RU2412155C1 - 1-nitroxyadamantane synthesis method - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutical chemistry, specifically to a method for synthesis of 1-nitroxyadamantane, an intermediate product in synthesis of 1-adamantane carboxylic acid, a fundamental intermediate product in synthesis of remantadin antiviral drug. According to the disclosed method, adamantine is added to 10-15% solution of ammonium nitrate in 98% nitric acid, taken in amount of 4.5-5.6 weight parts per 1 part of adamantine at temperature 3-5°C and then held for 1.5 hours at 22-25°C, poured on ice and the reaction product is separated.

EFFECT: output of 1-nitroxyadamantane is equal to 90-91% in accordance with the disclosed method.

1 cl, 4 ex

Description

The invention relates to the field of pharmaceutical chemistry, namely, to a method for producing 1-nitroxyadamantane, an intermediate in the synthesis of 1-adamantanecarboxylic acid (1-ACC), the main intermediate in the synthesis of remantadine, an antiviral drug.

A known method of producing 1-nitroxyadamantane by nitration of adamantane with 98.0% nitric acid or solutions of acetic acid in nitric acid (Moiseev I.K., Belyaev P.G., Doroshenko R.I. Izvestiya VUZov, Chemistry and Chemical Technology, 1982 (10), pp. 1185-1187).

The use of 98.0% nitric acid gives a relatively low yield of 1-nitroxyadamantane (up to 72%). In addition, an admixture of 1-nitroadamantane is formed, which greatly complicates the purification of the main product.

The optimal conditions ensuring the maximum yield of 1-nitroxyadamantane (80%) are: an acid mixture containing 18 moles of nitric acid and 6 moles of acetic acid per 1 mole of adamantane, reaction time 3 hours, reaction temperature 20 ° C.

This method of obtaining 1-nitroxyadamantane was chosen by us as the closest analogue of the invention. Its main disadvantages are:

1. The relatively low yield of the target product is up to 80%.

2. High acid consumption: 9.2 parts by weight nitric acid and 2.6 wt.h. acetic acid per 1 part nitratable adamantane.

3. The formation of a mixture of acetic and nitric acids, the processing of which is associated with high hazard and environmental pollution.

4. Low quality of the resulting product.

The use of 1-nitroxyadamantane without preliminary purification directly in the carboxylation of formic acid in sulfuric acid showed the formation of a large amount of impurities of high-melting products, the main of which is 1,3-adamantane dicarboxylic acid. The formation of an impurity of this product indicates the presence in the starting 1-nitroxyadamantane of an impurity of 1,3-dinitroxyadamantane, which in turn indicates a significant degree of overshoot of adamantane under analog reaction conditions.

The problem to which this invention is directed, is to create a method for producing high-quality 1-nitroxyadamantane, allowing it to be used to obtain 1-adamantanecarboxylic acid without preliminary purification of by-products, as well as to increase the yield of 1-nitroxyadamantane with a simultaneous decrease in acid consumption and to obtain spent acids that can be processed by known safe processes.

The problem is achieved by a new method for producing 1-nitroxyadamantane, which is carried out as follows.

The initial adamantane is added to a 10 ÷ 15% solution of ammonium nitrate at a temperature of 3 ÷ 5 ° C and a mass ratio of 98.0% nitric acid to adamantane 4,5 ÷ 5,6: 1 and the nitration reaction is completed at a temperature of 22 ÷ 25 ° C for 1.5 hours. The product is isolated by dilution with ice water, filtered off, washed with water and dried in air to constant weight. The yield of 1-nitroxyadamantane is 90-91% of theory with a melting point of 102-103 ° C. The high quality of the obtained 1-nitroxyadamantane was confirmed by the preparation of 1-AKA from it by carboxylation of formic acid in sulfuric acid by the Koch-Haaf reaction. The yield of 1-ACA reaches 95-99% with a melting point of 177-186 ° C without the admixture of high-melting products that are formed when using 1-nitroxyadamantane obtained by analogy.

The yield of 1-nitroxyadamantane increases in this case by 10-11%. The consumption of nitric acid is reduced almost twice, and the use of expensive acetic acid is completely eliminated. The spent nitric acid contains 3–5% ammonium nitrate and can be easily converted to ammonium nitrate by neutralization with ammonia to produce nitrate suitable for use as fertilizers or in the manufacture of emulsion explosives for the mining industry.

The duration of the nitration reaction is reduced by half, which can significantly increase the productivity of the equipment.

The following examples illustrate the essence of the invention. Example 1

7.5 g of ammonium nitrate are added to 45 ml of 98% nitric acid, stirred until complete dissolution and the resulting 10% solution is cooled to 3 ÷ 5 ° C, then 13.6 g of adamantane are added in small portions. The mass ratio of nitric acid to adamantane is 5: 1. They stop cooling and allow the temperature to rise to 22 ÷ 25 ° C. At this temperature, give an exposure of 1.5 hours, periodically cooling. The exothermic phase of the reaction lasts 60-70 minutes. At the end of the nitration reaction, the resulting solution was poured onto ice, filtered, washed with water and dried in air to constant weight. The yield of 1-nitroxyadamantane 17.9 g (90% of theory). Melting point 102-104 ° C. IR spectrum (cm ^-1 ): 1615, 1315, 1300, 1284 is identical to the spectrum of the sample obtained by analogy to the carboxylation of the product by the Koch-Haaf reaction, 1-ACA was obtained in 99% yield.

Example 2

The nitration of adamantane is carried out similarly to the description in example 1, using 9.6 g of ammonium nitrate to obtain a 12.5% solution of nitrate in nitric acid. The mass ratio of nitric acid to adamantane is 5: 1. The yield of 1-nitroxyadamantane was 18.0 g (91% of theory), melting point 102-103 ° C. The yield of ACC when using the crude product in the Koch-Haaf reaction was 95%.

Example 3

Adamantane nitration was carried out similarly to the description in Example 1 using 50 ml of 98% nitric acid and 13.3 g of ammonium nitrate (15% solution). The mass ratio of nitric acid to adamantane is 5: 1. The yield of 1-nitroxyadamantane 17.9 g (90% of theory), T _mp 102-103 ° C.

Example 4

The nitration of adamantane was carried out similarly to the description in example 1, using 41 ml of 98% nitric acid and 8.8 g of ammonium nitrate (12.5% solution). The mass ratio of nitric acid to adamantane is 4.5: 1. The yield of 1-nitroxyadamantane 17.9 g (90% of theory), T _mp 102-103 ° C.

Claims (1)

The method of producing 1-nitroxyadamantane by nitration of adamantane with 98% nitric acid, characterized in that the nitration of adamantane is carried out at a temperature of 3 ÷ 5 ° C with a mass ratio of nitric acid to adamantane 4,5 ÷ 5,6: 1 in the presence of 10 ÷ 15% ammonium nitrate, complete the reaction at 22 ÷ 25 ° C for 1.5 hours and isolate the product by dilution with ice water.