Method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren -9-one dihydrochloride (thylorone)

FIELD: chemistry.

SUBSTANCE: improved method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride, known as thylorone or amixine, and used as an immunostimulating and antiviral agent, involves treating 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one in methylene chloride with hydrogen chloride in gaseous state of in form of hydrochloric acid, preferably in molar ratio 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one : hydrochloric acid equal to 1:2.05-3.0. A solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride in methylene chloride is obtained, which is cooled to temperature not below minus 12°C to obtain a suspension and then filtered and dried. The filtered residue is dried in inert gas or air at temperature from 90 to 110°C or in a vacuum, as a rule. Completion of salt formation is usually controlled from increase in temperature of the reaction mass and its stabilisation to a value between 32 and 34°C, as well as from the pH value, which must not be higher than 4.0. The filtered residue is dried in an inert gas or air, at temperature from 90 to 110°C or in a vacuum, as a rule.

EFFECT: simplification of the process due to exclusion of inflammable solvents and obtaining a product of high quality with high output.

6 cl, 1 dwg, 3 ex

 

The invention relates to the field of organic chemistry and chemical technology, in particular to the chemical synthesis of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride of the formula I

drug substance Tilaran.

Tilaran (Amiksin) is an inducer of endogenous interferon, which is used as immunostimulating and anti-viral agents.

A method of obtaining salt - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (S.M.Burke, M.Joullie. New Synthetic Pathways to Tilorone Hydrochloride. Synthetic Comm, 1976, v.6(5), 371-376). In this way, the synthesized base - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is at the last stage is dissolved in methanol followed by treatment of the resulting solution with dry hydrogen chloride in diethyl ether, which leads to the formation of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride. Then crystallized the precipitation from a mixture of methanol : isopropanol at a ratio of 1:3 in the mixture. Exit at the stage of 50%. In the literature, however, indicated that this method was tested at industrial scale technology.

The disadvantages of this method are the low yield and low quality of the final product, is incompatible with the requirement for the purity requirements of the pharmaceutical product, the explosive last stage, the absence of promyshlennogo scaling technology.

It is known the use of hydrogen chloride, which is dissolved in ethanol (patent JP 9031036 from 04.02.97), then this solution affect the solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in isopropanol to obtain 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride.

The disadvantage of this method is the hazard process and has not been able industrial scale process.

A method of obtaining salt - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (EN 2218327, SS 225/18, 17.03.1999). In this way, the synthesized based on the last stage is dissolved in acetone and converted into the salt by the action of 35%hydrochloric acid, is added to the acetone solution of the base -2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it. The output at this stage 57%. In the examples of the patent indicates that this method was tested at industrial scale and used for series production of the drug substance "Amiksin" (Tilaran).

The disadvantages of this method are the low yield and explosive last stage.

A method of obtaining salt - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (patent application RU2003121101, SS 225/18, 14.07.2003), including preliminary stage of obtaining the base - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it, which is 2,7-bis[2-(diethylamino)

ethoxy]fluoren-9-it is the dihydrochloride is obtained by exposure to a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it in acetone dried gaseous hydrogen chloride.

In the abstract of the application, however, indicated that this method was tested at industrial scale technology.

In this publication there is no information about the output and the quality of the final product. A significant disadvantage of this method is explosive on the last stage.

Closest to the proposed invention is a method of obtaining salt - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (EN 2076097, SS 225/18, 17.01.1994). In this way, the synthesized basis in the form of an aqueous suspension is treated with 20-25%solution of hydrochloric acid, filtered off, washed until neutral and dried, obtaining the target product - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is the dihydrochloride with the release of 90% at this stage.

In the patent doesn't mention that when using this method can be achieved the same output at industrial scale technology.

The disadvantage of this method is not a high yield of product and the lack of industrial scale technology.

Object of the present invention is to provide a method of obtaining 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride of tilorone).

The technical result that can be obtained by using the present invention, the yield of the final product - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride and, in addition, the high purity of the final product at the industrial scale technology, the elimination of the explosive.

To solve the stated problem, the present invention proposes a method of obtaining 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride, which is 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is dissolved in methylene chloride, the resulting solution is treated with hydrogen chloride in the form of gaseous hydrogen chloride or hydrochloric acid, to complete the salt formation. Then a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride in methylene chloride is cooled to obtain a slurry and filtered, after which the filter cake is dried.

The process of salt formation during the processing of a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in dry methylene chloride hydrogen chloride control for raising the temperature of the reaction mass to a value of plus 32-34°C and its stabilization and completion stages - value of aqueous extract pH of the reaction mass, which must be not more than 4.0.

When using hydrochloric acid in the process colabrative the Oia to a solution of base - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride add the calculated amount of hydrochloric acid, providing a full translation of the base salt, at a molar ratio of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-he : hydrochloric acid 1:2,05-3,0, then after salt formation spend the azeotropic distillation of water.

The cooling solution of salt of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride in methylene chloride is conducted to a temperature not lower than minus 12°C.

When processing a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride used is preferably a dry gaseous hydrogen chloride.

The filter cake is dried at a temperature of 90-110°C in inert gas or air, or vacuum.

During vacuum drying of the product preferably drying is carried out at a residual pressure of not higher than 10 mm Hg with periodic stirring of the product.

The duration of the drying process in inert gas or air 22 to 26 hours in a vacuum 6-9 hours.

Thus, receive 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (pharmacopoeial substance Tilaran) with high quality output 90,4-95,0% in terms of the initial base - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-he.

Separated from 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-methylene chloride dihydrochloride healthy lifestyles who are on regeneration with the aim of re-use of purified methylene chloride in the process.

The possibility of implementation of the present invention is illustrated by the following examples of synthesis of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-dihydrochloride - a medicinal substance Tilaran.

Example 1.

200 l reactor pump 150 l of methylene chloride. Include the stirrer in the reactor and load it with 15 kg base - 2,7-bis[2-(diethylamino)ethoxy] fluoren-9-it. Mix the contents of the reactor for 30 minutes to dissolve the Foundation. In the resulting solution serves gaseous hydrogen chloride. The supply of dry gaseous hydrogen chloride in the reactor for the production of salt continue until the end of the growth temperature of the reaction mass (32-34°C). Then is withdrawn from the reactor test to determine the pH. When this selected sample (100 ml) is treated in the separating funnel with an equal volume of distilled water, separated methylene chloride and measure the pH of the aqueous layer. If the pH is less than the value of 4.0, the flow of gaseous hydrogen chloride ceased. If the pH is greater than about 4.0, then the flow of gaseous hydrogen chloride resume and continue until a pH of aqueous extract solution in the reactor equal to 4.0.

After completion of the process of salt formation is cooled mass in the reactor to a temperature of 20-25°C, at which crystallization starts 2,7-bis[2-(diethyl-the Mino)ethoxy]fluoren-9-it dihydrochloride. Then cool the mass in the reactor to a temperature of minus 10 To 12°C, which completes the crystallization of salt. The precipitate is filtered off on Druk-filter and dried for 24 hours in a shelf dryer in air with periodic stirring of the product. After drying, crushing and sieving get 15.5 kg of finished product (yield 90.4 percent). So pl. 234-235°C. (Kofler bench).

Example 2.

In odnogolosy apparatus load 80 kg 2,7-bis[2-(diethylamino) ethoxy]fluoren-9-it and fill in 800 l of methylene chloride. Stirred until complete dissolution of the Foundation. The supply of dry gaseous hydrogen chloride in the reactor for the synthesis of salts continue until the end of the growth temperature of the reaction mass (32-34°C). In the resulting solution serves hydrogen chloride to aqueous extract pH of 4.0.

Then the reaction mass is then cooled to + 5°C. the Resulting suspension is filtered under vacuum on the suction filter. Obtained 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride dried in a shelf dryer in a nitrogen atmosphere for 24 hours at a temperature of 90-110°C With periodic mixing.

After drying, crushing and sieving get to 88.4 kg of finished product (yield of 93.5%). So pl. 234-235°C. (Kofler bench).

Example 3.

200 l reactor fall asleep 8.2 kg 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-it and fill in with 140 l of methylene chloride. Re eshivot to dissolve the Foundation. To the solution was added with stirring 5.2 l of concentrated hydrochloric acid. After salt formation azeotrope distilled water from a solution of 2,7-bis[2-(diethylamino)ethoxy] fluoren-9-it dihydrochloride in methylene chloride. After the distillation of water, the solution is cooled to a temperature of 10-12°C.

The resulting suspension is filtered under vacuum, the residue is washed with cooled to 5°With methylene chloride. Obtained 2,7-bis[2-(diethylamino)ethoxy] fluoren-9-it dihydrochloride dried in a vacuum drying installation for 6 hours at a residual pressure of 10 mm Hg and a temperature of 90-110°C.

After drying, crushing and sieving get 9,19 kg (yield 95.2 percent). So different. 234,5-235,5°C (Kofler bench).

The chromatography was carried out samples of 2,7-bis[2-(diethylamino)ethoxy] fluoren-9-it dihydrochloride was performed under the following conditions: plate Merck, the system solvent for the chromatography was carried out - benzene : triethanolamine : methanol 100:10:1. Detection under UV light (254 nm).

The drawing shows a thin layer chromatogram (TLC) of the standard and the sample obtained in Example 1 (1-0,05 mcg 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-it dihydrochloride standard intensity for the determination of impurities is 0.1%; 2-50 μg of the sample obtained in Example 1; 3-100 μg of the same sample).

It is seen that in the sample obtained in Example 1, no impurities, comprising more than 0.1%.

The samples in Examples 2 and 3 are identical to the sample of Example 1 according to the analysis of thin-layer chromatography.

Method for obtaining 2,7-bis[2-(diethylamino)ethoxy] fluoren-9-it dihydrochloride, providing a high yield while ensuring its Pharmacopoeia purity using noncombustible cheap methylene chloride, and dry gaseous hydrogen chloride or hydrochloric acid, followed by azeotropic distillation of water.

The presence of products on the market only one industrial domestic producers (CJSC "Biological research system) and one foreign (JSC "interkhim", Ukraine) 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride pharmacopoeial quality indicates the complexity of scaling the technological process of production of this product. In this normative documents of foreign origin (ND 42-100050-) in its pharmaceutical substance "Amiksin" (Tilaran) allowed two impurities.

In the drug substance Celoron, the output of which is on the proposed industrial invention tested by the applicant, impurities are absent.

Thus, the quality of a drug substance Tilaran on the proposed evaluation method taking into account industrial masshtabiv is of higher than the quality of a drug substance Amiksin (Tilaran), industrial manufactured by a foreign manufacturer.

In the proposed method the impact on the solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride with gaseous hydrogen chloride or hydrochloric acid provides a higher yield of the final product - 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride (90,4-95,2%, instead of 90% similar), as well as its high quality at industrial scale, which is proved with the release of pilot scale batches of the drug substance Tilaran (1 spot instead of 3 results TLC), and reduced the explosion due to the use in industrial output of the target product cheap widespread solvent - methylene chloride (instead of diethyl ether, methanol, acetone, isopropanol).

Conducted an information search did not reveal identical and similar technical solutions.

The technical result of the way with exposure to a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride with gaseous hydrogen chloride or hydrochloric acid is not obvious from the prior art. Methylene chloride does not belong to one of the groups of compounds, which include previously used solvents for the implementation saleabration who I am. Therefore, the inventive method involves an inventive step.

The proposed method is currently tested in pilot conditions upon receipt experienced a series of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride in the form of the drug substance Tilaran in number from 9 to 92 kg, which indicates the industrial applicability of the proposed method.

1. The method of obtaining 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride, processing 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-she's in the solvent hydrogen chloride followed by filtration and drying, characterized in that the solvent used methylene chloride, hydrogen chloride is used in gaseous form or in the form of hydrochloric acid to obtain a solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it dihydrochloride in methylene chloride, which is before the filter is cooled to a temperature not lower than minus 12°C to obtain a suspension.

2. The method according to claim 1, characterized in that the processing solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride gaseous hydrogen chloride complete salt formation control for raising the temperature of the reaction mass and its stabilization to the value of 32-34°C, and pH, which must be not more than 4.0.

3. The method according to claim 1, characterized in that about which abode solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride spend hydrochloric acid at a molar ratio of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-he : hydrochloric acid, equal to 1:2,05-3,0 and after salt formation azeotrope distilled water.

4. The method according to claim 1, characterized in that the processing solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-it is in methylene chloride is preferably used dry gaseous hydrogen chloride.

5. The method according to claim 1, characterized in that the filter cake is dried in an inert gas or air in a vacuum at a temperature of 90-110°C.

6. The method according to claim 1, characterized in that the filter cake is dried in vacuum.



 

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that are used as intermediate product in synthesis of azo dyes useful for staining protein fibers and possessing the unique indices of thermal stability. Method involves steps for nitration reaction of substituted benzophenones with potassium nitrate in concentrated H2SO4, nucleophilic replacing halogen (wherein R means Cl) in interaction with O- and N-nucleophilic compounds in dimethylsulfoxide (DMSO) medium in the presence of K2CO3 and reduction of 3,4'-dinitro-4-R-benzophenones. The nitration reaction of synthesized benzophenones is carried out at temperature 20oC for 5 h in the mole ratio 4'-nitro-4-R-benzophenone : KNO3 = 1.0:1.15. Nucleophilic replacing halogen is carried out at temperature 40-60oC for 1-5 h in the mole ratio substrate : nucleophilic compound = 1.0:1.05, and reduction of dinitrobenzophenones is carried out with SnCl2 x 2H2O in 18% HCl medium, in the mole ratio 3,4'-dinitro-4-R-benzophenone : SnCl2 x 2H2O = 1:6, at temperature 20oC for 0.15 h. Invention provides decreasing cost of synthesis, reducing time and temperature in carrying out the process, enhancing purity and yield of end products.

EFFECT: improved method of synthesis.

4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of continuous production of alkylamino(meth)acrylamide of formula (C) by reacting a formula (B) compound with a formula (A) compound in the presence of a re-esterification catalyst in the presence of at least one polymerisation inhibitor in a continuous re-esterification installation. Reacting substances are continuously fed into the corresponding reactor (1) and the alcohol formed from the reaction is continuously removed in form of an azeotropic mixture of methanol and methyl(meth)acrylate (13) (mixture of ethanol and ethylacrylate 13, respectively) using a distillation column (2). The reaction mixture is constantly fed from the reactor into the distillation column (3) or, respectively, into evaporator (5). Highly volatile components (A, B, methanol or, respectively, ethanol) and a very small part of amide end product (C) are tapped from the head of the column and returned to the reactor. Amide end products (C) together with catalyst and polymerisation inhibitor, as well as heavy by-products are tapped from the bottom of the column. Material flow (15) from the bottom of the distillation column (3) is continuously taken for distillation to obtain pure end product.

EFFECT: improved quality of product, high efficiency and output.

15 cl, 1 tbl, 1 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: improved method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride, known as thylorone or amixine, and used as an immunostimulating and antiviral agent, involves treating 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one in methylene chloride with hydrogen chloride in gaseous state of in form of hydrochloric acid, preferably in molar ratio 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one : hydrochloric acid equal to 1:2.05-3.0. A solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride in methylene chloride is obtained, which is cooled to temperature not below minus 12°C to obtain a suspension and then filtered and dried. The filtered residue is dried in inert gas or air at temperature from 90 to 110°C or in a vacuum, as a rule. Completion of salt formation is usually controlled from increase in temperature of the reaction mass and its stabilisation to a value between 32 and 34°C, as well as from the pH value, which must not be higher than 4.0. The filtered residue is dried in an inert gas or air, at temperature from 90 to 110°C or in a vacuum, as a rule.

EFFECT: simplification of the process due to exclusion of inflammable solvents and obtaining a product of high quality with high output.

6 cl, 1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing and aminophenol compound of formula (1) , where each of R1 and R2, which can be identical or different, are a hydrogen atom, C1-C6 alkyl group, which can be substituted with phenyl, or phenyl; R1 and R2 together with the neighbouring nitrogen atom can form a 5- or 6-member heterocyclic group, selected from piperidinyl and piperazinyl; the heterocyclic group can be substituted with one substitute selected from hydroxyl group, C1-C6 alkyl group and phenoxy group, which can have a C1-C6 alkoxy group, substituted with 1-3 halogen atoms. The method involves reacting a cyclohexanedione compound of formula (2) with a amine compound of formula (3) , where R1 and R2 assume values given above, in neutral or basic conditions.

EFFECT: wider range of use of the compound.

8 cl, 4 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4-(dimethylamino)-1-alkyl-1-methyl-2-alkyn-1-ols of general formula (1): where R=C2H5, C4H9, C6H13, which are substances with physiological activity, particularly cholinolytic properties. The method involves reacting 3-alkyl-3-methyl-1-alkyn-3-ols with N,N,N1,N1-tetramethylmethanediamine in the presence of a copper monochloride catalyst in molar ratio 3-alkyl-3-methyl-1-alkyn-3-ol: N,N,N1,N1-tetramethylmethanediamine: CuCl=10:(10-12):(0.4-0.6) in an argon atmosphere at temperature 50-90°C and atmospheric pressure, predominantly at 80°C, for 3-5 hours. Output of 4-(dimethylamino)-1-alkyl-1-methyl-2-alkyn-1-ols (1) is 84-96%.

EFFECT: method increases output of products.

1 cl, 3 dwg, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2-[(dimethylamino)methyl]phenol used in the food industry and medicine, as well as lubrication and engine oil additives, corrosion inhibitors for different types of steel, stabilisers of motor car and rocket fuel, monomers, plastic and different types of rubbers. The method involves reacting phenol with N,N,N,N-tetramethylmethylenediamine. The reaction is carried out in the presence of a copper (I) chloride catalyst in molar ratio phenol: N,N,N,N-tetramethylmethylenediamine: CuCl=10:(10-11):(0.2-0.4) at atmospheric pressure, mainly at temperature of 50°C for 3.5-4.5 hours.

EFFECT: increased selectivity of the process and output of the desired product, reduced reaction temperature.

1 cl, 2 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

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