RU2076097C1 - Method for production of 2,7-bis[2-(diethylamino0ethoxy]fluorenone dihydrochloride - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: fluorenone is used as reagent 1, iodine being used as reagent 2. Their interaction is carried out in the medium of acetic acid in the presence of mixture of sulfuric acid (having density 1.83-1.84) with nitric acid (having density 1.4-1.52). Molar ratio of fluorenone, iodine, sulfuric acid and nitric acid is 1:1-1.1:2-5:0.6-1.2 respectively. The process takes place at 20-70 C, thus prepared product is then alkylated at 70-100 C. Said alkylation takes place in the presence of 18-crawn-6-ether in the medium of dimethylformamide or dioxane, it is followed by conversion of the base into corresponding dihydrochloride. Yield of desired product is 50.6-56.1 %. EFFECT: improves efficiency of the method. 2 cl, 1 tbl

Description

The invention relates to the field of organic chemistry, in particular to a new route for the synthesis of 2,7-bis [2-Diethylamino / ethoxy] fluorenone dihydrochloride I, which is an inducer of endogenous interferon with antiviral effect [1]
There is a known [2] method for producing 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride [1], which consists in sulfonation of fluorene (II) with a 10th oleum to a mixture containing 86 27-disulfonic acids of fluorene (III) and 7 ^o C 12 2-sulfonic acids of fluorene (IV), isolated in the form of sodium salts, followed by purification of the sulfonic mixture from monosubstituted by recrystallization from water. The purified 2,7-disulfonic acid of fluorene (III) in the form of disodium salt is subjected to alkaline melting in the presence of a mixture of sodium hydroxide and sodium nitrate, taken in the ratio sulfosol III: sodium hydroxide: sodium nitrate equal to 1: 2.5: 1 at 260,270 ^o C as a result of which, along with the replacement of sulfo groups by hydroxy groups, the fluorene ring also splits to form 4,4'-dihydroxy-2-carboxybiphenyl (V). Compound V is fused with zinc chloride at 200 ^° C. to give 2,7-dihydroxyfluorenone (VI), which is then alkylated with 2-diethylaminoethyl chloride hydrochloric acid obtained in yield 50 by treatment of 2-diethylaminoethanol in a mixture of thionyl chloride and toluene. The output at the stage of alkylation 48 The total yield of the target product I is 18.5 counting on fluorene (II). The synthesis scheme is given below.

Недостатками этого способа являются очень низкий выход целевого продукта, большое количество трудноутилизируемых стоков, многостадийный синтез, использование дорогостоящего и дефицитного хлористого цинка.

The disadvantages of this method are the very low yield of the target product, a large number of difficult to dispose of effluents, multi-stage synthesis, the use of expensive and scarce zinc chloride.

К недостаткам этого способа относятся очень низкий выход соединения I, многостадийность синтеза, трудоемкость его получения, большое количество трудноутилизируемых стоков из-за применения хлористого алюминия и практическая невозможность технологической реализации данного способа в промышленном масштабе из-за дорогостоящего и дефицитного хлористого алюминия, а главное из-за отсутствия промышленного оборудования для проведения реакции алкилирования, как в данном способе, выбранного нами в качестве прототипа.There is also known [3] a method for producing 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride I, which consists in the fact that fluorene (II) is acetylated with acetyl chloride in the presence of aluminum chloride according to the Friedel Crafts reaction with the formation of 62 2 , 7-diacetylfluorene (VII), which is then subjected to the Bayer-Wiliger oxidative rearrangement by perchlorobenzoic acid in chloroform medium in the presence of catalytic amounts of trifluoroacetic acid when heated. The 2,7-diacetoxyfluorene (VIII) thus formed with a yield of 62 is oxidized by boiling it in a solution of glacial acetic acid with sodium dichromate, whereby, with a yield of 53, 2,7-diacetoxyfluorenone (IX) is obtained. Compound IX is alkylated under the conditions of an interphase catalysis reaction with 2-diethylaminoethyl chloride in the presence of potassium hydroxide in a toluene-water mixture for 24 hours. After the completion of the reaction using a benzyltrimethylammonium bromide interphase transfer catalyst, the reaction mixture is cooled, the toluene layer is separated, washed twice with water, then with saturated chloride solution sodium and then dried with anhydrous magnesium sulfate. The drying agent is filtered off, the toluene solution is evaporated to dryness. The oily residue is dissolved in methanol and saturated with gaseous hydrogen chloride in dry sulfuric ether. Obtained after recrystallization from a mixture of isopropyl alcohol, methanol equal to 3: 1 with a yield of 50 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride I. The total yield of compound I, counting on fluorene, (II) according to the scheme below is 10

The disadvantages of this method include the very low yield of compound I, the multi-stage synthesis, the complexity of its production, a large number of difficult-to-utilize effluents due to the use of aluminum chloride and the practical impossibility of technological implementation of this method on an industrial scale due to the expensive and scarce aluminum chloride, and most importantly from due to the lack of industrial equipment for the alkylation reaction, as in this method, we have chosen as a prototype.

These disadvantages are eliminated by the proposed method for producing 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride I, which consists in using fluorenone (X) as the starting compound to obtain the desired product, which is dissolved in glacial acetic acid, then treated with iodine when heated in the presence of a mixture of sulfuric (d 1.83 1.84) acid and nitric (d 1.4 1.52) acid, taken in the ratio fluorenone (X): iodine: sulfuric acid: nitric acid equal to 1: 1 , 0 ^o C 1.1: 2 ^o C 5: 0.6 ^o C 1.2 at 20 70 ^o C. Receive with the release of 71.3 78 2,7-diiodofluorenone (XI ) which is further alkylated with 2 ^° C. 2.1 mol of the potassium salt of 2-diethylaminoethanol in the presence of 18-crown-6 ether, taken in the ratio of compound XI: 2-diethylaminoethylate potassium: 18-crown-6 ether, equal to 1: 2.1: 2.0. The reaction is carried out in dimethylformamide or dioxane at 70,100 ^° C. The yield in the alkylation step until the base is converted, 2,7-bis [2- (diethylamino) ethoxy] fluorenone (XII) is 80 ^° C in dihydrochloride ^. 82 Synthesis scheme of the target product I is shown below.

Дигидрохлорид 1 получают в отличи от ранее описанных способов его получения, обработкой основания XII 20 ^oC 25-ным раствором соляной кислоты с выходом 90 Суммарный выход 2,7-бис[2-(Диэтиламино)этокси]флуоренона дигидрохлорида составляет 50,6 56,2 считая на флуоренон (Х) и около 48 считая на флуорен (II).

Dihydrochloride 1 is obtained, in contrast to the previously described methods for its preparation, by treating the base with XII 20 ^° C. with 25% hydrochloric acid solution in 90 yield. The total yield of 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride is 50.6 56, 2 counting on fluorenone (X) and about 48 counting on fluorenone (II).

 The use of lower ratios of reagents, both at the iodination stage and at the alkylation stage, leads to a significant decrease in the yield of reaction products, and an increase in the ratio of components does not significantly affect the yield of products at all stages of the process of obtaining the target product, but only leads to an increase in the cost of this production method .

 As for the parameters of the processes of iodination and alkylation, they are also selected optimal, based on the objectives of the present invention, i.e. changing them in one direction or another does not lead to the achievement of the goal.

Distinctive features of the invention are:
1. Use as starting compound fluorenone (X);
2. A fundamentally new scheme for the synthesis of 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride, based on other than previously described reactions for its preparation;
3. Finding process parameters to achieve the objectives of the invention not only by reducing the number of stages of the process, but also at each stage;
4. Obtaining dihydrochloride I from the base by carrying out a salt formation reaction by applying a solution of hydrochloric acid to the base with 20 ^° C. 25 instead of the reaction used for this purpose, which is carried out in dry ether by passing gaseous hydrogen chloride through a solution of the product in sulfuric ether.

 Example 1. 2,7-Diiodofluorenone (XI).

To a solution of 18.0 g (0.1 g mol) of fluorenone (X) in 200 ml of glacial acetic acid was added 25.4 g (0.1 g mol) of iodine in 200 ml of acetic acid, stirred for 30 minutes and the mixture was added consisting of 2 ml (0.05 g mol) nitric (d 1.52) and 10.6 ml (0.2 g mol) sulfuric (d 1.83) acids. The reaction mixture was stirred at 20-25 ^° C. for one hour and poured onto ice. The precipitate formed is filtered off, washed with water and recrystallized from glacial acetic acid. 32.4 g of (75) 2,7-diiodofluorenone (XI) are obtained with a melting point of 200 200.5 ^o C. Lit. [4] mp 199,200 ^o C.

 Examples 2 to 11.

Examples 2 to 4, HNO ₃ concentration _of 1.52; Example 5 1, 5; Example 6 1.48; Example 7 1.44; examples 8 to 11 concentration of 1.4; Example 11 is executed as in reference 4; Example 12 1.48. In all examples, the sulfuric acid concentration is 1.84.

 Example 13. 2,7-bis- [2- (Diethylamino) ethoxy] fluorenone dihydrochloride I.

To a solution of 4.32 g (0.01 g / mol) of 2,7-diiodofulorenone (XI) in 30 ml of DMF, 2.1 g (0.2 g mol) of 2-diethylaminoethanol in 50 ml of dimethylformamide (DMF) are added, 1.2 g of potassium hydroxide (0.02 g-mol) and 5.26 g (0.02 g-mol) of 18-crown-6 ether. The reaction mixture is heated to 70 ^o C and maintained at this temperature for 3 hours, then cooled to room temperature and poured onto ice. The precipitate formed is filtered off, washed until neutral and transferred to dihydrochloride I by suspension in 30 ml of water, followed by the addition of 50 ml of 20% hydrochloric acid. The dark red precipitate is filtered off, washed with a small amount of cold water and dried. 3.65 g of (71.3) 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride (I) are obtained in the form of an orange powder with a pinkish tint, mp. 234 235 ^o C. Lit. [2] mp 234 - 235 ^o C.

Example 14. The same conditions as in example 13, only a 20-th excess of 2-diethanolamine was taken. Exit 72
Example 15. To a solution of 4.32 g (0.01 g mol) of 2,7-diiodofluorenone (XI) in 40 ml of dry dimethylformamide was added 3.2 g (0.021 g mol) of potassium 2-diethylaminoethylate, 5.26 g (0.02 g-mol) of 18-crown-6 ether in 50 ml of dry dimethylformamide. The reaction mixture is heated to 70 ^o C, maintained at this temperature for 3 hours and poured onto ice. The precipitate formed is filtered off, washed with cold water and dried. The product is suspended in 30 ml of water and 50 ml of 20% hydrochloric acid are added. The precipitate is filtered off, washed with cold water and dried. 3.68 g (71.8) of compound I are obtained, identical by mp. and the IR spectrum of the compound described in example 13.

Example 16. To a solution of 43.2 g (0.1 g mol) of 2,7-diiodofluorenone (XI) in 350 ml of dry dimethylformamide was added 32 g (0.21 g mol) of potassium 2-diethylaminoethylate, 5.26 g (0.20 g-mol) 18-crown-6 ether in 400 ml of dry dimethylformamide. The reaction mixture is heated to 100 ^o C, kept at this temperature for 2 hours, cooled to room temperature and poured onto ice. The precipitate formed is filtered off, washed with water and the base paste is suspended in 300 ml of water, to which 350 ml of 25% hydrochloric acid are added. The precipitate was stirred, then filtered off, washed with water to pH 7 and dried. Obtain 37 g of (72) 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride I, identical to the samples from previous experiments.

Example 17. To a solution of 43.2 g (0.1 g mol) of 2,7-diiodofluorenone (XI) in 300 ml of dry dioxane was added 32 g (0.21 g mol) of potassium 2-diethylaminoethylate, 5.26 g (0.2 g-mol) of 18-crown-6 ether in 300 ml of dry dioxane. The reaction mixture is heated to 70 ^o C, maintained at this temperature for 2 hours, cooled and poured onto ice. The precipitate formed is filtered off, washed with water and suspended in 300 ml of water. To a suspension of the base, 350 ml of 20% hydrochloric acid are added. The precipitate is filtered off, washed until neutral and dried. 37.2 g (72) of compound I are obtained, identical by mp. and the IR spectrum of compound I obtained in example 13.

 Thus, the proposed method for producing 2,7-bis [2- (Diethylamino) ethoxy] fluorenone dihydrochloride I allows more than 2 times to increase the yield of the target product, reduce the number of stages, the total time of the process of its production and reduce the amount of difficult to utilize effluents.

Claims (2)

1. The method of producing 2,7-bis [2- (diethylamino) ethoxy] fluorenone dihydrochloride using an alkylation reaction of a fluorenone derivative, characterized in that the fluorenone is iodinated with iodine in an acetic acid medium in the presence of a mixture of sulfuric acid (d 1.83 1.84 ) and nitric acid (d 1.4 1.52) at a molar ratio of fluorenone iodine sulfuric acid nitric acid equal to 1 1 1.1 2 5 0.6 1.2 at a temperature of 20 70 ^o With the subsequent alkylation of the obtained 2.7 -diiodofluorenone potassium 2-diethylaminoethylate in the presence of 18-crown-6-ether in a medium of dimethylformamide or diox ana at a ratio of 2,7-diiodofluorenone potassium 2-diethylaminoethylate 18-crown-6-ether, equal to 1 2.1 2.0 at a temperature of 70 100 ^o With the subsequent translation of the base 2,7-bis [2- (diethylamino) ethoxy ] fluorenone to the corresponding dihydrochloride.  2. The method according to p. 1, characterized in that for the conversion to dihydrochloride using a 20 25% aqueous hydrochloric acid solution.

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