RU2317974C1 - 2,7-bis[2-(diethylamino)ethoxy]fluorenone dihydrochloride (amixin) production process - Google Patents

Abstract

FIELD: industrial organic synthesis.

SUBSTANCE: invention provides improved 2,7-bis[2-(diethylamino)ethoxy]fluorenone dihydrochloride production process comprising stages of sulfurization of fluorenone followed by neutralization of obtained reaction mass, isolation of purified fluorenone-2,7-disulfonic acid disodium salt, "alkaline melting" of this salt in presence of sodium nitrate to form 4.4'-dihydroxydiphenyldicarboxylic acid, cyclization to form 2,7-dihydroxyfluorene and alkylation thereof. More specifically, 2,7-dihydroxyfluorene obtained in cyclization stage is converted into alkali metal salt and toluene solution of 2-diethylaminoethyl chloride is added to preheated aqueous solution of the above salt at molar ratio 1:(3-5), preferably 1:4, to form 2,7-bis[2-(diethylamino)ethoxy]fluorenone, which is then treated with concentrated aqueous hydrochloric acid at molar ratio 1:(3.5-4), preferably 1:3.5.

EFFECT: increased yield and improved quality of product, and simplified process.

3 cl, 3 dwg, 4 ex

Description

The invention relates to the field of organic chemistry, in particular to an improved method for producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone (amixin) dihydrochloride of the formula I:

which is currently widely used in medical practice as an antiviral and immunostimulating substance / Biol. Unteract. 1987, v.62, No. 1, p.25-42, patent of the Russian Federation 2122425, 11.27.1998, patent of the Russian Federation2141314, 20.11.1999 /.

A number of methods are known for producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I), starting from fluorene (II).

One of them / M. Burke Sister, Medeleine M. Joulie "New synthetic pathways to tilorone hydrochloride", Synthetic Com. 1976, 6 (5), p. 371-376 / consists in the fact that fluorene is converted into a fluorenone derivative by acetylation with acetyl chloride in the presence of aluminum chloride according to the Friedel-Crafts reaction with the formation of 2,7-diacetylfluorene (III), the resulting diacetate is oxidized according to Bayer-Wiliger superchlorobenzoic acid in a suitable organic solvent to form 2,7-diacetoxy fluorene (IV), which in turn is oxidized with sodium bichromate in acetic acid to form 2,7-diacetoxy fluorenone (V). The resulting compound (V) is alkylated with 2-diethylaminoethyl chloride hydrochloride in a mixture of toluene-aqueous potassium hydroxide solution in the presence of benzyltriethylammonium bromide as an interphase transfer catalyst, the organic layer is separated, washed with water and a saturated sodium chloride solution, dried with anhydrous magnesium sulfate, the filter is filtered off and the filter is dried. the solution is dry, the residue is dissolved in methanol and treated with dry hydrogen chloride in diethyl ether. After recrystallization from a mixture of methanol-isopropanol, the desired product 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) is obtained with a 50% yield in the alkylation step and with a total yield of 10%, see diagram:

Another method for producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) / RF Patent 2076097, 03/27/1997 / is that fluorenone (VI) obtained from fluorene (II) is dissolved in glacial acetic acid and treated with iodine under heating in the presence of a mixture of sulfuric and nitric acids, the resulting 2,7-diiodofluorenone (VII) is treated with potassium 2-diethylaminoethylate in the presence of 18-crown-6 in dry dimethylformamide or dioxane. The isolation of 2,7-bis [2- (diethylamino) ethoxy] fluorenone is carried out by diluting the reaction mass with water, separating by filtration of the base precipitate, washing with water, suspension in water, precipitation with concentrated hydrochloric acid, drying of the target product - 2.7 bis [ 2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) with 72% yield in the alkylation step and 24% in total yield, see diagram:

In another method / JP 9031036, 02/04/1997 / obtained by oxidation of fluorene with bichromate in acetic acid, fluorenone (VI) is nitrated with a mixture of nitric and sulfuric acids to form 2,7-dinitrofluorenone (VIII), which is reduced with tin chloride or hydrogen in the presence of Lindlar catalyst ( 10% palladium), poisoned with 5% lead at a pressure of 40-60 kg / cm ² , the resulting suspension of 2,7-diaminofluorenone (IX) in 50% tetrafluoroboric acid is diazotized with sodium nitrite, the explosive diazonium salt (X) is filtered off, which in turn, meter in boiling 50% sulfuric acid to form 2,7-dioxifluorenone (XI). Compound (XI) is alkylated with 2-diethylaminoethyl chloride hydrochloride in a mixture of a potassium hydroxide toluene solution, the organic layer containing 2,7-bis [2- (diethylamino) ethoxy] fluorenone is separated, washed with water and a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, the desiccant is filtered off, the solution is evaporated to dryness, the residue is dissolved in isopropanol, treated with a solution of hydrogen chloride in ethanol and 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) is obtained in 50% yield (at the alkylation stage) and the total m yield - 11%, see scheme:.

All of the above methods for producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) are characterized by a low total yield, insufficient quality of the target product (mp 235-236 ° С), significant consumption of solvents, using hard-to-reach, expensive and toxic reagents. All this makes these methods low-tech and not suitable for use in industrial production.

More technologically advanced and allowing to obtain the target product - 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) with a good yield is a method for producing 2,7-bis / 2- (diethylamino) ethoxy dihydrochloride O.V. Bogatsky, A.I. Gren, L.O. Litvinova and others. DAN of the Ukrainian SSR, ser. B. Geology, Chemistry, Biologist, Science, 1976, No. 7, pp. 610-611 /, which consists in sulfonation of fluorene with a low percentage oleum, isolation of disodium salt of 2,7-disulfonic acid fluorene (UP) fractional crystallization of the mixture from water, alkaline melting this salt under conditions of heating it at 270-275 ° C with 5 moles of sodium hydroxide in the presence of sodium nitrate for 8 hours. The resulting reaction after quenching and acidification of the alkaline melt with 50% sulfuric acid, 4,4'-dihydroxy-2-biphenylcarboxylic acid (IX) is subjected to a cyclodehydration reaction when contacted with zinc chloride at 200-210 ° C, resulting in 2 , 7-dihydroxyfluorenone (VI), which is subjected to alkylation by reaction with 2.5 moles of 2-diethylaminoethyl chloride hydrochloride in a two-phase toluene-water medium, in the presence of potassium hydroxide and catalytic amounts of trimethylbenzylammonium bromide during boiling for 24 hours. Then the organic layer is separated, it is evaporated to dryness, the residue is dissolved in methanol and the resulting solution is treated with saturated hydrogen chloride in sulfuric ether and the precipitate formed is recrystallized from ethanol: 1: 3 isopropanol is obtained in 50% yield of 2,7-bis- / 2- dihydrochloride. (diethylamino) ethoxy / fluorenone-9 ("amixin", I). The total yield of the target product is 28.8%, so pl. 235-235 ° C. The disadvantages of this method are: the duration of the synthesis, a huge amount of hard to utilize acidic effluents, low quality of the target product.

Closest to the proposed one is the method described in RF patent 2218327, 12/10/2003, which consists in sulfonation of fluorene with sulfuric acid with a density of 1.83-1.84 g / cm ³ at a temperature of 160-165 ° C for 20 minutes, dilution with water and neutralization with sodium hydroxide to a pH of 4-4.5 of a mixture of sulfonic acids, the allocation of purified disodium salt of 2,7-disulfonic acid fluorene (VII) by recrystallization of this mixture from water, after which the latter is subjected to alkaline melting, heating for 2.5-3 hours at 220-230 ° C with sodium hydroxide in the presence of catalytic t he a mixture of ammonia water and nitric acid and sodium nitric acid potassium taken in a weight ratio to each other of 5: 1. 4,4'-dihydroxy-2-biphenylcarboxylic acid (IX, 88% yield) formed after quenching of the alkaline melt and acidifying it with 50% sulfuric acid is converted to 2.7 at heating at a temperature of 200-205 ° C for 30 minutes -dihydroxyfluorenone (VI, 90% yield). Further, the obtained fluorenone (VI) is subjected to an alkylation reaction by reaction with 2.5-3 moles of 2-diethylaminoethyl chloride hydrochloride while boiling for 20 hours in toluene with 40% potassium hydroxide solution. The resulting base of "amixin" - 2,7-bis- / 2- (diethylamino) ethoxy / fluorenone-9 (I) is dissolved in acetone and converted into "amixin" - dihydrochloride 2,7-bis- / 2- (diethylamino ) ethoxy / fluorenone-9 (I) by adding 35% hydrochloric acid to an amixin base solution in acetone. The total yield of amixin is 32-34%, counting on the initial fluorene (II), during alkylation - 57%, so pl. 233-235 ° C. However, this method of producing 2,7-bis- / 2- (diethylamino) ethoxy / fluorenone-9 dihydrochloride has several disadvantages.

First of all, it requires strict observance of the process conditions. Changing conditions in one direction or another can lead to a decrease in the yield of the target product, and a decrease in its quality. For example, the use of sulfuric acid with a density below 1.83 g / cm ³ 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 is above 1.84 g / cm ³ without increasing the yield of the target product, leads to an overspending of the sulfonating agent and an increase in acidic effluents, a decrease in the temperature of the alkaline melting reaction below 210 ° C leads to a decrease in the yield of the reaction product and a significant synthesis time, an increase in the temperature of the reaction of alkaline melting above 230-280 ° C does not contribute an increase in the yield of the final product, and significantly increases the energy consumption for the reaction and, thereby, increases the cost of the target product. The alkylation process of 2,7-dihydroxyfluorenone involves the distillation of the toluene solution almost to dryness, requires a significant consumption of volatile solvents - hexane and acetone. In addition, it is complicated by adverse reactions of 2-diethylaminoethyl chloride in basic media, which reduces the quality of the target product.

Thus, none of the known methods allows to obtain the dihydrochloride of 2,7-bis- / 2- (diethylamino) ethoxy / florenone-9 of the required quality according to a more technological scheme, which involves reducing the volume of organic solvents, reducing the possibility of side reactions.

The objective of the invention is to develop a new and improved method for producing dihydrochloride 2,7-bis- / 2- (diethylamino) ethoxy / florenone-9, which allows to increase its yield, improve the quality of the target product, simplify the process of its synthesis and eliminate expensive reagents from use.

The problem is solved by the proposed method for the production of 2,7-bis / 2- (diethylamino) ethoxy / fluorenone-9 dihydrochloride (1), which includes the stages of sulfonation of fluorene followed by neutralization of the resulting reaction mass and isolation of the purified disodium salt of 2,7-disulfonic acid fluorene, " alkaline melting of this salt in the presence of nitric acid sodium to produce 4,4 'dioxidiphenylcarboxylic acid, cyclization and alkylation of 2,7-dioxifluorenone, consisting in the fact that 2,7-dioxifluorenone is converted in the cyclization step They are added to an alkali metal salt and a toluene solution of 2-diethylaminoethyl chloride is added to a preheated aqueous solution of this salt at a molar ratio of 1: 3-1: 5, preferably 1: 4, the resulting 2,7-bis / 2- (diethylamino) ethoxy fluorenone is treated concentrated hydrochloric acid in a molar ratio of 1: 3.5-1: 4, preferably 1: 3.5.

The proposed method allows to obtain the target product with so pl. 237-238 ° C, with a total yield of about 50-55%, output at the stage of alkylation - 95%.

Comparison of the proposed method for the preparation of 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) with analogs showed that a technical solution to the problem in which the proposed combination of features would take place that would produce the indicated result is not known.

A change in the dosage order does not lead to the achievement of the task, on the contrary, the yield of 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride even decreases. Also, the dosage of 2-diethylaminoethyl chloride hydrochloride does not increase the yield. Such an unexpected result, as it turned out, is associated with the occurrence of adverse reactions of 2-diethylaminoethyl chloride in basic media. The dosage of the toluene solution of 2-diethylaminoethyl chloride allows an exhaustive alkylation reaction to be carried out, the amount of impurities is significantly reduced, and the product is isolated by dosage to the toluene solution of 2,7-bis [2- (diethylamino) ethoxy] fluorenone concentrated hydrochloric acid. The base, 2,7-bis [2- (diethylamino) ethoxy] fluorenone, is dissolved in a stoichiometric amount of concentrated hydrochloric acid and does not precipitate upon prolonged exposure to low temperature and the introduction of the seed. The dihydrochloride 2,7-bis [2- (diethylamino) ethoxy] fluorenone (I) is released during the evaporation of the water-toluene mixture, during which the water is separated in the form of an azeotropic mixture and crystallization of the target product. Using this isolation method for methods with a lower yield leads to the formation of an oily rather than crystalline product that is heavily contaminated with impurities, including unreacted 2,7-dioxifluorenone (according to TLC, HPLC).

Only the proposed combination of distinctive features from the closest technical solution allows not only to increase the yield at the stage of alkylation and the quality of the target product, but, in general, to significantly improve the processability of the process of producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride, this is what gives reason to consider the proposed method as inventive.

Information confirming the possibility of implementing the method is given in the examples below. The alkylated 2,7-dioxifluorenone is obtained from fluorene under the conditions described in RF patent 2218327.

Example 1

To a degassed solution of 34 g of potassium hydroxide (or 24 g of sodium hydroxide) in 200 ml of water, 63.6 g of 2,7-dioxifluorenone (0.3 mol) are added under a stream of nitrogen, kept under stirring for 15 minutes and an aqueous solution of 86.4 is obtained g of a dipotassium salt of 2,7-dioxifluorenone (76.8 g of a disodium salt of 2,7-dioxifluorenone). To the resulting solution, heated to 82-85 ° C for 15 hours, a solution of 163.8 g (1.2 mol) of 2-diethylaminoethyl chloride in 900 ml of toluene is dosed. At the end of the dosage, the reaction mass was kept for another 5 hours. The reaction mixture was separated, the toluene solution was washed with water (100 ml) and 93 g of 35% hydrochloric acid was treated. The mixture was evaporated until the water evolution ceased (in the form of an azeotropic toluene-water mixture), cooled to room temperature and filtered, to obtain 137.8 g (95% of theory) of 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride. Mp = 237-238 ° C.

Found C ₂₅ H ₃₆ Cl ₂ O ₃ : C = 62.15%, H = 7.50%, N = 5.82%, Cl = 14.5%.

Calculated: C = 62.11%, H = 7.51%, N = 5.79%, Cl = 14.67%.

NMR spectrum ¹ H (D ₂ O): 1.00 ppm. (12H, t, CH ₃ ), 2.56 ppm. (8H, q, CH ₂ ), 2.61 and 4.32 ppm. (8H, two m, CH ₂ ), 6.00 ppm. (2H, broad s, ArH-1), 7.15 ppm. (2H, brq, ArH-3), 7.00 ppm. (2H, brq, ArH-4).

NMR spectrum ¹³ C (D ₂ O): 7.3 ppm (CH ₃ ), 49.3 ppm. (CH ₂ ), 57.6 ppm. (CH ₂ ), 71.7 ppm. (CH ₂ ), 106.9 ppm. (CH, Ar-1), 157.4 ppm. (C, Ar-2), 117.7 ppm. (CH, Ar-3), 120.9 ppm. (CH, Ar-4), 191.0 ppm (C = O), 142.4 ppm (C, Ar-10), 134.6 ppm. (C, Ar-11).

Examples 2-4

A change in the molar ratio of the salt of 2,7-dioxifluorenone: diethylaminoethyl chloride indicates a sufficient ratio of 1: 4, a decrease in it does not lead to a yield, an increase does not lead to an improvement in the technical result:

Example The number of diethylaminoethyl chloride, g Molar ratio Exit, % 2 112.8 1: 3 73 3 143.3 1: 3,5 84 four 204.8 1: 5 96

Examples 5-7

The effect on the yield of dihydrochloride 2,7-bis [2- (diethylamino) ethoxy] fluorenone amount of hydrochloric acid is reflected in the examples:

Example Amount of hydrochloric acid, g Molar ratio Exit, % 5 62 1: 2 72 6 108,5 1: 3,5 96 7 124 1: 4 96

The technological design of the proposed method is much simpler than the closest analogue. The isolation operation now does not include distillation of toluene to dryness, does not require the use of hexane and dissolution of the residue in acetone before treatment with concentrated hydrochloric acid. By reducing the total volume of organic solvents, process safety has been improved. Toluene can be reused in the process. Without further purification, it is sent to the stage of preparation of a toluene solution of 2-diethylaminoethyl chloride. This allows not only to increase the efficiency of the method, but also significantly reduce the volume of organic solvents.

The implementation of this method allows to obtain 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride (I) without the use of toxic and expensive reagents while increasing the yield and processability of the process, using standard equipment and available reagents, therefore, the proposed technical solution corresponds industrial applicability criteria.

Claims (3)

1. A method for producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone-9 dihydrochloride, comprising the steps of sulfonation of fluorene, followed by neutralization of the resulting reaction mass, isolation of the purified disodium salt of 2,7-disulfonic acid fluorene, "alkaline melting" of this salts in the presence of sodium nitrate with the formation of 4,4'-dioxiphenylcarboxylic acid, cyclization and alkylation of 2,7-dioxifluorenone, characterized in that the 2,7-dioxifluorenone obtained in the cyclization step is converted to an alkali metal salt and preliminarily a heated aqueous solution of this salt is added a toluene solution of 2-diethylaminoethyl chloride in a molar ratio of 1: 3-1: 5, and the resulting 2,7-bis [2- (diethylamino) ethoxy] fluorenone is treated with concentrated hydrochloric acid in a molar ratio of 1: 3.5 -1: 4. 2. The method according to claim 1, characterized in that a toluene solution of 2-diethylaminoethyl chloride is added to a preheated solution of an alkali metal salt of 2,7-dioxifluorenone in a 1: 4 molar ratio. 3. The method according to claim 1, characterized in that 2,7-bis [2- (diethylamino) ethoxy] fluorenone is treated with concentrated hydrochloric acid in a molar ratio of 1: 3.5.