RU2104994C1 - Method of synthesis of 1-hydroxyadamantane-4-one (medicinal agent "kemantan") - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: invention proposes new method of synthesis of 1-hydroxyadamantane-4-one (immunostimulating medicinal agent "Kemantan") by oxidation of adamantanone with a mixture of concentrated sulfuric and nitric acids in the presence of catalysts. The used catalysts are metal oxides of transient valency and alkaline metal nitrites. Formed chelate compounds were decomposed by boiling in the presence of inert carriers. EFFECT: increased yield, efficiency and quality of the end product. 3 cl

Description

 The invention relates to the pharmaceutical industry and relates to a method for producing 1-hydroxyadamantan-4-one (cemantan) - an immunostimulating agent effective in treating diseases of the vascular system of the extremities of autoimmune genesis, chronic bronchitis, tuberculosis, infectious-allergic bronchial asthma, chronic aphthous stomatitis, herpes and others. [1].

 Several methods are known for producing 1-hydroxyadamantan-4-one, including the oxidation of 2-hydroxyadamantane with 70% sulfuric acid, followed by repeated extraction of the mixture of oxidation products and further oxidation of the resulting mixture with chromic anhydride [2]. The yield in this case of 1-hydroxyadamantan-4-one is not more than 25%.

 In other methods, the target product is obtained by oxidation of adamantanone with chromic anhydride in acetic, propionic or trifluoroacetic acids [3] or by oxidation of adamantanone with a 12-fold amount of nitric acid [4].

 The disadvantages of these methods are low yields of the final product, the use of large quantities of scarce oxidizing agents and a large number of fire and explosion hazardous reagents.

There is also known a method of hydroxylation of aminoadamantane derivatives with a mixture of nitric and sulfuric acids [5]. The reaction is carried out mainly at 20 ^o C. The reaction mass according to this method, after dilution with water, is neutralized with a 40% sodium hydroxide solution, extracted with chloroform and the product is isolated after evaporation of the solvent.

 The use of this method for the synthesis of kemantan showed that the disadvantage of this method is low productivity due to the low reaction rate. Another disadvantage is the complexity of the instrumentation of the process due to the formation of a large amount of organic salts as a precipitate after alkalization, which complicates the extraction of the target product.

 Upon nitric acid oxidation of adamantanone, as shown by Geluk [6], rather stable complexes of oxygen-containing derivatives of adamantane with nitric acid are formed. Under the conditions of isolation of the product according to the above method, they do not completely decompose and crystallization also fails to free themselves from their impurities.

 In order to speedily introduce into the industry the production of the immunostimulating drug Kemantan, an improved method for its preparation has been developed, which allows increasing the reaction rate by an order of magnitude, increasing the yield and obtaining a drug of sufficient purity.

This goal is achieved by the fact that according to the method of producing cemantan by the interaction of adamantanone with nitric and sulfuric acids, the process is conducted in the presence of metal oxides of variable valence or sodium or potassium nitrites. At the end of the reaction, the mass is poured onto ice, and then, for complete decomposition of the nitrogen complexes, it is boiled with activated carbon and aluminum oxide or silica gel and the initial adamantanone is distilled off with steam. The distillation is carried out until the absence of adamantanone in the cube and the cessation of the emission of nitrogen oxides. The acidic reaction mass is filtered, and then kemantan is extracted from the filtrate. The solvent is evaporated and get a technical product with a yield of 80%. After crystallization from carbon tetrachloride, kemantan is obtained with so pl. 226-228 ^o C.

The resulting cemantan is a white crystalline substance, readily soluble in water. The purity of cemantan obtained by the present method is confirmed by the data of IR, NMR spectra, elemental analysis and TLC analysis. The infrared spectrum of cemantan contains characteristic absorption bands inherent in the adamantane cycle located in the region: 2857-2929 cm ^-1 , as well as bands at 1450, 1352, 1336, 1287, 1235, 1111, 1094, 1069, 1054, 901, and 452 cm ^-1 ; the carbonyl absorption band is observed at 1725 cm ^-1 , the wide absorption band of the OH group of cemantan is observed in the region of 3396 cm ^-1 , NMR spectra: ¹ H (CLCl ₃ δ, ppm) signal at 2.64 (2H) (proton α position to the C = 0 group), 2.34 (1H) tertiary proton at C ₇ , 1.93 (10h) secondary protons, 1.87 (1H) proton in the OH group; ¹³ C (CDCl ₃ ): 29.83 ppm, C ₇ , d, CH; 38.22 M.D. C ₈ , c ₁₀ , t, CH ₂ ; 44.16 M.D., C ₁ , C ₃ , d, CH; 67.19 ppm, C ₅ , s, C; 216.59 ppm, C ₂ , s, C = 0.

TLC analysis, solvent system petroleum ether - ethyl acetate - ethanol - ammonia = 5: 3: 2: 1, R _f 0.254 (iodine vapor).

 A mixture of sulfuric and nitric acids is an oxidizing agent, leading to the formation of carbocation at the nodal position. The use of metal oxides of variable valency or potassium and sodium nitrites increases the rate of formation of the adamantyl cation.

The use of oxides of metals of variable valency and nitrites leads to the formation of nitrosocation NO ⁺ from HNO ₂ , resulting from the interaction of nitrites with sulfuric acid, or indirectly metal oxides of variable valence with sulfuric acid and nitric acid.

Example 1. To a solution of 30 ml (0.45 mol) of 67.7% nitric acid in 200 ml (3.53 mol) of 94.6% sulfuric acid, 2.5 g (0.16 mol) are gradually added. adamantanone and 1.9 g (0.13 mol) of sodium nitrate, maintaining the temperature not higher than 30 ^o C, maintain the reaction mass until the content of cemantan in it is not <80%, pour the mass onto ice, add 4.0 g of activated carbon to the reaction mass coal and 4.0 g of aluminum oxide, 2.1 g of adamantanone are distilled off from the reaction mass with a sharp steam (4 h), the mass obtained after distillation is filtered, extracted with chloroform, the solvent is distilled off and 19.1 g of kemantan, yield 75.4% (counting on the reacted adamantanon), mp 226-228 ^o C (from CCl ₄ ), yield on crystallization of 80%.

Example 2. To a solution of 30 ml (0.45 mol) of 67.7% nitric acid in 200 ml (3.53 mol) of 94.6% sulfuric acid, 25.0 g (0.16 mol) are gradually added. adamantanone and 1.33 g (0.013 mol) of potassium nitrate, maintaining the temperature no higher than 30 ^o C. The reaction mass is maintained until the content of cemantan in it is at least 80%, poured onto ice, 4.0 alumina and 4.0 g activated coal, 2.5 g of unreacted adamantanone are distilled off with hot steam, the reaction mixture is filtered after distillation of adamantanone, extracted with chloroform, the solvent is distilled off, and 20.0 g are obtained by whom ntana, yield 80.3%, m. pl. 24-226 ^o C (from CCl ₄ ), R _f - 0.254 in the solvent system (petroleum ether - ethyl acetate - ethanol - ammonia = 5: 3: 2: 1) (manifestation by iodine vapor).

Example 3. In a reactor equipped with a stirrer, a dropping funnel and a thermometer, 300 ml (4.2 mol) of 94.6% nitric acid and 2000 ml (35.3 mol) of sulfuric acid 94.6% were placed, and 20 g of active manganese dioxide, 250 g (1.7 mol) of adamantanone are gradually added to the reaction mass, maintaining the temperature in the mass not higher than 35 ^o C, the reaction mass is maintained with stirring and a temperature of 30 ^o C until the content of kemantan in the mass is not <80% (≈ 10 h), poured onto ice, 40 g of activated carbon and 40 g of aluminum oxide are added, the mass is boiled and sharp steam is passed through it for 4 hours for complete distillation of adamantanone and decomposition of product complexes with nitric acid, after which the reaction mass is filtered, extracted from the filtrate with kemantan chloroform, the solvent is distilled off to dryness and 201 g of kemantan are obtained; adamantonone 19 g), is 78.6%, so pl. 227-228 ^o C (from CCl ₄ ). Elemental analysis: found,%: C 72.49; H, 8.47; calculated,%: C, 72.25; H 8.49.

Example 4. In a three-necked flask, 30 ml of 0.45 mol of 64.6% nitric acid, 200 ml (3.53 mol) of 94.6% sulfuric acid, 2.0 g of chromic anhydride are charged and added with vigorous stirring 25 g (0.16 mol) of adamantanone so that the temperature does not rise above 35 ^o C, the mixture is kept under stirring at a temperature of 30-34 ^o C until the content of cemantan in the reaction mass is not <80% (reaction time 8-10 h). At the end of the reaction, the mass is poured onto ice, 4.0 g of aluminum oxide and 4.0 g of activated carbon are added and boiled for 4 hours, sharp steam is passed through the mass (while 3.0 g of unreacted adamantanone is distilled off). At the end of boiling, the mass is filtered, the reaction product is extracted from the filter with chloroform, the solvent is distilled off to dryness and 19.8 g of cemantan are obtained, 81.32% yield (based on the reacted adamantanone), so pl. 224-226 ^° C (from CCl ₄ ). Elemental analysis: found,%: C 72.52; H 8.57, calculated,%: C 72.25; H 8.49.

Claims (3)

 1. The method of producing 1-hydroxyadamantan-4-one (cemantane) by the oxidation of adamantanone with nitric acid, characterized in that the process is carried out with the addition of sulfuric acid in the presence of a catalyst and the resulting reaction mass, after dilution with water, is boiled with activated carbon and aluminum oxide or silica gel.  2. The method according to p. 1, characterized in that the catalysts used are metal oxides of variable valency.  3. The method according to p. 1, characterized in that the catalyst used is nitrous potassium or sodium.