WO2022211680A1

WO2022211680A1 - Process for producing the anticoagulant n-(5-chloropyridin-2-yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride

Info

Publication number: WO2022211680A1
Application number: PCT/RU2022/050098
Authority: WO
Inventors: Дмитрий Николаевич ТАРАСОВ; Дмитрий Геннадьевич ТОВБИН; Олег Егорович БАЛАШОВ
Original assignee: Общество С Ограниченной Ответственностью "Фармадиол"
Priority date: 2021-03-30
Filing date: 2022-03-25
Publication date: 2022-10-06

Abstract

The present invention relates to the field of organic chemistry, and more particularly to a novel process for producing the compound of formula I (where n=1) that is N-(5-chloropyridin-2-yl)-2-({4-[ethanimidoyl(methyl)amino]-benzoyl}amino)-5-methylbenzamide hydrochloride, which can be used as a factor Xa inhibitor for controlling the clotting ability of blood in humans and other mammals, and also for treating blood clotting-related disorders.

Description

Method for producing anticoagulant 1\1-(5-xporpyridin-2-yl)-2-({4-[ethane imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride

Technical field

The invention relates to the field of organic chemistry, namely to a method for producing 1H-(5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which can be used as an inhibitor of factor Xa to control blood clotting in humans and other mammals, as well as to treat diseases associated with blood clotting.

State of the art

Blood clotting can be controlled with anticoagulants, which are inhibitors of the protein (factor) Xa. Factor Xa belongs to the family of serine proteases. Unlike thrombin, which acts on multiple substrate proteins and specific receptors, factor Xa appears to only act on a single substrate, namely prothrombin. Direct factor Xa inhibitors, such as inhibitors of thrombin formation, can be used to effectively control blood clotting. Therefore, it is clear that substances that inhibit factor Xa can be used as drugs for diseases associated with blood clotting.

Patent EA015918 describes the compound 1H-(5-chloropyridin-2-yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide which is highly active against factor Xa:

Proposed in patent EA 015918 method for obtaining the specified connection includes the following steps:

1) reaction of 5-methyl-2-nitrobenzoic acid with thionyl chloride and 2-amino-5-chloropyridine to give 1M-(5-chloropyridin-2-yl)-5-methyl-2-nitrobenzamide;

2) reduction of 1\1-(5-chloropyridin-2-yl)-5-methyl-2-nitrobenzamide with tin chloride to give 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide; 3) interaction of 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide with 4-methylaminobenzoic acid trifluoroacetate and amide coupling agent EDCI to give 1\1-(5-chloropyridin-2-yl)-2 -[(4-methyl(trifluoroacetyl)aminophenylcarbonyl)amino]-5-methylbenzamide;

4) removal of the trifluoroacetyl protecting group by alkaline hydrolysis to give 1H-(5-chloropyridin-2-yl)-2-[(4-methylaminophenylcarbonyl)amino]-5-methylbenzamide;

5) synthesis of amidine from 1H-(5-chloropyridin-2-yl)-2-[(4-methylaminophenyl- carbrnyl)amino]-5-methylbenzamide by reacting with acetonitrile and passing gaseous HCI, followed by treatment with sodium bicarbonate to obtain 1H- (5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide.

The disadvantages of the method disclosed in the patent EA 015918 include a large number of stages, the need to use tin (II) chloride to restore the nitro group, which leads to a long procedure for separating side tin compounds, the need to use hydrochloric acid to restore the nitro group, inefficient use of protective groups , as well as the need to isolate and purify the products by column chromatography after each step.

Another patent RU2698202C2 proposes a method for obtaining the compound N-(5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which includes the following steps : a) interaction of 5-methylanthranilic acid with thionyl chloride in toluene; reacting the product of the previous reaction with 2-amino-5-chloropyridine in tetrahydrofuran to give 2-amino-1H-(5-chloropyridin-2-yl)-5-methyl-benzamide;

6) reaction of 2-amino-1N-(5-chloropyridin-2-yl)-5-methylbenzamide with 4-[(tert-butoxycarbonyl)-1N-methyl]aminobenzoic acid; c) removing the mpem-butoxycarbonyl protecting group from the reaction product of step (b) to give 1\1-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)benzamido)benzamide; d) reaction of 1\1-(5-chloropyridin-2-yl)-5-methyl-2-(4-(methylamino)- benzamido)benzamide with imidoacetic acid chloride to give N-(5-chloropyridin-2-yl) -2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methyl-benzamide hydrochloride.

The disadvantages of the method disclosed in patent RU2698202C2 include inefficient use of protective groups, a large number of stages and a linear synthesis strategy.

Thus, there is a need to develop a new method for the preparation of the compound 1\1-(5-xporpyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride, which would be devoid of these shortcomings. Disclosure of invention

The objective of the present invention is to develop and create a new method for producing anticoagulant 1H-(5-chloropyridin-2-yl)-2-({4-

[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride.

The technical result of the present invention is to create a new and effective method for producing anticoagulant 1H-(5-xporpyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride (compound of formula I), which makes it possible to obtain a product with a high degree of purity (>99%) and a high yield; the technical result of the present invention also lies in the simplification of the synthesis of the compound of formula I, the reduction of risks in industrial implementation and the scaling of the synthesis.

The specified technical result is achieved through the implementation of a method for obtaining a compound of formula I:

which includes the following steps: a) interaction of 5-methylanthranilic acid and 5-xporpyridine-2-amine to obtain 2-amino-1H-(5-xporpyridin-2-yl)-5-methylbenzamide II:

b) interaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(1H-methylacetimidamido)benzoic acid hydrochloride III:

¹¹¹ c) reaction of 4-(1H-methylacetimidamido)benzoic acid hydrochloride III and acid chloride to give 4-(1H-methylacetimidamido)benzoyl chloride hydrochloride IV:

IV d) interaction of 4-(1H-methylacetimidamido) benzoyl chloride hydrochloride IV and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II to obtain 1H-(5-chloropyridin-2-yl)- 2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride I', where n=2:

(n=2> e) reaction of 1\1-(5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]-benzoyl}amino)-5-methylbenzamide dihydrochloride and a base with preparation of N-(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride I:

V (11=2) I (11=1)

In particular embodiments of the invention in step a), the interaction is the interaction of 5-methylanthranilic acid with thionyl chloride in an aromatic solvent, an organochlorine solvent, a solvent containing an ether moiety or without a solvent; reaction of the product of the previous reaction with 5-chloropyridine-2-amine in dialkyl ether of mono-, di- or polyethylene glycol or in another solvent containing a structural fragment of a simple ether in the presence of a base to obtain 2-amino-1H- (5-xporpyridine-2 -yl)-5-methyl-benzamide.

In some embodiments, the aromatic solvent in step a) is benzene.

In some embodiments, in step a), the organochlorine solvent is methylene chloride, chloroform, carbon tetrachloride, or dichloroethane.

In some embodiments, in step a), the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether.

In some embodiments, in step a), the diethylene glycol dialkyl ether is diethylene glycol dimethyl ether.

In particular embodiments of the invention in step a), the base is independently selected and is pyridine, substituted pyridine, dialkylaniline, or trialkylamine. In some embodiments, the substituted pyridine is independently selected and is an alkyl pyridine or a dialkylamino pyridine.

In particular embodiments of the invention, the interaction in step b) of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride is carried out with the participation of dry gaseous hydrogen chloride and / or its solution in an organic solvent and / or with the participation of reagents capable of generating hydrogen chloride directly in the reaction system. In some embodiments, the organic solvent is acetonitrile. In particular embodiments of the invention in step b), hydrogen chloride can be generated in the reaction system by reacting an acid chloride with an equivalent amount of water or alcohol, and the acid chloride can be an organic or inorganic acid chloride, the alcohol can be primary, secondary and tertiary aliphatic alcohols.

In particular embodiments of the invention in step b), the acid chloride of an organic or inorganic acid is independently selected and is thionyl chloride, sulfuryl chloride, phosphorus oxychloride, boron chloride, oxalyl chloride, acetyl chloride, alkyl carboxylic acid chlorides, benzoyl chloride, benzoic acid chloride or cyanuric chloride.

In particular embodiments of the invention in step b), the alcohol is independently selected and is methanol, ethanol, 2-propanol or mpem-butanol.

In particular embodiments of the invention at stage c) the interaction of 4-(1H-methylacetimidamido)benzoic acid hydrochloride III and acid chloride is carried out in an aromatic solvent, an organochlorine solvent, in a solvent containing a structural fragment of a simple ether or without a solvent in the presence of a catalyst to obtain hydrochloride 4 -(1H-methylacetimidamido) benzoyl chloride.

In particular embodiments of the invention in step c), the acid chloride is independently selected and is thionyl chloride, oxalyl chloride, cyanuric chloride, phosgene, phosphorus trichloride, or phosphorus pentachloride.

In particular embodiments of the invention in step c), the aromatic solvent is independently selected and is benzene or toluene.

In particular embodiments of the invention in step c), the organochlorine solvent is independently selected and is methylene chloride, chloroform, carbon tetrachloride or dichloroethane.

In particular embodiments of the invention in step c), the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di- or polyethylene glycol dialkyl ether.

In particular embodiments of the invention in step c), the catalyst is independently selected and is dimethylformamide or N,N-disubstituted carboxylic acid amide.

In particular embodiments of the invention in step c), the N,N-disubstituted carboxylic acid amide is dimethiacetamide, N-methylformanilide.

In particular embodiments of the invention, the reaction at stage d) of 4-(1H-methylacetimidamido)benzoyl chloride IV hydrochloride and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II is carried out in tetrahydrofuran or in another a solvent containing an ether moiety such as diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether, or an alkyl carboxylate.

In particular embodiments of the invention in step d), the alkyl carboxylate is ethyl acetate.

In particular embodiments of the invention, the interaction in step e) of N-(5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]-benzoyl}amino)-5-methylbenzamide dihydrochloride I with organic and an inorganic base is carried out in a solvent or water.

In particular embodiments of the invention in step e), the organic or inorganic base is independently selected and is ammonia, mono-, di- or trialkylamine, pyridine, alkylpyridine, dialkylaminopyridine, alkali or alkaline earth metal hydroxide.

In particular embodiments of the invention at stage e), the solvent is selected independently and is a primary, secondary or tertiary aliphatic alcohol, an alkyl carboxylate, a solvent containing an ether structural fragment.

In particular embodiments of the invention in step e), the aliphatic alcohol is methanol, ethanol, 2-propanol or mpem-butanol, the alkyl carboxylate is ethyl acetate, the solvent containing the ether moiety is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, dialkyl ether of mono-, di- or polyethylene glycol.

Detailed disclosure of the invention

Definitions (terms)

For a better understanding of the present invention, below are some of the terms used in the present description of the invention. In addition, unless otherwise indicated, all occurrences of functional groups are chosen independently, two occurrences can be either the same or different.

In the description of the present invention, the terms "comprises" and "comprising" are interpreted to mean "includes, among other things." These terms are not intended to be construed as "consisting only of".

The term "alkyl" in this document means both straight and branched. In addition, "alkyl" may be either substituted or unsubstituted. The term "alkyl" as used herein refers to groups typically having one to five carbon atoms. Brief description of the drawings.

Figure 1. ¹ H-NMR spectrum of compound II.

Figure 2. ¹³ C-NMR spectrum of compound II.

Figure 3. ¹ H-NMR spectrum of compound III.

Figure 4. 1H NMR spectra ^of compound IV in D2O at 25°C compared to the starting acid (compound III), presented as 2 rotamers.

Figure 5. ¹ H NMR spectrum of compound G (n=2).

Figure 6. ¹ H NMR spectrum of compound I (n=1).

Figure 7. Spectrum ¹³ With NMR I (n=1).

Implementation of the invention

Below, in order to explain the essential differences of the proposed invention, a general scheme for the synthesis of the invention is presented.

Scheme 1. General synthesis scheme according to the invention.

Within the framework of this synthesis scheme, the following stages can be distinguished.

Step 1. Reaction of 5-methylanthranilic acid with 2-amino-5-chloropyridine to give 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide (compound II).

Stage 2. Interaction of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride to obtain 4-(1H-methylacetimidamido)benzoic acid hydrochloride (III). The reaction proceeds through the formation of an intermediate product of the interaction of hydrogen chloride with acetonitrile, acetimidoyl chloride hydrochloride, which further reacts with 4-(methylamino)benzoic acid.

Stage 3. Interaction of 4-(1H-methylacetimidamido) benzoic acid hydrochloride (III) and acid chloride, in particular, thionyl chloride, in particular, in toluene in the presence of dimethylformamide to obtain 4-(N-methylacetimidamido)benzoyl chloride hydrochloride (IV).

Stage 4. Interaction of 4-(1H-methylacetimidamido)benzoyl chloride hydrochloride (IV) and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide (II) to obtain N-(5-chloropyridin-2 -yl)-2-({4-[ethanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I', n=2).

Step 5. Interaction of 1H-(5-xporpyridin-2-yl)-2-({4-

[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I', n=2) and a base, in particular ammonia, to give 1H-(5-chloropyridin-2-yl)-2-({4 -[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride (I, n=1).

Obtaining 2-amino-M-(5-xporpyridin-2-yl)-5-methylbenzamide, II

In a 250 ml flat-bottomed flask equipped with a magnetic anchor and a reflux condenser, 100 ml of benzene, 20 ml (~280 mmol) of thionyl chloride and 10 g (66 mmol) of 5-methylanthranilic acid were mixed. The mixture was stirred at room temperature for 15–30 min, then gradually heated to boiling and boiled for 2–4 h. The intermediate was used further without further purification.

75 ml of dry diglyme was added to the resulting acid chloride, the mixture was stirred until dissolved, and the system was cooled to +10°C. A solution of 8.5 g (66 mmol) of 5-chloropyridine-2-amine and 5.2 g (66 mmol) of pyridine in 25 ml of diglyme was added dropwise to a cooled stirred solution of acid chloride (a precipitate formed). The cooling was removed and the orange suspension was stirred for 1-2 hours at room temperature. Then a solution of 8.5 g (212.5 mmol) of NaOH in 200 ml of water was added to the reaction mixture and stirred for 1–2 h. The resulting yellow suspension was filtered, the precipitate was washed with water and dried in an oil pump vacuum, which gave 12.8 g of a light yellow product. Yield: 74% based on 5-methylanthranilic acid, ~95% purity ⁽ 1H NMR, ^13C NMR).

Preparation of 4-(M-methylacetimidamido)benzoic acid hydrochloride, III

100 ml of dry acetonitrile was placed in a 250 ml flat-bottomed flask equipped with a magnetic anchor, cooled to +10 °C, and dry hydrogen chloride was bubbled through it until an HCl concentration of ~3 mol/l was reached (determined by the increase in the mass of the flask) (Notes 1 below text). 10.6 g (0.07 mol) of 4-(methylamino)benzoic acid was added to the resulting solution without removing the cooling. The flask was hermetically sealed and the resulting suspension was stirred at room temperature (20–30°C) for 5–10 days. The precipitate was filtered off, washed with 20 ml of acetonitrile and dried in an oil pump vacuum to give 11.2 g of a white crystalline product. Yield - 70%, purity - 98% ( ¹ H NMR).

Note 1. For this reaction, hydrogen chloride can be produced directly in the reaction system by reacting an organic or inorganic acid chloride with an equivalent amount of water or alcohol. For example, if 17.9 g (0.15 mol) of thionyl chloride is added to 100 ml of dry acetonitrile, the mixture is cooled to +10 °C, and 2.7 g (0.15 mol) of distilled water is added, then a solution of HCI in acetonitrile with a concentration of ~3 mol/l will be obtained.

Preparation of 4-(M-methylacetimidamido)benzoyl chloride hydrochloride, IV

III IV

In a 250 ml flat-bottomed flask equipped with a magnetic anchor and a reflux condenser, 13.0 g (57 mmol) of acid III, 10 ml of toluene, 13 ml (~180 mmol) of thionyl chloride were mixed and 150 μl of dimethylformamide were added. The reaction mixture was heated at 50–60°C for 4–6 h with stirring. After cooling, 80 ml of toluene was added to the mixture and stirred until a crystalline precipitate appeared, which was filtered off, washed with 15 ml of toluene, and dried in an oil pump vacuum, which gave 12.4 g white crystalline substance. Yield - 88%.

Preparation of M-(5-chloropyridin-2-yl)-5-methyl-2-(4-(M-methylacetimidamido)-benzamido)benzamide dihydrochloride, I' (n=2)

In a 500 ml flat-bottom flask equipped with a magnetic anchor, 150 ml of dry tetrahydrofuran and 13.1 g (50 mmol) of compound II were mixed and stirred at room temperature until the precipitate dissolved. Then 12.4 g (50 mmol) of acid chloride IV were added in portions. The resulting suspension was stirred at room temperature for 10-30 hours. The precipitate was filtered off, washed with 70 ml of tetrahydrofuran and dried in an oil pump vacuum to give 24.5 g of light yellow product I' (n=2). Yield: 96%, purity - 96% ( ¹ H NMR).

Preparation of M-(5-chloropyridin-2-yl)-5-methyl-2-(4-(M-methylacetimidamido)-benzamido)benzamide hydrochloride, I (n=1)

In a beaker equipped with a magnetic anchor, 15 g (29.5 mmol) of product I (n=2) and 150 ml of distilled water were mixed. 3.2 g (30 mmol) of an ammonia solution (16%) in 30 ml of water was added to the resulting mixture, which led to the isolation of a thick precipitate. The reaction mixture was heated with stirring until dissolved and allowed to crystallize, the precipitate was filtered off, washed with 10 ml of water and dried in an oil pump vacuum to give 10.7 g of a white product. Yield - 77%, purity >99% ⁽ 1H NMR, ^13C NMR).

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that various modifications are possible without departing from the essence of the present invention.

Claims

Claim

1. Method for obtaining the compound of formula I:

which includes the following steps: a) the interaction of 5-methylanthranilic acid and 5-chloropyridine-2-amine to obtain 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II:

III c) reaction of 4-(1H-methylacetimidamido)benzoic acid hydrochloride III and acid chloride to obtain 4-(1H-methylacetimidamido)benzoyl chloride hydrochloride IV:

III d) reaction of 4-(M-methylacetimidamido)benzoyl chloride hydrochloride IV and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II to give 1H-(5-chloropyridin-2-yl )-2-({4-[ethane-imidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide dihydrochloride

I', where n=2:

D ί ^h =ϊί e) reaction of 1H-(5-chloropyridin-2-yl)-2-({4-[ethane-imidoyl(methyl)amino]-benzoyl}amino)-5-methylbenzamide dihydrochporide and a base to give N -(5-chloropyridin-2-yl)-2-({4-[etanimidoyl(methyl)amino]benzoyl}amino)-5-methylbenzamide hydrochloride I:

2. The method according to claim 1, in which in step a) the interaction is the interaction of 5-methylanthranilic acid with thionyl chloride in aromatic a solvent, an organochlorine solvent, in a solvent containing an ether moiety or without a solvent; reaction of the product of the previous reaction with 5-chloropyridine-2-amine in dialkyl ether of mono-, di- or polyethylene glycol or in another solvent containing a structural fragment of a simple ether in the presence of a base to obtain 2-amino-M-(5-chloropyridine-2 -yl)-5-methyl-benzamide.

3. The method of claim 2 wherein the aromatic solvent is benzene.

4. The method of claim 2 wherein the organochlorine solvent is methylene chloride, chloroform, carbon tetrachloride or dichloroethane.

5. The method of claim 2 wherein the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di- or polyethylene glycol dialkyl ether.

6. The method of claim 2 wherein the diethylene glycol dialkyl ether is diethylene glycol dimethyl ether.

7. The method of claim 2 wherein the base is independently selected and is pyridine, substituted pyridine, dialkylaniline, or trialkylamine.

8. The method of claim 7 wherein the substituted pyridine is independently selected and is an alkyl pyridine or a dialkylamino pyridine.

9. The method according to claim 1, where the interaction in step b) of 4-(methylamino)benzoic acid, acetonitrile and hydrogen chloride is carried out with the participation of dry gaseous hydrogen chloride and / or its solution in an organic solvent and / or with the participation of reagents capable of generating hydrogen chloride directly in reaction system.

10. The method of claim 9 wherein the organic solvent is acetonitrile.

eleven . The method according to claim 9, in which hydrogen chloride can be generated in the reaction system by reacting the acid chloride of the acid with an equivalent amount of water or alcohol, and the acid chloride of the acid can be organic or inorganic acid chloride, the alcohol can be primary, secondary and tertiary aliphatic alcohols .

12. The method of claim 11 wherein the organic or inorganic acid chloride is independently selected and is thionyl chloride, sulfuryl chloride, phosphorus oxychloride, boron chloride, oxalyl chloride, acetyl chloride, alkyl carboxylic acid chlorides, benzoyl chloride, benzoic acid chloride, or cyanuric chloride. .

13. The method of claim 11 wherein the alcohol is independently selected and is methanol, ethanol, 2-propanol or mpem-butanol.

14. The method according to claim 1, in which in step c) the reaction of 4-(N-methylacetimidamido)benzoic acid hydrochloride III and the acid chloride is carried out in an aromatic solvent, an organochlorine solvent, in a solvent containing an ether structural fragment or without a solvent in the presence of catalyst to produce 4-(1H-methylacetimidamido)benzoyl chloride hydrochloride.

15. The method according to claim 1, wherein in step c) the acid chloride is independently selected and is thionyl chloride, oxalyl chloride, cyanuric chloride, phosgene, phosphorus trichloride or phosphorus pentachloride.

16. The method of claim 14 wherein the aromatic solvent is independently selected and is benzene or toluene.

17. The method of claim 14 wherein the organochlorine solvent is independently selected and is methylene chloride, chloroform, carbon tetrachloride or dichloroethane.

18. The method of claim 14 wherein the solvent containing the ether moiety is independently selected and is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di- or polyethylene glycol dialkyl ether.

19. The method of claim 14, wherein the catalyst is independently selected and is dimethylformamide or N,N-disubstituted carboxylic acid amide.

20. The method of claim 19 wherein the N,N-disubstituted carboxylic acid amide is dimethiacetamide, N-methylformanilide.

21. The method according to claim 1, in which the reaction in step d) of 4-(N-methylacetimidamido)benzoyl chloride hydrochloride IV and 2-amino-1H-(5-chloropyridin-2-yl)-5-methylbenzamide II is carried out in tetrahydrofuran or in another solvent containing an ether moiety such as diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, mono-, di-, or polyethylene glycol dialkyl ether, or an alkyl carboxylate.

22. The method of claim 21 wherein the alkyl carboxylate is ethyl acetate.

23. The method according to p. 1, in which the interaction in stage e) 1H- (5-chloropyridin-2-yl) - 2- ({4- [ethane-imidoyl (methyl) amino] -benzoyl} amino) -5- methylbenzamide dihydrochloride I with an organic and inorganic base is carried out in a solvent or water.

24. The method of claim 23 wherein the organic or inorganic base is independently selected and is ammonia, mono-, di- or trialkylamine, pyridine, alkyl pyridine, dialkylamino pyridine, alkali or alkaline earth metal hydroxide.

25. The method of claim 23 wherein the solvent is independently selected and is a primary, secondary or tertiary aliphatic alcohol, an alkyl carboxylate, a solvent containing an ether moiety.

26. The method according to claim 25, wherein the aliphatic alcohol is methanol, ethanol, 2-propanol or mpem-butanol, the alkyl carboxylate is ethyl acetate, the solvent containing the ether moiety is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dialkyl ether of mono-, di- or polyethylene glycol.