RU2218327C2 - Method for preparing 2,7-bis-[2-(diethylamino)- ethoxy]fluorenone-9 dihydrochloride as antiviral and immunomodulation preparation "amixinum" - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy. SUBSTANCE: invention relates to the development of the improved method for preparing 2,7-bis-[2- (diethylamino)ethoxyfluorenone-9 dihydrochloride. Method involves sulfonation reaction of fluorine to fluorine 2,7-disulfoacid disodium salt, its alkaline melting and the following cyclization with zinc chloride, alkylation with 2-diethylaminoethylchloride hydrochloride. Sulfonation reaction is carried out with sulfuric acid with its density 1.83-1.84 g/sm³ and alkaline melting reaction is carried out in wetting substrate with ammonia water and using mixture sodium nitrate and potassium nitrate taken in the ratio each to other = 5:1. EFFECT: improved preparing method. 2 cl

Description

 The invention relates to the field of pharmaceutical chemistry and chemical technology, in particular to the use of a known chemical compound as an antiviral drug and to improve the technology for its preparation.

 At present, interferon is widely used in medical practice for the prevention and treatment of viral diseases. Among antiviral drugs, liquid and solid outlet forms of drugs in the form of powders and tablets are known (M.D. Mashkovsky. Medicines. - M .: Medicine, 1985).

 In addition to exploring the possibilities of increasing the production of interferons, a search is constantly underway for substances that can stimulate the production of endogenous interferon in the human body. Such substances include derivatives of the basic esters and thioesters of fluorenone, fluorenol and fluorene.

One of the fluorenone derivatives is "amixin" - 2,7-bis- [2- (diethylamino) ethoxy] fluorenone-9- dihydrochloride (C ₂₅ H ₃₆ Cl ₂ N ₂ O ₃ ).

 The drug "amiksin" has a pronounced interferon-inducing and antiviral effect against a wide range of DNA and RNA-containing viral infections. The drug is approved for medical use by order of the Minister of Health Ministry 252 of 06/18/96.

 The aim of the present invention is to develop an improved method for producing 2,7-bis- [2- (diethidamino) ethoxy] fluorenone-9-dihydrochloride - the substance of the drug "amixin".

 A known method of producing dihydrochloride of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone - 9 (I), which consists in the fact that the original fluorene (II) is acetylated with acetyl chloride in the presence of anhydrous aluminum chloride with the formation with a yield of 56% 2 , 7-diacetylfluorene (III), which is then oxidized under the Bayer-Wiliger reaction with m-hydrochlorobenzoic acid in chloroform medium in the presence of catalytic amounts of trifluoroacetic acid at room temperature for 3 days, with the formation of 62%, 2 7-diacetoxyfluorene (I V). Compound IV is further oxidized with sodium dichromate in acetic acid, whereby 53% of 2,7-diacetoxyfluorenone (V) is obtained, which is hydrolyzed with 50% sulfuric acid to form 95% of 2,7-dihydroxyfluorenone (VI) ) The interaction of 2,7-dihydroxyfluorenone (VI) with 2.5 moles of 2-diethylaminoethyl chloride hydrochloride in a two-phase toluene-water medium, in the presence of caustic potassium and catalytic amounts of trimethylbenzylammonium bromide during boiling for 24 hours, subsequent separation of the organic layer, evaporation of it to dryness, dissolving the residue in methanol, followed by treating the resulting solution with saturated hydrogen chloride in sulfuric ether and recrystallizing the precipitate from the mixture ethanol: isopropanol = 1: 3 leads to the formation of 50% dihydride chloride, 2,7-bis [2- (diethylamino) ethoxy] fluorenone - 9 (1). The total yield of the target product is 8.74%, counting on the initial fluorene (II). [S.M. Burke, M.M. Joullie - NEW SYNTHETIC TO TILORONE HYDROCHLORIDE - SYNTHETIC COMM, v. 6, 5, 371-376]. The disadvantages of this method are the low yield and quality of the target product, multi-stage, a large number of difficult to dispose of waste water, the use of scarce and toxic anhydrous aluminum chloride and a long synthesis time.

A known method of producing dihydrochloride of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone - 9 (I) ("amixin"), we have chosen as a prototype method, which consists in sulfonation of fluorene (II) with a low percentage of oleum to a mixture of di - (VII) and mono- (VIII) fluorene sulfonic acids, which are isolated as fluorene di- and monosodium salts, then the necessary disodium salt of 2,7-disulfonic fluorene (VII) is separated from the monoisomer (VIII) by fractional crystallization of the obtained mixtures of water. The purified disodium salt of 2,7-disulfonic acid fluorene (VII) is subjected to an alkaline melting reaction by heating it at 270 ± 5 ^° C with 5 moles of sodium hydroxide in the presence of sodium nitrate for 8 hours. As a result of the reaction after quenching and acidification of an alkaline melt, 50% - sulfuric acid is formed in 80% yield of 4,4'-dihydroxy-2-biphenylcarboxylic acid (IX). Compound IX, when reacted with zinc chloride at 200-210 ^{° C.,} forms a cyclodehydration reaction in 90% yield of 2,7-dihydroxyfluorenone (VI), which is alkylated as described above, and 50% 2,7-bis- dihydrochloride is obtained in 50% yield. 2- (diethylamino) ethoxy] fluorenone - 9 (I). The total yield of the target product is 28.8%. [A.V. Bogatsky, A.I. Gren, L.A. Litvinova, G.V. Lempart-Synthesis of 2,7-bis- [2- (diethylamino) ethoxy] fluoren-9-one - Dokl. USSR Academy of Sciences, ser. B: geol., Chem., Biol. Science, 1976, v. 7, pp. 610-612]. The disadvantages of this method is the low yield of compound I, the long time of its synthesis, a huge amount of difficult to utilize acidic effluents and the low quality of the target product (I).

These disadvantages are eliminated by the proposed production method, which consists in the fact that fluorene (II) is sulfonated with sulfuric acid with a density of 1.83 - 1.84 g / cm ³ at a temperature of 160 ± 5 ^o C for 20 minutes, the mixture of sulfonic acids is diluted with water and neutralized with caustic sodium to pH 4-4.5, a precipitate of a mixture of mono- (VIII) and di- (VII) sodium salts of fluorene sulfonic acids is recrystallized from water with the formation of 87% purified disodium salt of fluorene 2,7-disulfonic acid, which subjected to alkaline melting by heating for 2.5-3 hours at 22 0 ± 10 ^o With caustic soda in the presence of catalytic amounts of ammonia water and a mixture of nitric acid sodium and nitric acid potassium, taken in a weight ratio to each other of 5: 1. In this case, after quenching of the alkaline melt, its acidification with 50% sulfuric acid with a yield of 88% produces 4,4'-dihydroxy-2-biphenylcarboxylic acid (IX), which with a yield of 90% is converted to 2,7-dihydroxyfluorenone (VI) when heated at a temperature of 200 ± 5 ^o C for 30 min . Next, 2,7-dihydroxyfluorenone (VI) is subjected to an alkylation reaction by reaction with 2.5-3.0 moles of 2-diethylaminoethyl chloride hydrochloride while boiling for 20 hours in toluene with 40% potassium hydroxide solution. In this case, an amixin base is formed - 2,7-bis- [2- (diethylamino) ethoxy] fluorenone-9 (X). Amixin base is dissolved in acetone and converted to amixin - 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride 9 (I) by the action of 35% hydrochloric acid added to the amixin base acetone solution " Amixin is obtained in a yield of 57%. The total yield of amixin is 32 - 34%, counting on the initial fluorene (II). The amount of hydrochloric acid necessary to obtain the maximum yield of “amixin” is determined by the formula
V _ml = 4.9 M / s,
where M is the mass of the base "amixin";
C is the concentration of hydrochloric acid determined by titration.

 The use of sulfuric acid with a density below 1.83 leads to a decrease in the yield of disodium salt of 2,7-disulfonic acid fluorene (VII), and an increase in the density of the acid used above 1.84 does not increase the yield of the target product, but only leads to an overuse of the sulfonating agent and an increase in acidic effluents .

 The use of a mixture of nitric acid sodium and nitric acid sodium, taken in a weight ratio of 5: 1, at the alkaline melting stage increases the yield of the target product and reduces the reaction time. An increase in the weight ratio of nitric acid sodium: nitric acid potassium above 5: 1 leads to a certain decrease in the yield of the target product and an increase in the material reaction index (i.e., an increase in the consumption of reagents), while an increase in the weight fraction of nitric acid potassium also leads to a small reducing the yield of the reaction product and increasing the material reaction index.

The decrease in the temperature of the reaction of alkaline melting below 210 ^o With leads to a decrease in the yield of the reaction product and a significant increase in the time of synthesis.

The increase in the temperature of the reaction of alkaline melting above 230 - 280 ^o With does not lead to an increase in the yield of the final product, but leads to a significant increase in energy consumption for conducting the reaction and, therefore, increases the cost of the final product.

A decrease in the reaction temperature of obtaining 2,7-dihydroxyfluorenone below 190 ^{° C.} leads to a decrease in the yield of the target product, and an increase in temperature above 210 ^{° C.} also leads to a decrease in yield due to the resinification of the reaction product.

 The treatment of the amixin base acetone solution with hydrochloric acid instead of the treatment of its ether solution with hydrogen chloride gas at the stage of production of 2,7-bis [2- (diethylamino) ethoxy] fluorenone-9 dihydrochloride ("amixin") leads to an increase in the yield " amixin "and simplifies the technology of its production, which, ultimately, reduces the cost of the cost of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone dihydrochloride - 9 (" amixin ").

 The following examples illustrate the invention.

Example 1. Disodium salt of 2,7-disulfonic acid fluorene (VII)
166 kg (1 kg mol) of fluorene (II) is loaded into a steel enameled "sulfurator" using a metering device, melted by heating to 112-115 ^o С, the anchor stirrer is turned on and 200 l of sulfuric acid with a density of 1.83 g are loaded with stirring / cm ³ at such a rate that the temperature of the reaction mass does not exceed 165 ± 5 ^o C. The reaction mixture is kept at this temperature for 1 h and pumped into a 2000 L stainless steel apparatus filled with 200 kg of ice to separate disodium salt 2 , 7-disulfonic acid fluorene (VII). After pumping the sulphomass into the “separator”, a 20% sodium hydroxide solution is added from the measuring device, making sure that the pH of the suspension does not exceed 4.5-5 and the temperature of the mixture does not exceed 60 ^o C. from a measuring meter ^. The suspension is filtered off with warm suction filter, using “belting” as a filter material. After washing with cold water to a pH of 7 (20-200 L), 345 kg of a sulfosulfide mixture containing, according to HPLC, 92% of disodium salt of 2,7-disulfonic acid fluorene are obtained. The sulfosulfide mixture is poured into 400 L of water, heated to complete dissolution and cooled to a temperature of 75-80 ^o С. The precipitated precipitate, containing mainly the monosodium salt of 2-sulfonic acid fluorene, is filtered off, and the mother liquor is evaporated until turbidity appears, after which the evaporation is stopped, the solution is cooled to ambient temperature, and the precipitate formed is filtered off and dried. Get 300 kg (87%) of disodium salt of 2,7-disulfonic acid fluorene (VII).

Example 2
166 g (1 g mol) of fluorene (II) is loaded into a 4-necked glass flask, melted by heating to 112-115 ^° C, the stirrer is turned on, and 200 ml of sulfuric acid with a density of 1.83 g / cm ³ are charged with such speed, so that the temperature of the reaction mass does not exceed 165 ± 5 ^o C. the Reaction mixture is kept at this temperature for 1 h and poured onto ice. Then a 20% sodium hydroxide solution is added, making sure that the pH of the suspension does not exceed 4.5-5, and the temperature of the mixture does not exceed 60 ^o C. The suspension is filtered off with warm water, washed with cold water to pH 7 (20-100 ml) 350 g of sulfonic mixture containing, according to HPLC, 92% disodium salt of 2,7-disulfonic acid fluorene (VII). The sulfosulfide mixture is poured into 400 ml of water, heated to complete dissolution and cooled to a temperature of 75 - 80 ^o C. Precipitated upon standing, the precipitate containing mainly the monosodium salt of 2-sulfonic acid fluorene is filtered off, and the mother liquor is evaporated until turbidity appears, after which the evaporation is stopped, the solution is cooled to ambient temperature, and the precipitate formed is filtered off and dried. Obtain 302 g (~ 87%) of disodium salt of 2,7-disulfonic acid fluorene (XI).

Example 3. 4,4'-Dihydroxy-2-biphenylcarboxylic acid (IX)
370 kg (1 kg mol) of disodium salt of 2,7-disulfonic acid fluorene (XI) are loaded into an alkaline melting apparatus, the product is moistened with 20 l of ammonia water, 180 kg (4.5 kg mol) of caustic soda and mixture are added 85 kg (1 kg mol) of nitric acid sodium and 17 kg (0.17 kg mol) of nitric acid potassium. The reaction mixture is heated to a temperature of 220 10 ^o C, kept at this temperature for 2.5-3 hours, the mixture is cooled to a temperature of 100 ^o C and through the lower descent of the "melter" is transferred to a separator - enameled apparatus with a capacity of 2000 l, which is pre-loaded 500 L of water and 350 L of 94% sulfuric acid. The precipitate is filtered off, washed with hot water until neutral and dried. After washing with a mixture of 75 L of ethyl alcohol and 75 L of distilled water, 202.4 kg (88%) 4.4 '-dihydroxy-2-biphenyl-carboxylic acid (IX) with a mp of 273-274 ^o C.

Example 4
370 g (1 kg mol) of disodium salt of 2,7-disulfonic acid fluorene (XI) are loaded into an alkaline melting apparatus, the product is moistened with 20 ml of ammonia water, 180 g (4.5 kg mol) of caustic soda and mixture are added 85 g (1 kg mol) of nitric acid sodium and 17 g (0.17 kg mol) of nitric acid potassium. The reaction mixture is heated to a temperature of 220 ± 10 ^o C, maintained at this temperature for 2.5-3 hours, the mixture is cooled to a temperature of 100 ^o C and the reaction mixture is loaded into a 3000 ml flask containing 1000 ml of water and 350 ml of 94% sulfuric acid. The precipitate formed is filtered off, washed with hot water until neutral and dried. After washing with a mixture of 100 ml of ethyl alcohol and 100 ml of distilled water, 202.5 g (88%) of 4,4'-dihydroxy-2-biphenylcarboxylic acid (IX) are obtained with a mp of 273-274 ^o C.

Example 5. 2 2,7-Dihydroxyfluorenone
460 kg of zinc chloride and 230 kg (1 kg mol) of 4,4'-dihydroxy-2-biphenylcarboxylic acid are loaded into a heated enameled apparatus with a capacity of 2000 l, the reaction mixture is heated to 200 ± 10 ^o C, stirred at this temperature for 1 h, then cooled to ambient temperature and 1000 l of water are added. The precipitate is filtered off on a suction filter, washed until neutral with water and dried. Receive after recrystallization from isopropyl alcohol 190 kg (90%) of 2,7-dihydroxyfluorenone with so pl. 338-339 ^o C.

Example 6. 2,7-Bis- [2- (diethylamino) ethoxy] fluorenone - 9 dihydrochloride (I)
42.4 kg (0.2 kg mol) of 2,7-dihydroxyfluorenone, 300 l of toluene are loaded into a 1000 l glass apparatus of Simax company equipped with a propeller stirrer, a measuring device, a thermometer, a reflux condenser and a device for loading a dry substrate 100 l of distilled water, 40 kg (1 kg mol) of potassium hydroxide and 81.3 kg (0.6 kg mol) of 2-diethylaminoethyl chloride hydrochloride. The reaction mixture is heated to boiling and boiled for 20 hours, then cooled to ambient temperature and left to stand until it is divided into two layers. The lower inorganic layer is drained, the organic layer containing the solution of the target product is washed with water and distilled off practically to dryness. The residue was dissolved in hexane, filtered off from insoluble impurities and evaporated to dryness. The residue is dissolved in 100 - 120 L of acetone and transferred to 2,7-bis- [2- (diethylamino) ethoxy] fluorenone - 9 (I) dihydrochloride by treatment of the solution with concentrated hydrochloric acid, the volume of which is determined by the formula:
V _ml = 4.9 M / s,
where M is the mass of the base "amixin";
C is the concentration of hydrochloric acid determined by titration.

The orange precipitate formed is filtered off, washed on a suction filter with acetone and dried. Obtained after recrystallization from isopropyl alcohol 51 kg (57%) of dihydrochloride of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone - 9 (I), so pl. 233-235 ^o C. The total yield of compound I is 32.8-34%.

 Thus, the use of the indicated technical solution allows to increase the yield of the target product, improve its quality, simplify the technological solution of the process of its production, reduce the amount of difficult-to-utilize wastewater, reduce the time of the production process, and as a result significantly reduce the cost of the drug.

Claims (2)

1. A method of producing 2,7-bis- [2- (diethylamino) ethoxy] fluorenone-9 dihydrochloride by sulfonation of fluorene, purification of the resulting mixture of sulfonation products from the monosodium salt of 2-sulfonic acid fluorene, subsequent “alkaline melting” of the obtained purified disodium salt 2, 7-disulfonic acid fluorene with sodium hydroxide in the presence of nitric acid sodium to form 4,4'-dihydroxy-2-biphenylcarboxylic acid, followed by cyclization to 2,7-dihydroxyfluorenone by treating 4,4'-dihydroxy-2-biphenylcarboxylic acid with chloride Inc at a temperature of 200 ± 10 ° C, by alkylation of 2,7-dihydroxyfluorenone by boiling it with 2.5-3 moles of 2-diethylaminoethyl chloride hydrochloride in the presence of caustic potassium, and the resulting 2,7-bis - [2- (diethylamino) ethoxy] is converted fluorenone-9 to dihydrochloride, characterized in that, in order to increase the yield of the target product, improve its quality, reduce the reaction time, labor costs and energy intensity of the process, sulfonation is carried out with sulfuric acid with a density of 1.83-1.84 g / cm ³ , before the alkaline melting step of the purified disodium salt of 2,7-dis fluorene ultrafluoride is wetted with ammonia water and the alkaline melting process is carried out in the presence of a mixture of sodium nitrate: potassium nitrate, taken in a weight ratio of 5: 1 at a temperature of 220 ± 10 ° C. 2. The method according to claim 1, characterized in that the translation of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone-9 into its dihydrochloride is carried out by acting on an acetone solution of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone-9 concentrated hydrochloric acid, the amount of which is determined by the formula V _ml = 4.9 M / C, where V _ml is the amount of hydrochloric acid; M is the mass of the base of 2,7-bis- [2- (diethylamino) ethoxy] fluorenone – 9.