Method of producing hydrochlorides of amine-derivatives of adamantane

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

 

The invention relates to the chemistry of adamantane derivatives, namely to a new way of getting hydrochloride amino adamantane General formula

where R=H, CH3; n=0, 1,

which can find application in pharmaceutical industry.

It is known that compounds are biologically active substances, and hydrochloride 1-aminoadamantana (R=H, n=0) and 1-amino-3,5-dimethyladamantane (R=CH3, n=0) are used in medical practice under international nonproprietary names midantan and memantine, respectively, as a means to treat Parkinson's disease, Alzheimer's, neurodegenerative diseases, glaucoma, etc. respectively [reference Vidal, 2009. Drugs in Russia. Ed. 15-e, revised, Corr. and dopm: Attraversare, 2009. 1760 S.].

The number of known methods for producing hydrochloride amines of dimethyl - diamantane, namely, the hydrochloride of 1-amino-3,5-dimethyladamantane:

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

the reaction of the alkaline or acid hydrolysis of 1-atsetamino-3,5-dimethyladamantane obtained by treatment of 1,3-dimethyladamantane liquid bromine and subsequent interaction of the resulting 1-bromo-3,5-dimethyladamantane is on with acetonitrile in an environment of concentrated sulfuric acid with a total yield per 1,3-dimethyladamantane 63% [K.Gerson, .V.Krumkalns, R.L.Brindle, F.J.Marrshall, ..Root. J. Med. Chem., v.6. N 11, 1963, R-763] or by boiling 1,3-dimethyladamantane with liquid bromine and acetonitrile [Angeliki, Vframes, Vphr. ZHUR.ORG.CHEM. 32 VIP, 1996, str-1024. Interaction adamantane carboxylic acids adamantanol and bicyclo[3,3,1] nonanalog series with acetonitrile in the environment of liquid bromine];

the reaction of the acid hydrolysis of the formyl derivative of 1-amino-3,5-dimethyladamantane obtained by treatment of 1,3-dimethyladamantane liquid bromine and subsequent interaction of the resulting 1-bromo-3,5-dimethyladamantane the formamide at 150-160°C with a total yield per 1,3-dimethyladamantane 63-75% [U.S. Pat. RF 2309940, SS 211/38, SS 209/62, publ. 10.11.2007];

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

However, the above methods require hard-to-reach, highly toxic and expensive reagents, multistage, give difficult recycled waste, as well as the methods do not provide a qualitative indicators hydrochloride-amino-3,5-dimethyladamantane, requirements for medical preparations. In addition, the known methods do not allow to get hydrochloride amino adamantane containing methylene group between the amino group and adamantly radical.

A method of obtaining adamantaneacetic amines, namely, that 1,3-dimethyladamantane treated with sodium azide in 57% sulfuric acid and get azide, which restores lumogallion lithium in absolute ether and converted into 1-amino-3,5-dimethyladamantane. The total yield of 1-amino-3,5-dimethyladamantane in terms of 1,3-dimethyladamantane is 50-60% [.Sasaki, S.Eguchi, .Katada, and Onhook. Ogr. Chem. Vol.42, No. 23, 1977, R].

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

The technical result of the invention is the simplification of the process, the development of more technologically advanced and environmentally friendly way to get hydrochloride amino adamantane proceeding with a high output source adamantanecarbonyl acid.

The technical result is achieved by the proposed method to obtain hydrochloride amino adamantane, which consists in the interaction adamantanecarbonyl acid of General formula

where R=H, CH3; n=0, 1,

chloride tiomila at the temperature of its boiling for 1.5 hours at their molar ratio (1:1.1 to 1.2), respectively, with the formation of the acid chloride adamantanecarbonyl acid, which is subjected to interaction with sodium azide in anhydrous toluene at the temperature of its boiling point when a 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, maintaining the reaction mixture for 1 hour and the selection of the target product.

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

Advantages of the proposed method are the absence of hard regenerated waste, high output, as well as the possibility of obtaining a large number of homologues aminoadamantana.

The reaction of interaction adamantanecarboxylic acid chloride tiomila is held for 1.5 hours. Decreasing the duration of the reaction is not achieved a high yield of the main product. The increase in the duration of the reaction is impractical and uneconomical.

It is found that the optimum condition for the reaction of interaction adamantanecarboxylic acid chloride tiomila is in its implementation when the molar zootoxin and carboxylic acid chloride thionyl (1:1.1 to 1.2). Less excess has resulted in a slight decrease of the yield of the target products. Further increase in the chloride content of tonila did not affect the yield of target products was inappropriate.

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

The reaction of interaction of the acid chloride adamantanecarbonyl acid with sodium azide is carried out for 1.5-2 hours. Decreasing the duration of the reaction is not achieved a high yield of the main product. The increase in the duration of the reaction is impractical and uneconomical.

It is found that the optimum condition for the reaction between the acid chloride adamantanecarbonyl acid with sodium azide in toluene is in its implementation at a molar ratio of acid chloride adamantanecarbonyl acid : sodium azide : toluene 1:1:15-20. An excess of sodium azide resulted in some reduction of the yield of the target products. Less excess toluene led to a reduction in the output of the target issue for lighting the x products. A further increase in excess of toluene did not affect the yield of target products was inappropriate.

It is found that the optimum condition for the reaction between the acid chloride adamantanecarbonyl acid with sodium azide in toluene is in its implementation at the boiling point of the latter. Carrying out the reaction at a lower temperature resulted in a significant increase in reaction time, and a further increase in temperature is associated with high costs of energy and is impractical.

The process of hydrolysis with hydrochloric acid is carried out for 1 hour. Decreasing the duration of the reaction is not achieved a high yield of the main product. The increase in the duration of the reaction is impractical and uneconomical.

It is found that the optimum condition for hydrolysis is its implementation at a molar ratio adamantanecarbonyl acid : HCl = 1:1,1. Less excess has resulted in a slight decrease of the yield of the target products. A further increase of the excess of HCl did not affect the yield of target products was inappropriate.

It is found that the optimum condition for hydrolysis is its implementation at room temperature. Carrying out the reaction at a lower temperature resulted in a significant HC is the increase of the reaction time, and also demanded energy costs, a further increase in temperature did not lead to a significant decrease in reaction time and is impractical.

The method is as follows: to appropriate adamantanecarbonyl acid from the series: admanet-1-inkarbaeva, adamant-1-ilocana, 3,5-dimethyladamantane-1-inkarbaeva, 3,5-dimethyladamantane-1-ilocana add chloride thionyl in the ratio of 1:1.1 and boiled for 1.5 hours. Then the excess chloride tiomila distilled off in vacuum, and the remaining acid chloride corresponding adamantanecarbonyl acid was added dropwise during 30 minutes to a boiling suspension of sodium azide in toluene at a ratio of 1:1:15-20. The reaction mass is stirred for further 1 hour, cooled, filtered, added to the filtrate with stirring, concentrated hydrochloric acid and after 1 hour, the precipitation is filtered off, dried and recrystallized from water.

The invention is illustrated by the following examples.

Example 1.

Getting hydrochloride 1-aminoadamantana

(the substance of the medicinal product midantan).

A mixture of 18.0 g (0.1 M) 1-adamantanecarbonyl acid (R=H, n=0) and 14.8 g (0.12 M, 9,0 ml) chloride taanila (molar ratio 1:1,2) is boiled in a flask equipped with a reflux condenser and a tube for drainage of eye-catching chloride, bodoro is a, which absorb the chilled water in the bubbler, until the cessation of gassing (1.5 hours). Excess chloride tiomila distilled first at atmospheric pressure (volume of 1 ml of distillate)and then in vacuum. To the residue add 10 ml of toluene and the resulting solution was added dropwise during 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 a stirrer, reflux condenser and addition funnel. The reaction mass is stirred for further 1 hour, cooled, filtered, added to the filtrate with stirring, 10 ml of concentrated hydrochloric acid and after 1 hour, the precipitation is filtered off, dried and recrystallized from water. Get to 17.2 g of the hydrochloride of 1-aminoadamantana exit 92%, TPL-370°C. Mass spectrum, m/z, I %: 151 (4%, [M]+), 135 (100%, [Ad]+), the structure of the claimed compounds corresponds to literature data.

Example 2.

Obtain hydrochloride of 1-aminoethylamino.

Analogously to example 1, but the acid chloride adamantanecarbonyl acid is mixed with 10 ml of toluene and added dropwise during 30 minutes to a boiling suspension of sodium azide in 125 ml anhydrous toluene (molar ratio 1:1:16) and stirred for 1.5 hours, from 15.5 g (0.08 M) 1-adamantaneacetic acid (R=H, n=1) gain of 15.1 g hydrochloride-aminoethylamino exit 94%, TPL-340°C. Mass spectrum, m/z I %: 165 (5%, [M]+), 149 (30%, [M-CH2]+), 135 (100%, [Ad]+), the structure of the claimed compounds corresponds to literature data.

Example 3.

Obtain hydrochloride of 1-amino-3,5-dimethyladamantane

(substance drug memantine).

Analogously to example 1, but the acid chloride adamantanecarbonyl acid is mixed with 10 ml of toluene and added dropwise during 30 minutes to a boiling suspension of sodium azide in 190 ml of anhydrous toluene (molar ratio 1:1:19) of 20.9 g (0.1 M) of 3,5-dimethyl-1-adamantanecarboxylic acid (R=CH3, n=0), the gain of 20.1 g of the hydrochloride of 1-amino-3,5-dimethyladamantane with the release of 93%, TPL-294°C. Mass spectrum, m/z, I %: 179 (3%, [M]+), 163 (10%, [M-NH2]+), 135 (100%, [Ad]+), the structure of the claimed compounds corresponds to literature data.

Example 4.

Getting hydrochloride 1-aminomethyl-3,5-dimethyladamantane.

Analogously to example 1, but added 13.5 g of chloride taanila (molar ratio 1:1,1), and the acid chloride adamantanecarbonyl acid is mixed with 10 ml of toluene and added dropwise during 30 minutes to a boiling suspension of sodium azide in 200 ml of anhydrous toluene (molar ratio 1:1:20), of 22.3 g (0.1 M) of 3,5-dimethyladamantane-1-acetic acid (R=CH3, n=0) gain of 21.9 g of the hydrochloride of 1-aminoet the l-3,5-dimethyladamantane with the release of 95%, TPL 279-281°C. Mass spectrum, m/z, I %: 193 (4%, [M]+), 163 (12%, [M-NH2]+), 135 (100%, [Ad]+), the structure of the claimed compounds corresponds to literature data.

The proposed method allows to obtain final products with higher outputs. The advantage of this method is its versatility, as it can synthesize not only the substance drugs "midantan" and "memantine", but almost any of their homologues.

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 in its implementation is able to achieve a technical result.

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

The method of producing hydrochloride amino adamantane General formula

where R is H, CH3; n=0, 1,
which consists in the interaction adamantanecarbonyl acid of General formula

where R is H, CH3; n=0, 1,
chloride tiomila at the temperature of its boiling for 1.5 h at their molar ratio (1:1.1 to 1.2), respectively, with the formation of the acid chloride adamantanecarbonyl acid, which is subjected to interaction with sodium azide in anhydrous toluene at the temperature of its boiling point, when a molar ratio of 1:1:15-20, respectively, for 1.5-2 h followed by the addition of concentrated hydrochloric acid at a molar ratio of carboxylic acid : hydrochloric acid 1:1.1 and maintaining the reaction mixture for 1 h and the selection of the target product.



 

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< / BR>
< / BR>
< / BR>
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