1 M) of sodium azide in 150 ml of anhydrous toluene (molar ratio 1: 1: 15) in a flask equipped with an inverse stirrer refrigerator and drip funnel. The reaction mass is stirred for another 1 hour, cooled, filtered, 10 ml of concentrated hydrochloric acid is added to the filtrate with stirring, and after 1 hour the precipitate formed is filtered off, dried and recrystallized from water. 17.2 g of 1-aminoadamantane hydrochloride are obtained in a yield of 92%, mp 366-370 ° C. Mass spectrum, m / z, I%: 151 (4%, [M] ⁺ ), 135 (100%, [Ad] ⁺ ), the structure of the claimed compounds corresponds to the published data.

Example 2

Obtaining 1-aminomethyladamantane hydrochloride.

Analogously to example 1, but adamantanecarboxylic acid chloride is mixed with 10 ml of toluene and added dropwise within 30 minutes to a boiling suspension of sodium azide in 125 ml of anhydrous toluene (molar ratio 1: 1: 16) and stirred for 1.5 hours, out of 15, 5 g (0.08 M) of 1-adamantane acetic acid (R = H, n = 1) give 15.1 g of 1-aminomethyladamantane hydrochloride in 94% yield, mp 363-340 ° C. Mass spectrum, m / z., I%: 165 (5%, [M] ⁺ ), 149 (30%, [M-CH ₂ ] ⁺ ), 135 (100%, [Ad] ⁺ ), structure of the claimed compounds consistent with literature data.

Example 3

Obtaining 1-amino-3,5-dimethyladamantane hydrochloride

(drug substance memantine).

Analogously to example 1, but adamantanecarboxylic acid chloride is mixed with 10 ml of toluene and added dropwise for 30 minutes to a boiling suspension of sodium azide in 190 ml of anhydrous toluene (molar ratio 1: 1: 19) from 20.9 g (0.1 M) 3 , 5-dimethyl-1-adamantanecarboxylic acid (R = CH ₃ , n = 0), 20.1 g of 1-amino-3,5-dimethyladamantane hydrochloride are obtained in 93% yield, mp 293-294 ° C. Mass spectrum, m / z, I%: 179 (3%, [M] ⁺ ), 163 (10%, [M-NH ₂ ] ⁺ ), 135 (100%, [Ad] ⁺ ), structure of the claimed compounds consistent with literature data.

Example 4

Preparation of 1-aminomethyl-3,5-dimethyladamantane hydrochloride.

Analogously to example 1, but added 13.5 g of thionyl chloride (molar ratio 1: 1.1), and adamantanecarboxylic acid chloride was mixed with 10 ml of toluene and added dropwise for 30 minutes to a boiling suspension of sodium azide in 200 ml of anhydrous toluene (molar ratio 1: 1: 20), from 22.3 g (0.1 M) of 3,5-dimethyladamantyl-1-acetic acid (R = CH ₃ , n = 0), 21.9 g of 1-aminomethyl-3 hydrochloride are obtained, 5-dimethyladamantane with a yield of 95%, mp. 279-281 ° C. Mass spectrum, m / z, I%: 193 (4%, [M] ⁺ ), 163 (12%, [M-NH ₂ ] ⁺ ), 135 (100%, [Ad] ⁺ ), structure of the claimed compounds consistent with literature data.

The proposed method allows to obtain final products with higher yields. The advantage of the proposed method is its versatility, as it allows us to synthesize not only the substances of the Midantan and Memantine preparations, but also almost any homologs of them.

Thus, the above information indicates the fulfillment of the following set of conditions when using the claimed invention:

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

- for the claimed invention in the form described in the independent clause of the claims below, the possibility of its implementation using the means and methods described above or known prior to the priority date is confirmed;

- a tool embodying the claimed invention in its implementation is able to ensure the achievement of a technical result.

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

Claims (1)

The method of producing hydrochlorides of amine derivatives of adamantane of the General formula

where R is H, CH ₃ ; n = 0, 1,
consisting in the interaction of adamantanecarboxylic acid of the General formula

where R is H, CH ₃ ; n = 0, 1,
with thionyl chloride at its boiling point for 1.5 hours at their molar ratio (1: 1.1-1.2), respectively, with the formation of adamantanecarboxylic acid chloride, which is reacted with sodium azide in anhydrous toluene at its boiling point, at their molar ratio of 1: 1: 15-20, respectively, for 1.5-2 hours, followed by the addition of concentrated hydrochloric acid at a molar ratio of carboxylic acid: hydrochloric acid 1: 1.1 and keeping the reaction mass for 1 h and isolating the target product .